Abstract
Myopodin is a cytoskeleton protein that shuttles to the nucleus depending on the cellular differentiation and stress. It has shown tumor suppressor functions. Myopodin methylation status was useful for staging bladder and colon tumors and predicting clinical outcome. To our knowledge, myopodin has not been tested in kidney cancer to date. The purpose of this study was to evaluate whether myopodin methylation status could be clinically useful in renal cancer (1) as a prognostic biomarker and 2) as a predictive factor of response to antiangiogenic therapy in patients with metastatic disease. Methylation-specific polymerase chain reactions (MS-PCR) were used to evaluate myopodin methylation in 88 kidney tumors. These belonged to patients with localized disease and no evidence of disease during follow-up (n = 25) (group 1), and 63 patients under antiangiogenic therapy (sunitinib, sorafenib, pazopanib, and temsirolimus), from which group 2 had non-metastatic disease at diagnosis (n = 32), and group 3 showed metastatic disease at diagnosis (n = 31). Univariate and multivariate Cox analyses were utilized to assess outcome and response to antiangiogenic agents taking progression, disease-specific survival, and overall survival as clinical endpoints. Myopodin was methylated in 50 out of the 88 kidney tumors (56.8 %). Among the 88 cases analyzed, 10 of them recurred (11.4 %), 51 progressed (57.9 %), and 40 died of disease (45.4 %). Myopodin methylation status correlated to MSKCC Risk score (p = 0.050) and the presence of distant metastasis (p = 0.039). Taking all patients, an unmethylated myopodin identified patients with shorter progression-free survival, disease-specific survival, and overall survival. Using also in univariate and multivariate models, an unmethylated myopodin predicted response to antiangiogenic therapy (groups 2 and 3) using progression-free survival, disease-specific, and overall survival as clinical endpoints. Myopodin was revealed hypermethylated in kidney cancer. Myopodin methylation status identified which patients showed a more aggressive clinical behavior and predicted antiangiogenic response. These observations support the clinical utility of an unmethylated myopodin as a prognostic and predictive biomarker in kidney cancer.
Similar content being viewed by others
References
Siegel RL, Miller KD, Jemal A. Cancer statistics, 2015. CA Cancer J Clin. 2015;65:5–29.
Jerónimo C, Henrique R. Epigenetic biomarkers in urological tumors: a systematic review. Cancer Lett. 2014;342:264–74.
Christoph F, Weikert S, Kempkensteffen C, et al. Promoter hypermethylation profile of kidney cancer with new proapoptotic p53 target genes and clinical implications. Clin Cancer Res. 2006;12:5040–6.
Yamada D, Kikuchi S, Williams YN, et al. Promoter hypermethylation of the potential tumor suppressor DAL-1/4.1B gene in renal clear cell carcinoma. Int J Cancer. 2006;118:916–23.
Ingold B, Schraml P, Heppner FL, Moch H. Homogeneous MGMT immunoreactivity correlates with an unmethylated MGMT promoter status in brain metastases of various solid tumors. PLoS One. 2009;4:e4775.
Fisel P, Kruck S, Winter S, et al. DNA methylation of the SLC16A3 promoter regulates expression of the human lactate transporter MCT4 in renal cancer with consequences for clinical outcome. Clin Cancer Res. 2013;19:5170–81.
Sharpe K, Stewart GD, Mackay A, 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. 2013;19:6924–34.
Peters I, Dubrowinskaja N, Abbas M, Seidel C, Kogosov M, Scherer R, Gebