Skip to main content
Latest news
Browse specialties
Breast cancer Genitourinary cancers Lung & thoracic cancers
In focus
Next-generation sequencing: Emerging biomarkers in thyroid and NSCLCs ctDNA and bladder cancer: Current understanding and beyond ROS1 fusion-positive NSCLC NSCLC driver mutations: Discussing the importance of RET, ALK and ROS1 alterations in NSCLC Early-stage NSCLC management: Surgery, targeted treatment and immunotherapy ALK fusion-positive NSCLC: International approaches to management RET fusion-positive NSCLC: Informing on the use of pralsetinib for patients with RET fusion-positive, advanced NSCLC COVID-19 & cancer
Conferences
SABCS 2022 ESMO 2022 2022 ASCO Annual Meeting
About us
Medicine Matters Oncology
EXTENDED SEARCH
Top

04-06-2018 | Renal cell carcinoma | Article

Epigenetics in renal cell cancer: mechanisms and clinical applications

Journal: Nature Reviews Urology

Authors: Sophie C. Joosten, Kim M. Smits, Maureen J. Aarts, Veerle Melotte, Alexander Koch, Vivianne C. Tjan-Heijnen, Manon van Engeland

Publisher: Nature Publishing Group UK

Login to get access

Abstract

Renal cell carcinoma (RCC) is characterized by an infrequent number of somatic mutations. By contrast, epigenetic aberrations are commonly found in RCC, indicating that epigenetic reprogramming is an important event in RCC development. Epigenetic alterations comprise several different aberrations, such as changes in histone modifications, DNA methylation, and microRNA levels, and occur in the most important signalling pathways in RCC, such as the von Hippel–Lindau disease tumour suppressor (VHL)–hypoxia-inducible factor (HIF) pathway, the WNT–β-catenin pathway, and pathways involved in epithelial–mesenchymal transition. Owing to their involvement in these pathways and frequent occurrence in RCC, epigenetic alterations are regarded as potential biomarkers for the early detection of disease and for prediction of prognosis and treatment response. In addition, most of these alterations are potentially reversible, so they also provide new targets for therapy. At the moment, epigenetic biomarkers for RCC are not being used in clinical practice, but targeted epigenetic therapies are under investigation. Understanding the extent of epigenetic changes occurring in RCC and the mechanisms by which they influence disease progression and treatment response, as well as knowledge of current research on biomarkers and treatments, is crucial to successful clinical translation of epigenetics in RCC.
Literature
1.
Ferlay, J. et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int. J. Cancer 136, E359–E386 (2015).PubMedCrossRef
2.
Moch, H. An overview of renal cell cancer: pathology and genetics. Semin. Cancer Biol. 23, 3–9 (2013).PubMedCrossRef
3.
Maher, E. R. Genomics and epigenomics of renal cell carcinoma. Semin. Cancer Biol. 23, 10–17 (2013).PubMedCrossRef
4.
Baldewijns, M. M. et al. Genetics and epigenetics of renal cell cancer. Biochim. Biophys. Acta 1785, 133–155 (2008).PubMed
5.
Banks, R. E. et al. Genetic and epigenetic analysis of von Hippel-Lindau (VHL) gene alterations and relationship with clinical variables in sporadic renal cancer. Cancer Res. 66, 2000–2011 (2006).PubMedCrossRef
6.
Gnarra, J. R. et al. Mutations of the VHL tumour suppressor gene in renal carcinoma. Nat. Genet. 7, 85–90 (1994).PubMedCrossRef
7.
Schmidt, L. S. & Linehan, W. M. Genetic predisposition to kidney cancer. Semin. Oncol. 43, 566–574 (2016).PubMedPubMedCentralCrossRef
8.
Schmidt, L. S. & Linehan, W. M. Hereditary leiomyomatosis and renal cell carcinoma. Int. J. Nephrol. Renovasc Dis. 7, 253–260 (2014).PubMedPubMedCentralCrossRef
9.
Schmidt, L. S. & Linehan, W. M. Molecular genetics and clinical features of Birt-Hogg-Dube syndrome. Nat. Rev. Urol. 12, 558–569 (2015).PubMedPubMedCentralCrossRef
10.
Dalgliesh, G. L. et al. Systematic sequencing of renal carcinoma reveals inactivation of histone modifying genes. Nature 463, 360–363 (2010).PubMedPubMedCentralCrossRef
11.
Sato, Y. et al. Integrated molecular analysis of clear-cell renal cell carcinoma. Nat. Genet. 45, 860–867 (2013).PubMedCrossRef
12.
Guo, G. et al. Frequent mutations of genes encoding ubiquitin-mediated proteolysis pathway components in clear cell renal cell carcinoma. Nat. Genet. 44, 17–19 (2012).CrossRef
13.
Hakimi, A. A. et al. Adverse outcomes in clear cell renal cell carcinoma with mutations of 3p21 epigenetic regulators BAP1 and SETD2: a report by MSKCC and the KIRC TCGA research network. Clin. Cancer Res. 19, 3259–3267 (2013).PubMedPubMedCentralCrossRef
14.
Hakimi, A. A. et al. Clinical and pathologic impact of select chromatin-modulating tumor suppressors in clear cell renal cell carcinoma. Eur. Urol. 63, 848–854 (2013).PubMedCrossRef
15.
van Haaften, G. et al. Somatic mutations of the histone H3K27 demethylase gene UTX in human cancer. Nat. Genet. 41, 521–523 (2009).PubMedPubMedCentralCrossRef
16.
Pena-Llopis, S. et al. BAP1 loss defines a new class of renal cell carcinoma. Nat. Genet. 44, 751–759 (2012).PubMedPubMedCentralCrossRef
17.
Varela, I. et al. Exome sequencing identifies frequent mutation of the SWI/SNF complex gene PBRM1 in renal carcinoma. Nature 469, 539–542 (2011).PubMedPubMedCentralCrossRef
18.
Morris, M. R. & Maher, E. R. Epigenetics of renal cell carcinoma: the path towards new diagnostics and therapeutics. Genome Med. 2, 59 (2010).PubMedPubMedCentralCrossRef
19.
Cancer Genome Atlas Research Network. Comprehensive molecular characterization of clear cell renal cell carcinoma. Nature 499, 43–49 (2013).CrossRef
20.
Tessarz, P. & Kouzarides, T. Histone core modifications regulating nucleosome structure and dynamics. Nat. Rev. Mol. Cell Biol. 15, 703–708 (2014).PubMedCrossRef
21.
Kouzarides, T. Chromatin modifications and their function. Cell 128, 693–705 (2007).PubMedCrossRef
22.
Dawson, M. A. & Kouzarides, T. Cancer epigenetics: from mechanism to therapy. Cell 150, 12–27 (2012).PubMedCrossRef
23.
Herman, J. G. & Baylin, S. B. Gene silencing in cancer in association with promoter hypermethylation. N. Engl. J. Med. 349, 2042–2054 (2003).PubMedCrossRef
24.
Esteller, M. Molecular origins of cancer: epigenetics in cancer. N. Engl. J. Med. 358, 1148–1159 (2008).PubMedCrossRef
25.
Jones, P. A., Issa, J. P. & Baylin, S. Targeting the cancer epigenome for therapy. Nat. Rev. Genet. 17, 630–641 (2016).PubMedCrossRef
26.
Seles, M. et al. Current insights into long non-coding RNAs in renal cell carcinoma. Int. J. Mol. Sci. 17, 573 (2016).PubMedPubMedCentralCrossRef
27.
Du, Z. et al. Integrative analyses reveal a long noncoding RNA-mediated sponge regulatory network in prostate cancer. Nat. Commun. 7, 10982 (2016).PubMedPubMedCentralCrossRef
28.
Morris, M. R. et al. Identification of candidate tumour suppressor genes frequently methylated in renal cell carcinoma. Oncogene 29, 2104–2117 (2010).PubMedPubMedCentralCrossRef
29.
Ricketts, C. J., Hill, V. K. & Linehan, W. M. Tumor-specific hypermethylation of epigenetic biomarkers, including SFRP1, predicts for poorer survival in patients from the TCGA kidney renal clear cell carcinoma (KIRC) project. PLoS ONE 9, e85621 (2014).PubMedPubMedCentralCrossRef
30.
van Vlodrop, I. J. H. et al. A four-gene promoter methylation marker panel consisting of GREM1, NEURL, LAD1, and NEFH predicts survival of clear cell renal cell cancer patients. Clin. Cancer Res. 23, 2006–2018 (2017).PubMedCrossRef
31.
Esteller, M. et al. p14ARF silencing by promoter hypermethylation mediates abnormal intracellular localization of MDM2. Cancer Res. 61, 2816–2821 (2001).PubMed
32.
Dulaimi, E. et al. Promoter hypermethylation profile of kidney cancer. Clin. Cancer Res. 10, 3972–3979 (2004).PubMedCrossRef
33.
Hoque, M. O. et al. Quantitative detection of promoter hypermethylation of multiple genes in the tumor, urine, and serum DNA of patients with renal cancer. Cancer Res. 64, 5511–5517 (2004).PubMedCrossRef
34.
Okuda, H. et al. Epigenetic inactivation of the candidate tumor suppressor gene HOXB13 in human renal cell carcinoma. Oncogene 25, 1733–1742 (2006).PubMedCrossRef
35.
Hori, Y. et al. Oxidative stress and DNA hypermethylation status in renal cell carcinoma arising in patients on dialysis. J. Pathol. 212, 218–226 (2007).PubMedCrossRef
36.
Costa, V. L. et al. Quantitative promoter methylation analysis of multiple cancer-related genes in renal cell tumors. BMC Cancer 7, 133 (2007).PubMedPubMedCentralCrossRef
37.
Hauser, S., Zahalka, T., Fechner, G., Muller, S. C. & Ellinger, J. Serum DNA hypermethylation in patients with kidney cancer: results of a prospective study. Anticancer Res. 33, 4651–4656 (2013).PubMed
38.
Battagli, C. et al. Promoter hypermethylation of tumor suppressor genes in urine from kidney cancer patients. Cancer Res. 63, 8695–8699 (2003).PubMed
39.
Tanaka, T., Iwasa, Y., Kondo, S., Hiai, H. & Toyokuni, S. High incidence of allelic loss on chromosome 5 and inactivation of p15INK4B and p16INK4A tumor suppressor genes in oxystress-induced renal cell carcinoma of rats. Oncogene 18, 3793–3797 (1999).PubMedCrossRef
40.
Sanz-Casla, M. T. et al. Loss of heterozygosity and methylation of p16 in renal cell carcinoma. Urol. Res. 31, 159–162 (2003).PubMedCrossRef
41.
Arai, E. et al. Regional DNA hypermethylation and DNA methyltransferase (DNMT) 1 protein overexpression in both renal tumors and corresponding nontumorous renal tissues. Int. J. Cancer 119, 288–296 (2006).PubMedCrossRef
42.
Vidaurreta, M. et al. Inactivation of p16 by CpG hypermethylation in renal cell carcinoma. Urol. Oncol. 26, 239–245 (2008).PubMedCrossRef
43.
Arai, E. et al. Genetic clustering of clear cell renal cell carcinoma based on array-comparative genomic hybridization: its association with DNA methylation alteration and patient outcome. Clin. Cancer Res. 14, 5531–5539 (2008).PubMedCrossRef
44.
Onay, H., Pehlivan, S., Koyuncuoglu, M., Kirkali, Z. & Ozkinay, F. Multigene methylation analysis of conventional renal cell carcinoma. Urol. Int. 83, 107–112 (2009).PubMedCrossRef
45.
de Martino, M., Klatte, T., Haitel, A. & Marberger, M. Serum cell-free DNA in renal cell carcinoma: a diagnostic and prognostic marker. Cancer 118, 82–90 (2012).PubMedCrossRef
46.
Girgis, A. H. et al. Multilevel whole-genome analysis reveals candidate biomarkers in clear cell renal cell carcinoma. Cancer Res. 72, 5273–5284 (2012).PubMedCrossRef
47.
Dreijerink, K. et al. The candidate tumor suppressor gene, RASSF1A, from human chromosome 3p21.3 is involved in kidney tumorigenesis. Proc. Natl Acad. Sci. USA 98, 7504–7509 (2001).PubMedPubMedCentralCrossRef
48.
Morrissey, C. et al. Epigenetic inactivation of the RASSF1A 3p21.3 tumor suppressor gene in both clear cell and papillary renal cell carcinoma. Cancer Res. 61, 7277–7281 (2001).PubMed
49.
Yoon, J. H., Dammann, R. & Pfeifer, G. P. Hypermethylation of the CpG island of the RASSF1A gene in ovarian and renal cell carcinomas. Int. J. Cancer 94, 212–217 (2001).PubMedCrossRef
50.
Yano, T. et al. Hypermethylation of the CpG island of connexin 32, a candiate tumor suppressor gene in renal cell carcinomas from hemodialysis patients. Cancer Lett. 208, 137–142 (2004).PubMedCrossRef
51.
Tokinaga, K. et al. Hypermethylation of the RASSF1A tumor suppressor gene in Japanese clear cell renal cell carcinoma. Oncol. Rep. 12, 805–810 (2004).PubMed
52.
Gonzalgo, M. L. et al. Molecular profiling and classification of sporadic renal cell carcinoma by quantitative methylation analysis. Clin. Cancer Res. 10, 7276–7283 (2004).PubMedCrossRef
53.
Kawai, Y. et al. Methylation level of the RASSF1A promoter is an independent prognostic factor for clear-cell renal cell carcinoma. Ann. Oncol. 21, 1612–1617 (2010).PubMedCrossRef
54.
Ellinger, J. et al. DNA hypermethylation in papillary renal cell carcinoma. BJU Int. 107, 664–669 (2011).PubMedCrossRef
55.
Klacz, J. et al. Decreased expression of RASSF1A tumor suppressor gene is associated with worse prognosis in clear cell renal cell carcinoma. Int. J. Oncol. 48, 55–66 (2016).PubMedCrossRef
56.
Skrypkina, I. et al. Concentration and methylation of cell-free DNA from blood plasma as diagnostic markers of renal cancer. Dis. Markers 2016, 3693096 (2016).PubMedPubMedCentralCrossRef
57.
Minciu, R., Tudor, A., Pupca, G., Daminescu, L. & Dumache, R. Renal cancer diagnosed by noninvasive methods from body fluids by quantitative methylation-specific PCR(qMSP). Clin. Lab 62, 1563–1568 (2016).PubMed
58.
Morris, M. R. et al. Multigene methylation analysis of Wilms’ tumour and adult renal cell carcinoma. Oncogene 22, 6794–6801 (2003).PubMedCrossRef
59.
Wethkamp, N. et al. Expression of death-associated protein kinase during tumour progression of human renal cell carcinomas: hypermethylation-independent mechanisms of inactivation. Eur. J. Cancer 42, 264–274 (2006).PubMedCrossRef
60.
Christoph, F. et al. Promoter hypermethylation profile of kidney cancer with new proapoptotic p53 target genes and clinical implications. Clin. Cancer Res. 12, 5040–5046 (2006).PubMedCrossRef
61.
Christoph, F. et al. mRNA expression profiles of methylated APAF-1 and DAPK-1 tumor suppressor genes uncover clear cell renal cell carcinomas with aggressive phenotype. J. Urol. 178, 2655–2659 (2007).PubMedCrossRef
62.
Christoph, F. et al. Comparative promoter methylation analysis of p53 target genes in urogenital cancers. Urol. Int. 80, 398–404 (2008).PubMedCrossRef
63.
Ahmad, S. T., Arjumand, W., Seth, A., Saini, A. K. & Sultana, S. Methylation of the APAF-1 and DAPK-1 promoter region correlates with progression of renal cell carcinoma in North Indian population. Tumour Biol. 33, 395–402 (2012).PubMedCrossRef
64.
Esteller, M. et al. Inactivation of glutathione S-transferase P1 gene by promoter hypermethylation in human neoplasia. Cancer Res. 58, 4515–4518 (1998).PubMed
65.
Schouten, L. J., Deckers, I. A., van den Brandt, P. A., Baldewijns, M. M. & van Engeland, M. Alcohol and dietary folate intake and promoter CpG island methylation in clear-cell renal cell cancer. Nutr. Cancer 68, 1097–1107 (2016).PubMedCrossRef
66.
Deckers, I. A. et al. Promoter methylation of CDO1 identifies clear-cell renal cell cancer patients with poor survival outcome. Clin. Cancer Res. 21, 3492–3500 (2015).PubMedPubMedCentralCrossRef
67.
Banumathy, G. & Cairns, P. Signaling pathways in renal cell carcinoma. Cancer Biol. Ther. 10, 658–664 (2010).PubMedPubMedCentralCrossRef
68.
Shenoy, N. & Pagliaro, L. Sequential pathogenesis of metastatic VHL mutant clear cell renal cell carcinoma: putting it together with a translational perspective. Ann. Oncol. 27, 1685–1695 (2016).PubMedCrossRef
69.
Joosten, S. C. et al. Resistance to sunitinib in renal cell carcinoma: from molecular mechanisms to predictive markers and future perspectives. Biochim. Biophys. Acta 1855, 1–16 (2015).PubMed
70.
Gossage, L., Eisen, T. & Maher, E. R. VHL, the story of a tumour suppressor gene. Nat. Rev. Cancer 15, 55–64 (2015).PubMedCrossRef
71.
Hu, C. J., Wang, L. Y., Chodosh, L. A., Keith, B. & Simon, M. C. Differential roles of hypoxia-inducible factor 1alpha (HIF-1alpha) and HIF-2alpha in hypoxic gene regulation. Mol. Cell. Biol. 23, 9361–9374 (2003).PubMedPubMedCentralCrossRef
72.
Raval, R. R. et al. Contrasting properties of hypoxia-inducible factor 1 (HIF-1) and HIF-2 in von Hippel-Lindau-associated renal cell carcinoma. Mol. Cell. Biol. 25, 5675–5686 (2005).PubMedPubMedCentralCrossRef
73.
Yu, G. et al. Pseudogene PTENP1 functions as a competing endogenous RNA to suppress clear cell renal cell carcinoma progression. Mol. Cancer Ther. 13, 3086–3097 (2014).PubMedPubMedCentralCrossRef
74.
Dey, N. et al. microRNA-21 governs TORC1 activation in renal cancer cell proliferation and invasion. PLoS ONE 7, e37366 (2012).PubMedPubMedCentralCrossRef
75.
Szabo, Z. et al. Expression of miRNA-21 and miRNA-221 in clear cell renal cell carcinoma (ccRCC) and their possible role in the development of ccRCC. Urol Oncol 34, 533.e521–533.e527 (2016).CrossRef
76.
Ma, Q. et al. miR-19a correlates with poor prognosis of clear cell renal cell carcinoma patients via promoting cell proliferation and suppressing PTEN/SMAD4 expression. Int. J. Oncol. 49, 2589–2599 (2016).PubMedCrossRef
77.
Fan, W., Huang, J., Xiao, H. & Liang, Z. MicroRNA-22 is downregulated in clear cell renal cell carcinoma, and inhibits cell growth, migration and invasion by targeting PTEN. Mol. Med. Rep. 13, 4800–4806 (2016).PubMedCrossRef
78.
Lian, J. H., Wang, W. H., Wang, J. Q., Zhang, Y. H. & Li, Y. MicroRNA-122 promotes proliferation, invasion and migration of renal cell carcinoma cells through the PI3K/Akt signaling pathway. Asian Pac. J. Cancer Prev. 14, 5017–5021 (2013).PubMedCrossRef
79.
Zaman, M. S. et al. Inhibition of PTEN gene expression by oncogenic miR-23b-3p in renal cancer. PLoS ONE 7, e50203 (2012).PubMedPubMedCentralCrossRef
80.
Watson, C. J. et al. Hypoxia-induced epigenetic modifications are associated with cardiac tissue fibrosis and the development of a myofibroblast-like phenotype. Hum. Mol. Genet. 23, 2176–2188 (2014).PubMedCrossRef
81.
Mathew, L. K. et al. Restricted expression of miR-30c-2-3p and miR-30a-3p in clear cell renal cell carcinomas enhances HIF2alpha activity. Cancer Discov. 4, 53–60 (2014).PubMedCrossRef
82.
Huang, J. et al. Hypoxia-induced downregulation of miR-30c promotes epithelial-mesenchymal transition in human renal cell carcinoma. Cancer Sci. 104, 1609–1617 (2013).PubMedCrossRef
83.
Yoshino, H. et al. microRNA-210-3p depletion by CRISPR/Cas9 promoted tumorigenesis through revival of TWIST1 in renal cell carcinoma. Oncotarget 8, 20881–20894 (2017).PubMedPubMedCentralCrossRef
84.
McCormick, R. I. et al. miR-210 is a target of hypoxia-inducible factors 1 and 2 in renal cancer, regulates ISCU and correlates with good prognosis. Br. J. Cancer 108, 1133–1142 (2013).PubMedPubMedCentralCrossRef
85.
Neal, C. S., Michael, M. Z., Rawlings, L. H., Van der Hoek, M. B. & Gleadle, J. M. The VHL-dependent regulation of microRNAs in renal cancer. BMC Med. 8, 64 (2010).PubMedPubMedCentralCrossRef
86.
Nakada, C. et al. Overexpression of miR-210, a downstream target of HIF1alpha, causes centrosome amplification in renal carcinoma cells. J. Pathol. 224, 280–288 (2011).PubMedCrossRef
87.
Redova, M. et al. MiR-210 expression in tumor tissue and in vitro effects of its silencing in renal cell carcinoma. Tumour Biol. 34, 481–491 (2013).PubMedCrossRef
88.
Huang, X. & Zuo, J. Emerging roles of miR-210 and other non-coding RNAs in the hypoxic response. Acta Biochim. Biophys. Sin. 46, 220–232 (2014).PubMedCrossRef
89.
van Vlodrop, I. J. et al. Prognostic significance of Gremlin1 (GREM1) promoter CpG island hypermethylation in clear cell renal cell carcinoma. Am. J. Pathol. 176, 575–584 (2010).PubMedPubMedCentralCrossRef
90.
Mitola, S. et al. Gremlin is a novel agonist of the major proangiogenic receptor VEGFR2. Blood 116, 3677–3680 (2010).PubMedCrossRef
91.
Baldewijns, M. M. et al. High-grade clear cell renal cell carcinoma has a higher angiogenic activity than low-grade renal cell carcinoma based on histomorphological quantification and qRT-PCR mRNA expression profile. Br. J. Cancer 96, 1888–1895 (2007).PubMedPubMedCentralCrossRef
92.
Jain, R. K. Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy. Science 307, 58–62 (2005).PubMedCrossRef
93.
Qi, J. H. et al. A novel function for tissue inhibitor of metalloproteinases-3 (TIMP3): inhibition of angiogenesis by blockage of VEGF binding to VEGF receptor-2. Nat. Med. 9, 407–415 (2003).PubMedCrossRef
94.
Bachman, K. E. et al. Methylation-associated silencing of the tissue inhibitor of metalloproteinase-3 gene suggest a suppressor role in kidney, brain, and other human cancers. Cancer Res. 59, 798–802 (1999).PubMed
95.
Masson, D. et al. Loss of expression of TIMP3 in clear cell renal cell carcinoma. Eur. J. Cancer 46, 1430–1437 (2010).PubMedCrossRef
96.
Shay, G., Lynch, C. C. & Fingleton, B. Moving targets: emerging roles for MMPs in cancer progression and metastasis. Matrix Biol. https://​doi.​org/​10.​1016/​j.​matbio.​2015.​01.​019 (2015).
97.
Cai, Y., Li, H. & Zhang, Y. Downregulation of microRNA-206 suppresses clear cell renal carcinoma proliferation and invasion by targeting vascular endothelial growth factor A. Oncol. Rep. 35, 1778–1786 (2016).PubMedCrossRef
98.
Muller, S. & Nowak, K. Exploring the miRNA-mRNA regulatory network in clear cell renal cell carcinomas by next-generation sequencing expression profiles. Biomed. Res. Int. 2014, 948408 (2014).PubMedPubMedCentralCrossRef
99.
Yuan, H. X. et al. Elevated microRNA-185 is associated with high vascular endothelial growth factor receptor 2 expression levels and high microvessel density in clear cell renal cell carcinoma. Tumour Biol. 35, 12757–12763 (2014).PubMedCrossRef
100.
Jung, M. et al. MicroRNA profiling of clear cell renal cell cancer identifies a robust signature to define renal malignancy. J. Cell. Mol. Med. 13, 3918–3928 (2009).PubMedPubMedCentralCrossRef
101.
Shinmei, S. et al. MicroRNA-155 is a predictive marker for survival in patients with clear cell renal cell carcinoma. Int. J. Urol. 20, 468–477 (2013).PubMedCrossRef
102.
White, N. M. et al. miRNA profiling for clear cell renal cell carcinoma: biomarker discovery and identification of potential controls and consequences of miRNA dysregulation. J. Urol. 186, 1077–1083 (2011).PubMedCrossRef
103.
Slaby, O. et al. Expression of miRNA-106b in conventional renal cell carcinoma is a potential marker for prediction of early metastasis after nephrectomy. J. Exp. Clin. Cancer Res. 29, 90 (2010).PubMedPubMedCentralCrossRef
104.
Gao, Y. et al. miR-155 regulates the proliferation and invasion of clear cell renal cell carcinoma cells by targeting E2F2. Oncotarget 7, 20324–20337 (2016).PubMedPubMedCentral
105.
Wojcicka, A. et al. Epigenetic regulation of thyroid hormone receptor beta in renal cancer. PLoS ONE 9, e97624 (2014).PubMedPubMedCentralCrossRef
106.
Li, S. et al. microRNA-155 silencing inhibits proliferation and migration and induces apoptosis by upregulating BACH1 in renal cancer cells. Mol. Med. Rep. 5, 949–954 (2012).PubMedPubMedCentralCrossRef
107.
Kong, W. et al. Upregulation of miRNA-155 promotes tumour angiogenesis by targeting VHL and is associated with poor prognosis and triple-negative breast cancer. Oncogene 33, 679–689 (2014).PubMedCrossRef
108.
Pecot, C. V. et al. Tumour angiogenesis regulation by the miR-200 family. Nat. Commun. 4, 2427 (2013).PubMedPubMedCentralCrossRef
109.
Komiya, Y. & Habas, R. Wnt signal transduction pathways. Organogenesis 4, 68–75 (2008).PubMedPubMedCentralCrossRef
110.
Saini, S., Majid, S. & Dahiya, R. The complex roles of Wnt antagonists in RCC. Nat. Rev. Urol. 8, 690–699 (2011).PubMedCrossRef
111.
Urakami, S. et al. Wnt antagonist family genes as biomarkers for diagnosis, staging, and prognosis of renal cell carcinoma using tumor and serum DNA. Clin. Cancer Res. 12, 6989–6997 (2006).PubMedCrossRef
112.
Gumz, M. L. et al. Secreted frizzled-related protein 1 loss contributes to tumor phenotype of clear cell renal cell carcinoma. Clin. Cancer Res. 13, 4740–4749 (2007).PubMedCrossRef
113.
Dahl, E. et al. Frequent loss of SFRP1 expression in multiple human solid tumours: association with aberrant promoter methylation in renal cell carcinoma. Oncogene 26, 5680–5691 (2007).PubMedCrossRef
114.
Awakura, Y., Nakamura, E., Ito, N., Kamoto, T. & Ogawa, O. Methylation-associated silencing of SFRP1 in renal cell carcinoma. Oncol. Rep. 20, 1257–1263 (2008).PubMed
115.
Hirata, H. et al. Wnt antagonist DKK1 acts as a tumor suppressor gene that induces apoptosis and inhibits proliferation in human renal cell carcinoma. Int. J. Cancer 128, 1793–1803 (2011).PubMedCrossRef
116.
Hu, G. et al. miR-203a regulates proliferation, migration, and apoptosis by targeting glycogen synthase kinase-3beta in human renal cell carcinoma. Tumour Biol. 35, 11443–11453 (2014).PubMedCrossRef
117.
Kim, M. S. et al. Neurofilament heavy polypeptide regulates the Akt-beta-catenin pathway in human esophageal squamous cell carcinoma. PLoS ONE 5, e9003 (2010).PubMedPubMedCentralCrossRef
118.
Valenta, T., Hausmann, G. & Basler, K. The many faces and functions of beta-catenin. EMBO J. 31, 2714–2736 (2012).PubMedPubMedCentralCrossRef
119.
Evans, A. J. et al. VHL promotes E2 box-dependent E-cadherin transcription by HIF-mediated regulation of SIP1 and snail. Mol. Cell. Biol. 27, 157–169 (2007).PubMedCrossRef
120.
Mehlen, P., Delloye-Bourgeois, C. & Chedotal, A. Novel roles for slits and netrins: axon guidance cues as anticancer targets? Nat. Rev. Cancer 11, 188–197 (2011).PubMedCrossRef
121.
Dallol, A. et al. Tumour specific promoter region methylation of the human homologue of the Drosophila Roundabout gene DUTT1 (ROBO1) in human cancers. Oncogene 21, 3020–3028 (2002).PubMedCrossRef
122.
Astuti, D. et al. SLIT2 promoter methylation analysis in neuroblastoma, Wilms’ tumour and renal cell carcinoma. Br. J. Cancer 90, 515–521 (2004).PubMedPubMedCentralCrossRef
123.
Ma, W. J. et al. Reduced expression of Slit2 in renal cell carcinoma. Med. Oncol. 31, 768 (2014).PubMedCrossRef
124.
Machackova, T. et al. MiR-429 is linked to metastasis and poor prognosis in renal cell carcinoma by affecting epithelial-mesenchymal transition. Tumour Biol. 37, 14653–14658 (2016).PubMedCrossRef
125.
Wu, D. et al. Tumor-suppressing effects of microRNA-429 in human renal cell carcinoma via the downregulation of Sp1. Oncol. Lett. 12, 2906–2911 (2016).PubMedPubMedCentralCrossRef
126.
Mlcochova, H. et al. Epithelial-mesenchymal transition-associated microRNA/mRNA signature is linked to metastasis and prognosis in clear-cell renal cell carcinoma. Sci. Rep. 6, 31852 (2016).PubMedPubMedCentralCrossRef
127.
Chen, D. et al. Tumor suppressive microRNA429 regulates cellular function by targeting VEGF in clear cell renal cell carcinoma. Mol. Med. Rep. 13, 1361–1366 (2016).PubMedCrossRef
128.
He, H. et al. MicroRNA expression profiling in clear cell renal cell carcinoma: identification and functional validation of key miRNAs. PLoS ONE 10, e0125672 (2015).PubMedPubMedCentralCrossRef
129.
Cheng, T. et al. Differential microRNA expression in renal cell carcinoma. Oncol. Lett. 6, 769–776 (2013).PubMedPubMedCentralCrossRef
130.
Qiu, M. et al. MicroRNA-429 suppresses cell proliferation, epithelial-mesenchymal transition, and metastasis by direct targeting of BMI1 and E2F3 in renal cell carcinoma. Urol Oncol. https://​doi.​org/​10.​1016/​j.​urolonc.​2015.​03.​016 (2015).
131.
Wang, X. et al. MicroRNA-200a-3p suppresses tumor proliferation and induces apoptosis by targeting SPAG9 in renal cell carcinoma. Biochem. Biophys. Res. Commun. 470, 620–626 (2016).PubMedCrossRef
132.
Lu, R. et al. Tumor suppressive microRNA-200a inhibits renal cell carcinoma development by directly targeting TGFB2. Tumour Biol. 36, 6691–6700 (2015).PubMedCrossRef
133.
Silva-Santos, R. M. et al. MicroRNA profile: a promising ancillary tool for accurate renal cell tumour diagnosis. Br. J. Cancer 109, 2646–2653 (2013).PubMedPubMedCentralCrossRef
134.
Jiang, J. et al. Demethylation drug 5-Aza-2ʹ-deoxycytidine-induced upregulation of miR-200c inhibits the migration, invasion and epithelial-mesenchymal transition of clear cell renal cell carcinoma in vitro. Oncol. Lett. 11, 3167–3172 (2016).PubMedPubMedCentralCrossRef
135.
Wang, X. et al. miR-200c Targets CDK2 and suppresses tumorigenesis in renal cell carcinoma. Mol. Cancer Res. 13, 1567–1577 (2015).PubMedCrossRef
136.
Butz, H. et al. miRNA-target network reveals miR-124as a key miRNA contributing to clear cell renal cell carcinoma aggressive behaviour by targeting CAV1 and FLOT1. Oncotarget 6, 12543–12557 (2015).PubMedPubMedCentralCrossRef
137.
Chang, I. et al. Loss of miR-200c up-regulates CYP1B1 and confers docetaxel resistance in renal cell carcinoma. Oncotarget 6, 7774–7787 (2015).PubMedPubMedCentral
138.
Wang, X. et al. microRNA-200c modulates the epithelial-to-mesenchymal transition in human renal cell carcinoma metastasis. Oncol. Rep. 30, 643–650 (2013).PubMedCrossRef
139.
Liu, H. et al. Identifying mRNA targets of microRNA dysregulated in cancer: with application to clear cell renal cell carcinoma. BMC Syst. Biol. 4, 51 (2010).PubMedPubMedCentralCrossRef
140.
Nakada, C. et al. Genome-wide microRNA expression profiling in renal cell carcinoma: significant down-regulation of miR-141 and miR-200c. J. Pathol. 216, 418–427 (2008).PubMedCrossRef
141.
Yoshino, H. et al. Epithelial-mesenchymal transition-related microRNA-200s regulate molecular targets and pathways in renal cell carcinoma. J. Hum. Genet. 58, 508–516 (2013).PubMedCrossRef
142.
Liep, J. et al. Cooperative effect of miR-141-3p and miR-145-5p in the regulation of targets in clear cell renal cell carcinoma. PLoS ONE 11, e0157801 (2016).PubMedPubMedCentralCrossRef
143.
Chen, X. et al. miR-141 is a key regulator of renal cell carcinoma proliferation and metastasis by controlling EphA2 expression. Clin. Cancer Res. 20, 2617–2630 (2014).PubMedCrossRef
144.
Yu, X. Y., Zhang, Z., Liu, J., Zhan, B. & Kong, C. Z. MicroRNA-141 is downregulated in human renal cell carcinoma and regulates cell survival by targeting CDC25B. Onco Targets Ther. 6, 349–354 (2013).PubMedPubMedCentral
145.
Chen, Z. et al. miRNA-205 is a candidate tumor suppressor that targets ZEB2 in renal cell carcinoma. Oncol. Res. Treat. 37, 658–664 (2014).PubMedCrossRef
146.
Majid, S. et al. MicroRNA-205 inhibits Src-mediated oncogenic pathways in renal cancer. Cancer Res. 71, 2611–2621 (2011).PubMedPubMedCentralCrossRef
147.
Gregory, P. A. et al. The miR-200 family and miR-205 regulate epithelial to mesenchymal transition by targeting ZEB1 and SIP1. Nat. Cell Biol. 10, 593–601 (2008).PubMedCrossRef
148.
Wang, R. N. et al. Bone morphogenetic protein (BMP) signaling in development and human diseases. Genes Dis. 1, 87–105 (2014).PubMedPubMedCentralCrossRef
149.
Samavarchi-Tehrani, P. et al. Functional genomics reveals a BMP-driven mesenchymal-to-epithelial transition in the initiation of somatic cell reprogramming. Cell Stem Cell 7, 64–77 (2010).PubMedCrossRef
150.
Mitsui, Y. et al. Inactivation of bone morphogenetic protein 2 may predict clinical outcome and poor overall survival for renal cell carcinoma through epigenetic pathways. Oncotarget 6, 9577–9591 (2015).PubMedPubMedCentralCrossRef
151.
Ricketts, C. J. et al. Genome-wide CpG island methylation analysis implicates novel genes in the pathogenesis of renal cell carcinoma. Epigenetics 7, 278–290 (2012).PubMedPubMedCentralCrossRef
152.
Massague, J. TGFbeta signalling in context. Nat. Rev. Mol. Cell Biol. 13, 616–630 (2012).PubMedPubMedCentralCrossRef
153.
Xu, J., Lamouille, S. & Derynck, R. TGF-beta-induced epithelial to mesenchymal transition. Cell Res. 19, 156–172 (2009).PubMedPubMedCentralCrossRef
154.
Morris, M. R. et al. Genome-wide methylation analysis identifies epigenetically inactivated candidate tumour suppressor genes in renal cell carcinoma. Oncogene 30, 1390–1401 (2011).PubMedCrossRef
155.
ten Dijke, P. & Arthur, H. M. Extracellular control of TGFbeta signalling in vascular development and disease. Nat. Rev. Mol. Cell Biol. 8, 857–869 (2007).PubMedCrossRef
156.
Michos, O. et al. Gremlin-mediated BMP antagonism induces the epithelial-mesenchymal feedback signaling controlling metanephric kidney and limb organogenesis. Development 131, 3401–3410 (2004).PubMedCrossRef
157.
Lin, Y. L., Wang, Y. L., Fu, X. L. & Ma, J. G. Aberrant methylation of PCDH8 is a potential prognostic biomarker for patients with clear cell renal cell carcinoma. Med. Sci. Monit. 20, 2380–2385 (2014).PubMedPubMedCentralCrossRef
158.
Liu, M., Zhou, J., Chen, Z. & Cheng, A. S. Understanding the epigenetic regulation of tumours and their microenvironments: opportunities and problems for epigenetic therapy. J. Pathol. 241, 10–24 (2017).PubMedCrossRef
159.
Dunn, J. & Rao, S. Epigenetics and immunotherapy: the current state of play. Mol. Immunol. 87, 227–239 (2017).PubMedCrossRef
160.
Blondeau, J. J. et al. Identification of novel long non-coding RNAs in clear cell renal cell carcinoma. Clin. Epigenetics 7, 10 (2015).PubMedPubMedCentralCrossRef
161.
Qin, C. et al. Expression pattern of long non-coding RNAs in renal cell carcinoma revealed by microarray. PLoS ONE 9, e99372 (2014).PubMedPubMedCentralCrossRef
162.
Yu, G. et al. LncRNAs expression signatures of renal clear cell carcinoma revealed by microarray. PLoS ONE 7, e42377 (2012).PubMedPubMedCentralCrossRef
163.
Brito, G. C. et al. Identification of protein-coding and intronic noncoding RNAs down-regulated in clear cell renal carcinoma. Mol. Carcinog. 47, 757–767 (2008).PubMedCrossRef
164.
Wu, Y. et al. Suppressed expression of long non-coding RNA HOTAIR inhibits proliferation and tumourigenicity of renal carcinoma cells. Tumour Biol. 35, 11887–11894 (2014).PubMedCrossRef
165.
Mehdi, A. & Riazalhosseini, Y. Epigenome aberrations: emerging driving factors of the clear cell renal cell carcinoma. Int. J. Mol. Sci. 18, 1774 (2017).PubMedCentralCrossRef
166.
Xia, M. et al. Long noncoding RNA HOTAIR promotes metastasis of renal cell carcinoma by up-regulating histone H3K27 demethylase JMJD3. Oncotarget 8, 19795–19802 (2017).PubMedPubMedCentral
167.
Liu, L. et al. Enhancer of zeste homolog 2 (EZH2) promotes tumour cell migration and invasion via epigenetic repression of E-cadherin in renal cell carcinoma. BJU Int. 117, 351–362 (2016).PubMedCrossRef
168.
Zhang, H. M., Yang, F. Q., Chen, S. J., Che, J. & Zheng, J. H. Upregulation of long non-coding RNA MALAT1 correlates with tumor progression and poor prognosis in clear cell renal cell carcinoma. Tumour Biol. 36, 2947–2955 (2015).PubMedCrossRef
169.
He, H. & Magi-Galluzzi, C. Epithelial-to-mesenchymal transition in renal neoplasms. Adv. Anat. Pathol. 21, 174–180 (2014).PubMedCrossRef
170.
Xiao, H. et al. LncRNA MALAT1 functions as a competing endogenous RNA to regulate ZEB2 expression by sponging miR-200s in clear cell kidney carcinoma. Oncotarget 6, 38005–38015 (2015).PubMedPubMedCentral
171.
Wang, L. et al. Down-regulated long non-coding RNA H19 inhibits carcinogenesis of renal cell carcinoma. Neoplasma 62, 412–418 (2015).PubMedCrossRef
172.
Raveh, E., Matouk, I. J., Gilon, M. & Hochberg, A. The H19 Long non-coding RNA in cancer initiation, progression and metastasis - a proposed unifying theory. Mol. Cancer 14, 184 (2015).PubMedPubMedCentralCrossRef
173.
Zhang, H. M., Yang, F. Q., Yan, Y., Che, J. P. & Zheng, J. H. High expression of long non-coding RNA SPRY4-IT1 predicts poor prognosis of clear cell renal cell carcinoma. Int. J. Clin. Exp. Pathol. 7, 5801–5809 (2014).PubMedPubMedCentral
174.
Wang, M. et al. Long non-coding RNA MEG3 induces renal cell carcinoma cells apoptosis by activating the mitochondrial pathway. J. Huazhong Univ. Sci. Technolog Med. Sci. 35, 541–545 (2015).PubMedCrossRef
175.
Qiao, H. P., Gao, W. S., Huo, J. X. & Yang, Z. S. Long non-coding RNA GAS5 functions as a tumor suppressor in renal cell carcinoma. Asian Pac. J. Cancer Prev. 14, 1077–1082 (2013).PubMedCrossRef
176.
Thompson, M. Polybromo-1: the chromatin targeting subunit of the PBAF complex. Biochimie 91, 309–319 (2009).PubMedCrossRef
177.
Reisman, D., Glaros, S. & Thompson, E. A. The SWI/SNF complex and cancer. Oncogene 28, 1653–1668 (2009).PubMedCrossRef
178.
Morris, M. R. & Latif, F. The epigenetic landscape of renal cancer. Nat. Rev. Nephrol. 13, 47–60 (2017).PubMedCrossRef
179.
Chowdhury, B. et al. PBRM1 regulates the expression of genes involved in metabolism and cell adhesion in renal clear cell carcinoma. PLoS ONE 11, e0153718 (2016).PubMedPubMedCentralCrossRef
180.
Nargund, A. M. et al. The SWI/SNF protein PBRM1 restrains VHL-loss-driven clear cell renal cell carcinoma. Cell Rep. 18, 2893–2906 (2017).PubMedPubMedCentralCrossRef
181.
Gao, W., Li, W., Xiao, T., Liu, X. S. & Kaelin, W. G. Jr. Inactivation of the PBRM1 tumor suppressor gene amplifies the HIF-response in VHL−/− clear cell renal carcinoma. Proc. Natl Acad. Sci. USA 114, 1027–1032 (2017).PubMedPubMedCentralCrossRef
182.
Su, X. et al. NSD1 inactivation and SETD2 mutation drive a convergence toward loss of function of H3K36 writers in clear cell renal cell carcinomas. Cancer Res. 77, 4835–4845 (2017).PubMedCrossRef
183.
Bertolotto, C. et al. A SUMOylation-defective MITF germline mutation predisposes to melanoma and renal carcinoma. Nature 480, 94–98 (2011).PubMedCrossRef
184.
Linehan, W. M. et al. Comprehensive molecular characterization of papillary renal-cell carcinoma. N. Engl. J. Med. 374, 135–145 (2016).PubMedCrossRef
185.
Calderaro, J. et al. Balanced translocations disrupting SMARCB1 are hallmark recurrent genetic alterations in renal medullary carcinomas. Eur. Urol. 69, 1055–1061 (2016).PubMedCrossRef
186.
Kohashi, K. & Oda, Y. Oncogenic roles of SMARCB1/INI1 and its deficient tumors. Cancer Sci. 108, 547–552 (2017).PubMedPubMedCentralCrossRef
187.
Knutson, S. K. et al. Durable tumor regression in genetically altered malignant rhabdoid tumors by inhibition of methyltransferase EZH2. Proc. Natl Acad. Sci. USA 110, 7922–7927 (2013).PubMedPubMedCentralCrossRef
188.
Rydzanicz, M., Wrzesinski, T., Bluyssen, H. A. & Wesoly, J. Genomics and epigenomics of clear cell renal cell carcinoma: recent developments and potential applications. Cancer Lett. 341, 111–126 (2013).PubMedCrossRef
189.
Ambani, S. N. & Wolf, J. S. Jr. Renal mass biopsy for the small renal mass. Urol. Oncol. 36, 4–7 (2018).PubMedCrossRef
190.
Rini, B. I. & Atkins, M. B. Resistance to targeted therapy in renal-cell carcinoma. Lancet Onc 10, 992–1000 (2009).CrossRef
191.
Heng, D. Y. et al. Primary anti-vascular endothelial growth factor (VEGF)-refractory metastatic renal cell carcinoma: clinical characteristics, risk factors, and subsequent therapy. Ann. Oncol. 23, 1549–1555 (2012).PubMedCrossRef
192.
193.
Lerner, S. E. et al. Disease outcome in patients with low stage renal cell carcinoma treated with nephron sparing or radical surgery. J. Urol. 155, 1868–1873 (1996).PubMedCrossRef
194.
Speed, J. M., Trinh, Q. D., Choueiri, T. K. & Sun, M. Recurrence in localized renal cell carcinoma: a systematic review of contemporary data. Curr. Urol. Rep. 18, 15 (2017).PubMedCrossRef
195.
Kattan, M. W., Reuter, V., Motzer, R. J., Katz, J. & Russo, P. A postoperative prognostic nomogram for renal cell carcinoma. J. Urol. 166, 63–67 (2001).PubMedCrossRef
196.
Frank, I. et al. An outcome prediction model for patients with clear cell renal cell carcinoma treated with radical nephrectomy based on tumor stage, size, grade and necrosis: the SSIGN score. J. Urol. 168, 2395–2400 (2002).PubMedCrossRef
197.
Zisman, A. et al. Improved prognostication of renal cell carcinoma using an integrated staging system. J. Clin. Oncol. 19, 1649–1657 (2001).PubMedCrossRef
198.
Zisman, A. et al. Risk group assessment and clinical outcome algorithm to predict the natural history of patients with surgically resected renal cell carcinoma. J. Clin. Oncol. 20, 4559–4566 (2002).PubMedCrossRef
199.
Karakiewicz, P. I. et al. Multi-institutional validation of a new renal cancer-specific survival nomogram. J. Clin. Oncol. 25, 1316–1322 (2007).PubMedCrossRef
200.
Cindolo, L. et al. A preoperative clinical prognostic model for non-metastatic renal cell carcinoma. BJU Int. 92, 901–905 (2003).PubMedCrossRef
201.
Patard, J. J. et al. Use of the University of California Los Angeles integrated staging system to predict survival in renal cell carcinoma: an international multicenter study. J. Clin. Oncol. 22, 3316–3322 (2004).PubMedCrossRef
202.
Zigeuner, R. et al. External validation of the Mayo Clinic stage, size, grade, and necrosis (SSIGN) score for clear-cell renal cell carcinoma in a single European centre applying routine pathology. Eur. Urol. 57, 102–109 (2010).PubMedCrossRef
203.
Cindolo, L. et al. Comparison of predictive accuracy of four prognostic models for nonmetastatic renal cell carcinoma after nephrectomy: a multicenter European study. Cancer 104, 1362–1371 (2005).PubMedCrossRef
204.
Ravaud, A. et al. Adjuvant sunitinib in high-risk renal-cell carcinoma after nephrectomy. N. Engl. J. Med. 375, 2246–2254 (2016).PubMedCrossRef
205.
Motzer, R. J. et al. Survival and prognostic stratification of 670 patients with advanced renal cell carcinoma. J. Clin. Oncol. 17, 2530–2540 (1999).PubMedCrossRef
206.
Heng, D. Y. et al. Prognostic factors for overall survival in patients with metastatic renal cell carcinoma treated with vascular endothelial growth factor-targeted agents: results from a large, multicenter study. J. Clin. Oncol. 27, 5794–5799 (2009).PubMedCrossRef
207.
Heng, D. Y. et al. External validation and comparison with other models of the International Metastatic Renal-Cell Carcinoma Database Consortium prognostic model: a population-based study. Lancet Oncol. 14, 141–148 (2013).PubMedPubMedCentralCrossRef
208.
Gerlinger, M. et al. Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N. Engl. J. Med. 366, 883–892 (2012).PubMedPubMedCentralCrossRef
209.
Gerlinger, M. et al. Genomic architecture and evolution of clear cell renal cell carcinomas defined by multiregion sequencing. Nat. Genet. 46, 225–233 (2014).PubMedPubMedCentralCrossRef
210.
Sharpe, K. et al. The effect of VEGF-targeted therapy on biomarker expression in sequential tissue from patients with metastatic clear cell renal cancer. Clin. Cancer Res. 19, 6924–6934 (2013).PubMedCrossRef
211.
Stewart, G. D. et al. Dynamic epigenetic changes to VHL occur with sunitinib in metastatic clear cell renal cancer. Oncotarget 18, 25241–25250 (2016).
212.
Wei, J. H. et al. A CpG-methylation-based assay to predict survival in clear cell renal cell carcinoma. Nat. Commun. 6, 8699 (2015).PubMedPubMedCentralCrossRef
213.
Costa, V. L. et al. TCF21 and PCDH17 methylation: an innovative panel of biomarkers for a simultaneous detection of urological cancers. Epigenetics 6, 1120–1130 (2011).PubMedCrossRef
214.
Xin, J. et al. Clinical potential of TCF21 methylation in the diagnosis of renal cell carcinoma. Oncol. Lett. 12, 1265–1270 (2016).PubMedPubMedCentralCrossRef
215.
Zhao, A., Li, G., Peoc’h, M., Genin, C. & Gigante, M. Serum miR-210 as a novel biomarker for molecular diagnosis of clear cell renal cell carcinoma. Exp. Mol. Pathol. 94, 115–120 (2013).PubMedCrossRef
216.
Iwamoto, H. et al. Serum miR-210 as a potential biomarker of early clear cell renal cell carcinoma. Int. J. Oncol. 44, 53–58 (2014).PubMedCrossRef
217.
Fedorko, M. et al. Combination of MiR-378 and MiR-210 serum levels enables sensitive detection of renal cell carcinoma. Int. J. Mol. Sci. 16, 23382–23389 (2015).PubMedPubMedCentralCrossRef
218.
Li, G., Zhao, A., Peoch, M., Cottier, M. & Mottet, N. Detection of urinary cell-free miR-210 as a potential tool of liquid biopsy for clear cell renal cell carcinoma. Urol. Oncol. 35, 294–299 (2017).PubMedCrossRef
219.
Redova, M. et al. Circulating miR-378 and miR-451 in serum are potential biomarkers for renal cell carcinoma. J. Transl. Med. 10, 55 (2012).PubMedPubMedCentralCrossRef
220.
Hauser, S. et al. Analysis of serum microRNAs (miR-26a-2*, miR-191, miR-337-3p and miR-378) as potential biomarkers in renal cell carcinoma. Cancer Epidemiol. 36, 391–394 (2012).PubMedCrossRef
221.
Wang, C. et al. A panel of five serum miRNAs as a potential diagnostic tool for early-stage renal cell carcinoma. Sci. Rep. 5, 7610 (2015).PubMedPubMedCentralCrossRef
222.
Atschekzei, F. et al. SFRP1 CpG island methylation locus is associated with renal cell cancer susceptibility and disease recurrence. Epigenetics 7, 447–457 (2012).PubMedCrossRef
223.
Peters, I. et al. DNA methylation biomarkers predict progression-free and overall survival of metastatic renal cell cancer (mRCC) treated with antiangiogenic therapies. PLoS ONE 9, e91440 (2014).PubMedPubMedCentralCrossRef
224.
Dubrowinskaja, N. et al. Neurofilament heavy polypeptide CpG island methylation associates with prognosis of renal cell carcinoma and prediction of antivascular endothelial growth factor therapy response. Cancer Med. 3, 300–309 (2014).PubMedPubMedCentralCrossRef
225.
Peters, I. et al. GATA5 CpG island methylation in renal cell cancer: a potential biomarker for metastasis and disease progression. BJU Int. 110, E144–E152 (2012).PubMedCrossRef
226.
Peters, I. et al. GATA5 CpG island hypermethylation is an independent predictor for poor clinical outcome in renal cell carcinoma. Oncol. Rep. 31, 1523–1530 (2014).PubMedPubMedCentralCrossRef
227.
Faragalla, H. et al. The clinical utility of miR-21 as a diagnostic and prognostic marker for renal cell carcinoma. J. Mol. Diagn. 14, 385–392 (2012).PubMedCrossRef
228.
Tang, K. & Xu, H. Prognostic value of meta-signature miRNAs in renal cell carcinoma: an integrated miRNA expression profiling analysis. Sci. Rep. 5, 10272 (2015).PubMedPubMedCentralCrossRef
229.
Vergho, D. et al. Combination of expression levels of miR-21 and miR-126 is associated with cancer-specific survival in clear-cell renal cell carcinoma. BMC Cancer 14, 25 (2014).PubMedPubMedCentralCrossRef
230.
Vergho, D. C. et al. Impact of miR-21, miR-126 and miR-221 as prognostic factors of clear cell renal cell carcinoma with tumor thrombus of the inferior vena cava. PLoS ONE 9, e109877 (2014).PubMedPubMedCentralCrossRef
231.
Zaman, M. S. et al. Up-regulation of microRNA-21 correlates with lower kidney cancer survival. PLoS ONE 7, e31060 (2012).PubMedPubMedCentralCrossRef
232.
Samaan, S. et al. miR-210 is a prognostic marker in clear cell renal cell carcinoma. J. Mol. Diagn. 17, 136–144 (2015).PubMedCrossRef
233.
Ge, Y. Z. et al. MicroRNA expression profiles predict clinical phenotypes and prognosis in chromophobe renal cell carcinoma. Sci. Rep. 5, 10328 (2015).PubMedPubMedCentralCrossRef
234.
Christinat, Y. & Krek, W. Integrated genomic analysis identifies subclasses and prognosis signatures of kidney cancer. Oncotarget 6, 10521–10531 (2015).PubMedPubMedCentralCrossRef
235.
Wu, X. et al. Identification of a 4-microRNA signature for clear cell renal cell carcinoma metastasis and prognosis. PLoS ONE 7, e35661 (2012).PubMedPubMedCentralCrossRef
236.
Khella, H. W. et al. Low expression of miR-126 is a prognostic marker for metastatic clear cell renal cell carcinoma. Am. J. Pathol. 185, 693–703 (2015).PubMedCrossRef
237.
Slaby, O. et al. Identification of MicroRNAs associated with early relapse after nephrectomy in renal cell carcinoma patients. Genes Chromosomes Cancer 51, 707–716 (2012).PubMedCrossRef
238.
Liu, W. et al. Pseudohypoxia induced by miR-126 deactivation promotes migration and therapeutic resistance in renal cell carcinoma. Cancer Lett. 394, 65–75 (2017).PubMedPubMedCentralCrossRef
239.
Rogenhofer, S. et al. Global histone H3 lysine 27 (H3K27) methylation levels and their prognostic relevance in renal cell carcinoma. BJU Int. 109, 459–465 (2012).PubMedCrossRef
240.
Ellinger, J. et al. Prognostic relevance of global histone H3 lysine 4 (H3K4) methylation in renal cell carcinoma. Int. J. Cancer 127, 2360–2366 (2010).PubMedCrossRef
241.
Rogenhofer, S. et al. Decreased levels of histone H3K9me1 indicate poor prognosis in patients with renal cell carcinoma. Anticancer Res. 32, 879–886 (2012).PubMed
242.
Ho, T. H. et al. Loss of histone H3 lysine 36 trimethylation is associated with an increased risk of renal cell carcinoma-specific death. Mod. Pathol. 29, 34–42 (2016).PubMedCrossRef
243.
Seligson, D. B. et al. Global levels of histone modifications predict prognosis in different cancers. Am. J. Pathol. 174, 1619–1628 (2009).PubMedPubMedCentralCrossRef
244.
Wang, J. et al. Prognostic value of UTX expression in patients with clear cell renal cell carcinoma. Urol. Oncol. 34, 338.e319–327 (2016).
245.
Pires-Luis, A. S. et al. Expression of histone methyltransferases as novel biomarkers for renal cell tumor diagnosis and prognostication. Epigenetics 10, 1033–1043 (2015).PubMedPubMedCentralCrossRef
246.
Pompas-Veganzones, N. et al. Myopodin methylation is a prognostic biomarker and predicts antiangiogenic response in advanced kidney cancer. Tumour Biol. 37, 14301–14310 (2016).PubMedCrossRef
247.
Gamez-Pozo, A. et al. MicroRNA expression profiling of peripheral blood samples predicts resistance to first-line sunitinib in advanced renal cell carcinoma patients. Neoplasia 14, 1144–1152 (2012).PubMedPubMedCentralCrossRef
248.
Prior, C. et al. Identification of tissue microRNAs predictive of sunitinib activity in patients with metastatic renal cell carcinoma. PLoS ONE 9, e86263 (2014).PubMedPubMedCentralCrossRef
249.
Merhautova, J. et al. miR-155 and miR-484 are associated with time to progression in metastatic renal cell carcinoma treated with sunitinib. Biomed. Res. Int. 2015, 941980 (2015).PubMedPubMedCentralCrossRef
250.
Garcia-Donas, J. et al. Deep sequencing reveals microRNAs predictive of antiangiogenic drug response. JCI Insight 1, e86051 (2016).PubMedPubMedCentralCrossRef
251.
Khella, H. W. et al. miR-221/222 are involved in response to sunitinib treatment in metastatic renal cell carcinoma. Mol. Ther. 23, 1748–1758 (2015).PubMedPubMedCentralCrossRef
252.
Berkers, J. et al. A possible role for microRNA-141 down-regulation in sunitinib resistant metastatic clear cell renal cell carcinoma through induction of epithelial-to-mesenchymal transition and hypoxia resistance. J. Urol. 189, 1930–1938 (2013).PubMedCrossRef
253.
Ioannidis, J. P. A. & Bossuyt, P. M. M. Waste, leaks, and failures in the biomarker pipeline. Clin. Chem. 63, 963–972 (2017).PubMedCrossRef
254.
van Vlodrop, I. J. et al. Analysis of promoter CpG island hypermethylation in cancer: location, location, location! Clin. Cancer Res. 17, 4225–4231 (2011).PubMedCrossRef
255.
Malouf, G. G. et al. DNA methylation signature reveals cell ontogeny of renal cell carcinomas. Clin. Cancer Res. 22, 6236–6246 (2016).PubMedPubMedCentralCrossRef
256.
Hainsworth, J. D. et al. A phase II trial of panobinostat, a histone deacetylase inhibitor, in the treatment of patients with refractory metastatic renal cell carcinoma. Cancer Invest. 29, 451–455 (2011).PubMedCrossRef
257.
US National Library of Medicine. ClinicalTrials.gov https://​clinicaltrials.​gov/​ct2/​show/​NCT00278395 (2017).
258.
Stadler, W. M., Margolin, K., Ferber, S., McCulloch, W. & Thompson, J. A. A phase II study of depsipeptide in refractory metastatic renal cell cancer. Clin. Genitourin Cancer 5, 57–60 (2006).PubMedCrossRef
259.
Gollob, J. A. et al. Phase I trial of sequential low-dose 5-aza-2ʹ-deoxycytidine plus high-dose intravenous bolus interleukin-2 in patients with melanoma or renal cell carcinoma. Clin. Cancer Res. 12, 4619–4627 (2006).PubMedCrossRef
260.
Covre, A. et al. Epigenetics meets immune checkpoints. Semin. Oncol. 42, 506–513 (2015).PubMedCrossRef
261.
Issa, J. J. et al. Safety and tolerability of guadecitabine (SGI-110) in patients with myelodysplastic syndrome and acute myeloid leukaemia: a multicentre, randomised, dose-escalation phase 1 study. Lancet Oncol. 16, 1099–1110 (2015).PubMedPubMedCentralCrossRef
262.
Kantarjian, H. M. et al. Guadecitabine (SGI-110) in treatment-naive patients with acute myeloid leukaemia: phase 2 results from a multicentre, randomised, phase 1/2 trial. Lancet Oncol. 18, 1317–1326 (2017).PubMedCrossRefPubMedCentral
263.
Pili, R. et al. Combination of the histone deacetylase inhibitor vorinostat with bevacizumab in patients with clear-cell renal cell carcinoma: a multicentre, single-arm phase I/II clinical trial. Br. J. Cancer 116, 874–883 (2017).PubMedPubMedCentralCrossRef
264.
Zibelman, M. et al. Phase I study of the mTOR inhibitor ridaforolimus and the HDAC inhibitor vorinostat in advanced renal cell carcinoma and other solid tumors. Invest. New Drugs 33, 1040–1047 (2015).PubMedPubMedCentralCrossRef
265.
Dasari, A. et al. A phase I study of sorafenib and vorinostat in patients with advanced solid tumors with expanded cohorts in renal cell carcinoma and non-small cell lung cancer. Invest. New Drugs 31, 115–125 (2013).PubMedCrossRef
266.
US National Library of Medicine. ClinicalTrials.gov https://​clinicaltrials.​gov/​ct2/​show/​NCT01005797 (2017).
267.
Roulois, D. et al. DNA-demethylating agents target colorectal cancer cells by inducing viral mimicry by endogenous transcripts. Cell 162, 961–973 (2015).PubMedPubMedCentralCrossRef
268.
Chiappinelli, K. B. et al. Inhibiting dna methylation causes an interferon response in cancer via dsRNA including endogenous retroviruses. Cell 162, 974–986 (2015).PubMedPubMedCentralCrossRef
269.
Chiappinelli, K. B., Zahnow, C. A., Ahuja, N. & Baylin, S. B. Combining epigenetic and immunotherapy to combat cancer. Cancer Res. 76, 1683–1689 (2016).PubMedPubMedCentralCrossRef
270.
Reu, F. J. et al. Overcoming resistance to interferon-induced apoptosis of renal carcinoma and melanoma cells by DNA demethylation. J. Clin. Oncol. 24, 3771–3779 (2006).PubMedCrossRef
271.
Garzon, R., Marcucci, G. & Croce, C. M. Targeting microRNAs in cancer: rationale, strategies and challenges. Nat. Rev. Drug Discov. 9, 775–789 (2010).PubMedPubMedCentralCrossRef
272.
US National Library of Medicine. ClinicalTrials.gov https://​clinicaltrials.​gov/​ct2/​show/​NCT01829971 (2016).
273.
Altman, D. G., McShane, L. M., Sauerbrei, W. & Taube, S. E. Reporting recommendations for tumor marker prognostic studies (REMARK): explanation and elaboration. BMC Med. 10, 51 (2012).PubMedPubMedCentralCrossRef
274.
Bossuyt, P. M. et al. STARD 2015: an updated list of essential items for reporting diagnostic accuracy studies. Clin. Chem. 61, 1446–1452 (2015).PubMedCrossRef
275.
Moons, K. G. et al. Transparent reporting of a multivariable prediction model for Individual Prognosis or Diagnosis (TRIPOD): explanation and elaboration. Ann. Intern. Med. 162, W1–W73 (2015).PubMedCrossRef
276.
Herman, J. G. et al. Silencing of the VHL tumor-suppressor gene by DNA methylation in renal carcinoma. Proc. Natl Acad. Sci. USA 91, 9700–9704 (1994).PubMedPubMedCentralCrossRef
277.
Brauch, H. et al. VHL alterations in human clear cell renal cell carcinoma: association with advanced tumor stage and a novel hot spot mutation. Cancer Res. 60, 1942–1948 (2000).PubMed
278.
Oh, R. R. et al. Expression of HGF/SF and Met protein is associated with genetic alterations of VHL gene in primary renal cell carcinomas. Apmis 110, 229–238 (2002).PubMedCrossRef
279.
Kim, J. H. et al. Somatic VHL alteration and its impact on prognosis in patients with clear cell renal cell carcinoma. Oncol. Rep. 13, 859–864 (2005).PubMed
280.
Smits, K. M. et al. Genetic and epigenetic alterations in the von hippel-lindau gene: the influence on renal cancer prognosis. Clin. Cancer Res. 14, 782–787 (2008).PubMedCrossRef
281.
Patard, J. J. et al. Absence of VHL gene alteration and high VEGF expression are associated with tumour aggressiveness and poor survival of renal-cell carcinoma. Br. J. Cancer 101, 1417–1424 (2009).PubMedPubMedCentralCrossRef
282.
Young, A. C. et al. Analysis of VHL gene alterations and their relationship to clinical parameters in sporadic conventional renal cell carcinoma. Clin. Cancer Res. 15, 7582–7592 (2009).PubMedPubMedCentralCrossRef
283.
Moore, L. E. et al. Von Hippel-Lindau (VHL) inactivation in sporadic clear cell renal cancer: associations with germline VHL polymorphisms and etiologic risk factors. PLoS Genet. 7, e1002312 (2011).PubMedPubMedCentralCrossRef
284.
Gossage, L. et al. Clinical and pathological impact of VHL, PBRM1, BAP1, SETD2, KDM6A, and JARID1c in clear cell renal cell carcinoma. Genes Chromosomes Cancer 53, 38–51 (2014).PubMedCrossRef
285.
Lessi, F. et al. VHL and HIF-1alpha: gene variations and prognosis in early-stage clear cell renal cell carcinoma. Med. Oncol. 31, 840 (2014).PubMedCrossRef
286.
Khaliq, S. et al. Unique molecular alteration patterns in von Hippel-Lindau (VHL) gene in a cohort of sporadic renal cell carcinoma patients from Pakistan. Mutat. Res. https://​doi.​org/​10.​1016/​j.​mrfmmm.​2014.​03.​008 (2014).
287.
Motzer, R. J. et al. Investigation of novel circulating proteins, germ line single-nucleotide polymorphisms, and molecular tumor markers as potential efficacy biomarkers of first-line sunitinib therapy for advanced renal cell carcinoma. Cancer Chemother. Pharmacol. 74, 739–750 (2014).PubMedPubMedCentralCrossRef
288.
Kagara, I. et al. CpG hypermethylation of the UCHL1 gene promoter is associated with pathogenesis and poor prognosis in renal cell carcinoma. J. Urol. 180, 343–351 (2008).PubMedCrossRef
289.
Morris, M. R. et al. Functional epigenomics approach to identify methylated candidate tumour suppressor genes in renal cell carcinoma. Br. J. Cancer 98, 496–501 (2008).PubMedPubMedCentralCrossRef
290.
Liu, Q. et al. Epigenetic inactivation of the candidate tumor suppressor gene ASC/TMS1 in human renal cell carcinoma and its role as a potential therapeutic target. Oncotarget 6, 22706–22723 (2015).PubMedPubMedCentral
291.
Zhang, Q. et al. Aberrant promoter methylation of DLEC1, a critical 3p22 tumor suppressor for renal cell carcinoma, is associated with more advanced tumor stage. J. Urol. 184, 731–737 (2010).PubMedCrossRef
292.
Ibanz de Caceres, I. & Cairns, P. Methylated DNA sequences for early cancer detection, molecular classification and chemotherapy response prediction. Clin. Transl Oncol. 9, 429–437 (2007).CrossRef
293.
Morris, M. R. et al. Tumor suppressor activity and epigenetic inactivation of hepatocyte growth factor activator inhibitor type 2/SPINT2 in papillary and clear cell renal cell carcinoma. Cancer Res. 65, 4598–4606 (2005).PubMedCrossRef
294.
Yamada, D. et al. Promoter hypermethylation of the potential tumor suppressor DAL-1/4.1B gene in renal clear cell carcinoma. Int. J. Cancer 118, 916–923 (2006).PubMedCrossRef
295.
Paiva, F. et al. Functional and epigenetic characterization of the KRT19 gene in renal cell neoplasms. DNA Cell Biol. 30, 85–90 (2011).PubMedCrossRef
296.
Li, H. et al. Epigenetic alterations of Kruppel-like factor 4 and its tumor suppressor function in renal cell carcinoma. Carcinogenesis 34, 2262–2270 (2013).PubMedCrossRef
297.
Song, E. et al. Attenuation of kruppel-like factor 4 facilitates carcinogenesis by inducing g1/s phase arrest in clear cell renal cell carcinoma. PLoS ONE 8, e67758 (2013).PubMedPubMedCentralCrossRef
298.
Li, Y. et al. miR30a5p in the tumorigenesis of renal cell carcinoma: a tumor suppressive microRNA. Mol. Med. Rep. 13, 4085–4094 (2016).PubMedCrossRef
299.
Zheng, B. et al. MiRNA-30a-mediated autophagy inhibition sensitizes renal cell carcinoma cells to sorafenib. Biochem. Biophys. Res. Commun. 459, 234–239 (2015).PubMedCrossRef
300.
Jin, L. et al. Identification of miR30b as an oncogene in renal cell carcinoma. Mol. Med. Rep. 15, 1837–1846 (2017).PubMedCrossRef
301.
Yang, H. et al. Expression of microRNA-30c via lentivirus vector inhibits the proliferation and enhances the sensitivity of highly aggressive ccRCC Caki-1 cells to anticancer agents. Onco Targets Ther. 10, 579–590 (2017).PubMedPubMedCentralCrossRef
302.
Yu, H. et al. Proliferation inhibition and the underlying molecular mechanisms of microRNA-30d in renal carcinoma cells. Oncol. Lett. 7, 799–804 (2014).PubMedCrossRef
303.
Wu, C. et al. MiR-30d induces apoptosis and is regulated by the Akt/FOXO pathway in renal cell carcinoma. Cell Signal 25, 1212–1221 (2013).PubMedCrossRef
304.
Yu, G. et al. miRNA-34a suppresses cell proliferation and metastasis by targeting CD44 in human renal carcinoma cells. J. Urol. 192, 1229–1237 (2014).PubMedCrossRef
305.
Zhang, C. et al. Tumor suppressor microRNA-34a inhibits cell proliferation by targeting notch1 in renal cell carcinoma. Oncol. Lett. 7, 1689–1694 (2014).PubMedPubMedCentralCrossRef
306.
Weng, W. et al. YY1-C/EBPalpha-miR34a regulatory circuitry is involved in renal cell carcinoma progression. Oncol. Rep. 31, 1921–1927 (2014).PubMedCrossRef
307.
Yamamura, S. et al. MicroRNA-34a suppresses malignant transformation by targeting c-Myc transcriptional complexes in human renal cell carcinoma. Carcinogenesis 33, 294–300 (2012).PubMedCrossRef
308.
Lodygin, D. et al. Inactivation of miR-34a by aberrant CpG methylation in multiple types of cancer. Cell Cycle 7, 2591–2600 (2008).PubMedCrossRef
309.
Vogt, M. et al. Frequent concomitant inactivation of miR-34a and miR-34b/c by CpG methylation in colorectal, pancreatic, mammary, ovarian, urothelial, and renal cell carcinomas and soft tissue sarcomas. Virchows Arch. 458, 313–322 (2011).PubMedCrossRef
310.
Cao, Y. et al. Downregulation of lncRNA CASC2 by microRNA-21 increases the proliferation and migration of renal cell carcinoma cells. Mol. Med. Rep. 14, 1019–1025 (2016).PubMedCrossRef
311.
Kowalczyk, A. E. et al. SATB1 is down-regulated in clear cell renal cell carcinoma and correlates with miR-21-5p overexpression and poor prognosis. Cancer Genomics Proteomics 13, 209–217 (2016).PubMed
312.
Cao, J. et al. MicroRNA-21 stimulates epithelial-to-mesenchymal transition and tumorigenesis in clear cell renal cells. Mol. Med. Rep. 13, 75–82 (2016).PubMedCrossRef
313.
Liang, T. et al. MicroRNA-21 regulates the proliferation, differentiation, and apoptosis of human renal cell carcinoma cells by the mTOR-STAT3 signaling pathway. Oncol. Res. 24, 371–380 (2016).PubMedCrossRef
314.
Petrozza, V. et al. Oncogenic microRNAs characterization in clear cell renal cell carcinoma. Int. J. Mol. Sci. 16, 29219–29225 (2015).PubMedPubMedCentralCrossRef
315.
Doberstein, K. et al. miR-21-3p is a positive regulator of L1CAM in several human carcinomas. Cancer Lett. 354, 455–466 (2014).PubMedCrossRef
316.
Bera, A. et al. microRNA-21-induced dissociation of PDCD4 from rictor contributes to Akt-IKKbeta-mTORC1 axis to regulate renal cancer cell invasion. Exp. Cell Res. 328, 99–117 (2014).PubMedPubMedCentralCrossRef
317.
Li, X. et al. MicroRNA-21 (miR-21) post-transcriptionally downregulates tumor suppressor PDCD4 and promotes cell transformation, proliferation, and metastasis in renal cell carcinoma. Cell Physiol. Biochem. 33, 1631–1642 (2014).PubMedCrossRef
318.
Lv, L. et al. MicroRNA-21 is overexpressed in renal cell carcinoma. Int. J. Biol. Markers 28, 201–207 (2013).PubMedCrossRef
319.
Zhang, H., Guo, Y., Shang, C., Song, Y. & Wu, B. miR-21 downregulated TCF21 to inhibit KISS1 in renal cancer. Urology 80, 1298–1302.e1291 (2012).PubMedCrossRef
320.
Osanto, S. et al. Genome-wide microRNA expression analysis of clear cell renal cell carcinoma by next generation deep sequencing. PLoS ONE 7, e38298 (2012).PubMedPubMedCentralCrossRef
321.
Zhang, A., Liu, Y., Shen, Y., Xu, Y. & Li, X. miR-21 modulates cell apoptosis by targeting multiple genes in renal cell carcinoma. Urology 78, 474.e413–479 (2011).
322.
Liu, T. Y., Zhang, H., Du, S. M., Li, J. & Wen, X. H. Expression of microRNA-210 in tissue and serum of renal carcinoma patients and its effect on renal carcinoma cell proliferation, apoptosis, and invasion. Genet. Mol. Res. 15, 15017746 (2016).PubMed
323.
Xiao, H. et al. MiR-1 downregulation correlates with poor survival in clear cell renal cell carcinoma where it interferes with cell cycle regulation and metastasis. Oncotarget 6, 13201–13215 (2015).PubMedPubMedCentral
324.
Kawakami, K. et al. The functional significance of miR-1 and miR-133a in renal cell carcinoma. Eur. J. Cancer 48, 827–836 (2012).PubMedCrossRef
325.
Li, Y. et al. Oncogenic cAMP responsive element binding protein 1 is overexpressed upon loss of tumor suppressive miR-10b-5p and miR-363-3p in renal cancer. Oncol. Rep. 35, 1967–1978 (2016).PubMedCrossRef
326.
Xiao, W., Gao, Z., Duan, Y., Yuan, W. & Ke, Y. Downregulation of miR-19a exhibits inhibitory effects on metastatic renal cell carcinoma by targeting PIK3CA and inactivating notch signaling in vitro. Oncol. Rep. 34, 739–746 (2015).PubMedCrossRef
327.
Zhang, S. et al. MicroRNA-22 functions as a tumor suppressor by targeting SIRT1 in renal cell carcinoma. Oncol. Rep. 35, 559–567 (2016).PubMedCrossRef
328.
Ishihara, T. et al. Expression of the tumor suppressive miRNA-23b/27b cluster is a good prognostic marker in clear cell renal cell carcinoma. J. Urol. 192, 1822–1830 (2014).PubMedCrossRef
329.
Li, Y. et al. MicroRNA-27a functions as a tumor suppressor in renal cell carcinoma by targeting epidermal growth factor receptor. Oncol. Lett. 11, 4217–4223 (2016).PubMedPubMedCentralCrossRef
330.
Nakata, W. et al. Expression of miR-27a-3p is an independent predictive factor for recurrence in clear cell renal cell carcinoma. Oncotarget 6, 21645–21654 (2015).PubMedPubMedCentralCrossRef
331.
Peng, H. et al. miR-27a promotes cell proliferation and metastasis in renal cell carcinoma. Int. J. Clin. Exp. Pathol. 8, 2259–2266 (2015).PubMedPubMedCentral
332.
Gottardo, F. et al. Micro-RNA profiling in kidney and bladder cancers. Urol. Oncol. 25, 387–392 (2007).PubMedCrossRef
333.
Wang, C. et al. miR-28-5p acts as a tumor suppressor in renal cell carcinoma for multiple antitumor effects by targeting RAP1B. Oncotarget 7, 73888–73902 (2016).PubMedPubMedCentral
334.
Hell, M. P. et al. miR-28-5p promotes chromosomal instability in VHL-associated cancers by inhibiting Mad2 translation. Cancer Res. 74, 2432–2443 (2014).PubMedCrossRef
335.
Xu, X., Liu, C. & Bao, J. Hypoxia-induced hsa-miR-101 promotes glycolysis by targeting TIGAR mRNA in clear cell renal cell carcinoma. Mol. Med. Rep. 15, 1373–1378 (2017).PubMedCrossRef
336.
Goto, Y. et al. The microRNA signature of patients with sunitinib failure: regulation of UHRF1 pathways by microRNA-101 in renal cell carcinoma. Oncotarget 7, 59070–59086 (2016).PubMedPubMedCentral
337.
Sakurai, T. et al. The enhancer of zeste homolog 2 (EZH2), a potential therapeutic target, is regulated by miR-101 in renal cancer cells. Biochem. Biophys. Res. Commun. 422, 607–614 (2012).PubMedCrossRef
338.
Ma, Y. et al. miR-106a* inhibits the proliferation of renal carcinoma cells by targeting IRS-2. Tumour Biol. 36, 8389–8398 (2015).PubMedCrossRef
339.
Mastropasqua, F. et al. TRIM8 restores p53 tumour suppressor function by blunting N-MYC activity in chemo-resistant tumours. Mol. Cancer 16, 67 (2017).PubMedPubMedCentralCrossRef
340.
Li, Y. et al. MicroRNA-106b functions as an oncogene in renal cell carcinoma by affecting cell proliferation, migration and apoptosis. Mol. Med. Rep. 13, 1420–1426 (2016).PubMedCrossRef
341.
Xiang, W. et al. miR-106b-5p targets tumor suppressor gene SETD2 to inactive its function in clear cell renal cell carcinoma. Oncotarget 6, 4066–4079 (2015).PubMedPubMedCentral
342.
Wang, Z. et al. MiR-122 promotes renal cancer cell proliferation by targeting sprouty2. Tumour Biol. 39, 1010428317691184 (2017).PubMed
343.
Zhang, G. M. et al. MicroRNA-126 inhibits tumor cell invasion and metastasis by downregulating ROCK1 in renal cell carcinoma. Mol. Med. Rep. 13, 5029–2036 (2016).PubMedPubMedCentralCrossRef
344.
Zhou, W., Bi, X., Gao, G. & Sun, L. miRNA-133b and miRNA-135a induce apoptosis via the JAK2/STAT3 signaling pathway in human renal carcinoma cells. Biomed. Pharmacother. 84, 722–729 (2016).PubMedCrossRef
345.
Wu, D. et al. microRNA-133b downregulation and inhibition of cell proliferation, migration and invasion by targeting matrix metallopeptidase-9 in renal cell carcinoma. Mol. Med. Rep. 9, 2491–2498 (2014).PubMedCrossRef
346.
Yamada, Y. et al. Tumor-suppressive microRNA-135a inhibits cancer cell proliferation by targeting the c-MYC oncogene in renal cell carcinoma. Cancer Sci. 104, 304–312 (2013).PubMedCrossRef
347.
Liang, J. et al. MiR-138 induces renal carcinoma cell senescence by targeting EZH2 and is downregulated in human clear cell renal cell carcinoma. Oncol. Res. 21, 83–91 (2013).PubMedCrossRef
348.
Yamasaki, T. et al. Tumor suppressive microRNA138 contributes to cell migration and invasion through its targeting of vimentin in renal cell carcinoma. Int. J. Oncol. 41, 805–817 (2012).PubMedPubMedCentralCrossRef
349.
Song, T. et al. MiR-138 suppresses expression of hypoxia-inducible factor 1alpha (HIF-1alpha) in clear cell renal cell carcinoma 786-O cells. Asian Pac. J. Cancer Prev. 12, 1307–1311 (2011).PubMed
350.
Li, Y. et al. Oncogenic microRNA-142-3p is associated with cellular migration, proliferation and apoptosis in renal cell carcinoma. Oncol. Lett. 11, 1235–1241 (2016).PubMedCrossRef
351.
Lou, N. et al. miR-144-3p as a novel plasma diagnostic biomarker for clear cell renal cell carcinoma. Urol. Oncol. 35, 36.e37–36.e14 (2017).CrossRef
352.
Liu, F., Chen, N., Xiao, R., Wang, W. & Pan, Z. miR-144-3p serves as a tumor suppressor for renal cell carcinoma and inhibits its invasion and metastasis by targeting MAP3K8. Biochem. Biophys. Res. Commun. 480, 87–93 (2016).PubMedCrossRef
353.
Xiang, C., Cui, S. P. & Ke, Y. MiR-144 inhibits cell proliferation of renal cell carcinoma by targeting MTOR. J. Huazhong Univ. Sci. Technolog Med. Sci. 36, 186–192 (2016).PubMedCrossRef
354.
Papadopoulos, E. I., Petraki, C., Gregorakis, A., Fragoulis, E. G. & Scorilas, A. Clinical evaluation of microRNA-145 expression in renal cell carcinoma: a promising molecular marker for discriminating and staging the clear cell histological subtype. Biol. Chem. 397, 529–539 (2016).PubMedCrossRef
355.
Wu, D. et al. microRNA145 inhibits cell proliferation, migration and invasion by targeting matrix metallopeptidase-11 in renal cell carcinoma. Mol. Med. Rep. 10, 393–398 (2014).PubMedCrossRef
356.
Lu, R. et al. miR-145 functions as tumor suppressor and targets two oncogenes, ANGPT2 and NEDD9, in renal cell carcinoma. J. Cancer Res. Clin. Oncol. 140, 387–397 (2014).PubMedCrossRef
357.
Doberstein, K. et al. MicroRNA-145 targets the metalloprotease ADAM17 and is suppressed in renal cell carcinoma patients. Neoplasia 15, 218–230 (2013).PubMedPubMedCentralCrossRef
358.
Jin, L. et al. Tumor suppressor miR-149-5p is associated with cellular migration, proliferation and apoptosis in renal cell carcinoma. Mol. Med. Rep. 13, 5386–5392 (2016).PubMedCrossRef
359.
Wang, X., Li, H., Cui, L., Feng, J. & Fan, Q. MicroRNA-182 suppresses clear cell renal cell carcinoma migration and invasion by targeting IGF1R. Neoplasma 63, 717–725 (2016).PubMedCrossRef
360.
Xu, X. et al. Downregulation of microRNA-182-5p contributes to renal cell carcinoma proliferation via activating the AKT/FOXO3a signaling pathway. Mol. Cancer 13, 109 (2014).PubMedPubMedCentralCrossRef
361.
Zhang, Q. et al. High serum miR-183 level is associated with poor responsiveness of renal cancer to natural killer cells. Tumour Biol. 36, 9245–9249 (2015).PubMedCrossRef
362.
Qiu, M. et al. MicroRNA-183 plays as oncogenes by increasing cell proliferation, migration and invasion via targeting protein phosphatase 2A in renal cancer cells. Biochem. Biophys. Res. Commun. 452, 163–169 (2014).PubMedCrossRef
363.
Ma, X. et al. MicroRNA-185 inhibits cell proliferation and induces cell apoptosis by targeting VEGFA directly in von Hippel-Lindau-inactivated clear cell renal cell carcinoma. Urol. Oncol. 33, 169.e161–111 (2015).CrossRef
364.
Jin, L. et al. Identification of miR1953p as an oncogene in RCC. Mol. Med. Rep. 15, 1916–1924 (2017).PubMedCrossRef
365.
Sun, P. et al. MicroRNA-195 targets VEGFR2 and has a tumor suppressive role in ACHN cells via PI3K/Akt and Raf/MEK/ERK signaling pathways. Int. J. Oncol. 49, 1155–1163 (2016).PubMedCrossRef
366.
Huang, J. et al. miR-199a-3p inhibits hepatocyte growth factor/c-Met signaling in renal cancer carcinoma. Tumour Biol. 35, 5833–5843 (2014).PubMedCrossRef
367.
Tsukigi, M. et al. Re-expression of miR-199a suppresses renal cancer cell proliferation and survival by targeting GSK-3beta. Cancer Lett. 315, 189–197 (2012).PubMedCrossRef
368.
Xiong, F. et al. MiR-204 inhibits the proliferation and invasion of renal cell carcinoma by inhibiting RAB22 A expression. Oncol. Rep. 35, 3000–3008 (2016).PubMedCrossRef
369.
Wu, D. et al. Upregulation of microRNA-204 inhibits cell proliferation, migration and invasion in human renal cell carcinoma cells by downregulating SOX4. Mol. Med. Rep. 12, 7059–7064 (2015).PubMedCrossRef
370.
Mikhaylova, O. et al. VHL-regulated MiR-204 suppresses tumor growth through inhibition of LC3B-mediated autophagy in renal clear cell carcinoma. Cancer Cell 21, 532–546 (2012).PubMedPubMedCentralCrossRef
371.
Imam, J. S. et al. Genomic loss of tumor suppressor miRNA-204 promotes cancer cell migration and invasion by activating AKT/mTOR/Rac1 signaling and actin reorganization. PLoS ONE 7, e52397 (2012).PubMedPubMedCentralCrossRef
372.
Wei, C., Wang, S., Ye, Z. Q. & Chen, Z. Q. miR-206 inhibits renal cell cancer growth by targeting GAK. J. Huazhong Univ. Sci. Technolog Med. Sci. 36, 852–858 (2016).PubMedCrossRef
373.
Xiao, H. et al. miR-206 functions as a novel cell cycle regulator and tumor suppressor in clear-cell renal cell carcinoma. Cancer Lett. 374, 107–116 (2016).PubMedCrossRef
374.
Khella, H. W. et al. miR-192, miR-194 and miR-215: a convergent microRNA network suppressing tumor progression in renal cell carcinoma. Carcinogenesis 34, 2231–2239 (2013).PubMedCrossRef
375.
Yamasaki, T. et al. MicroRNA-218 inhibits cell migration and invasion in renal cell carcinoma through targeting caveolin-2 involved in focal adhesion pathway. J. Urol. 190, 1059–1068 (2013).PubMedCrossRef
376.
Zhang, S. et al. Effect of microRNA-218 on the viability, apoptosis and invasion of renal cell carcinoma cells under hypoxia by targeted downregulation of CXCR7 expression. Biomed. Pharmacother. 80, 213–219 (2016).PubMedCrossRef
377.
Wang, J., Ying, Y., Bo, S., Li, G. & Yuan, F. Differentially expressed microRNA-218 modulates the viability of renal cell carcinoma by regulating BCL9. Mol. Med. Rep. 14, 1829–1834 (2016).PubMedCrossRef
378.
Lu, G. J. et al. miRNA-221 promotes proliferation, migration and invasion by targeting TIMP2 in renal cell carcinoma. Int. J. Clin. Exp. Pathol. 8, 5224–5229 (2015).PubMedPubMedCentral
379.
Zhu, S., Huang, Y. & Su, X. Mir-451 correlates with prognosis of renal cell carcinoma patients and inhibits cellular proliferation of renal cell carcinoma. Med. Sci. Monit. 22, 183–190 (2016).PubMedPubMedCentralCrossRef
380.
Tang, Y., Wan, W., Wang, L., Ji, S. & Zhang, J. microRNA-451 inhibited cell proliferation, migration and invasion through regulation of MIF in renal cell carcinoma. Int. J. Clin. Exp. Pathol. 8, 15611–15621 (2015).PubMedPubMedCentral
381.
Su, Z. et al. MicroRNA-451a is associated with cell proliferation, migration and apoptosis in renal cell carcinoma. Mol. Med. Rep. 11, 2248–2254 (2015).PubMedCrossRef
382.
Kim, E. A. et al. Inhibition of c-FLIPL expression by miRNA-708 increases the sensitivity of renal cancer cells to anti-cancer drugs. Oncotarget 7, 31832–31846 (2016).PubMedPubMedCentral
383.
Saini, S. et al. MicroRNA-708 induces apoptosis and suppresses tumorigenicity in renal cancer cells. Cancer Res. 71, 6208–6219 (2011).PubMedPubMedCentralCrossRef
384.
US National Library of Medicine. ClinicalTrials.gov https://​clinicaltrials.​gov/​ct2/​show/​NCT00561912 (2011).
385.
US National Library of Medicine. ClinicalTrials.gov https://​clinicaltrials.​gov/​ct2/​show/​NCT00217542 (2013).
386.
US National Library of Medicine. ClinicalTrials.gov https://​clinicaltrials.​gov/​ct2/​show/​NCT00934440 (2017).
387.
US National Library of Medicine. ClinicalTrials.gov https://​clinicaltrials.​gov/​ct2/​show/​NCT03165721 (2018).
388.
US National Library of Medicine. ClinicalTrials.gov https://​clinicaltrials.​gov/​ct2/​show/​NCT00324740 (2015).
389.
US National Library of Medicine. ClinicalTrials.gov https://​clinicaltrials.​gov/​ct2/​show/​NCT02619253 (2018).
390.
US National Library of Medicine. ClinicalTrials.gov https://​clinicaltrials.​gov/​ct2/​show/​NCT01582009 (2017).
391.
Stadler, W. M. et al. Safety and efficacy results of the advanced renal cell carcinoma sorafenib expanded access program in North America. Cancer 116, 1272–1280 (2010).PubMedCrossRef
392.
US National Library of Medicine. ClinicalTrials.gov https://​clinicaltrials.​gov/​ct2/​show/​NCT01638533 (2018).
393.
Pili, R. et al. Phase I study of the histone deacetylase inhibitor entinostat in combination with 13-cis retinoic acid in patients with solid tumours. Br. J. Cancer 106, 77–84 (2012).PubMedCrossRef
394.
US National Library of Medicine. ClinicalTrials.gov https://​clinicaltrials.​gov/​ct2/​show/​NCT01038778 (2018).
395.
US National Library of Medicine. ClinicalTrials.gov https://​clinicaltrials.​gov/​ct2/​show/​NCT03024437 (2018).
396.
US National Library of Medicine. ClinicalTrials.gov https://​clinicaltrials.​gov/​ct2/​show/​NCT02795819 (2018).
397.
Steele, N. L. et al. A phase 1 pharmacokinetic and pharmacodynamic study of the histone deacetylase inhibitor belinostat in patients with advanced solid tumors. Clin. Cancer Res. 14, 804–810 (2008).PubMedCrossRef
398.
US National Library of Medicine. ClinicalTrials.gov https://​clinicaltrials.​gov/​ct2/​show/​NCT02601950 (2018).
399.
US National Library of Medicine. ClinicalTrials.gov https://​clinicaltrials.​gov/​ct2/​show/​NCT01987362 (2018).
400.
US National Library of Medicine. ClinicalTrials.gov https://​clinicaltrials.​gov/​ct2/​show/​NCT02419417 (2018).
  • » This content is intended only for healthcare providers and was made possible by educational funding provided by F. Hoffmann-La Roche Ltd.
Image Credits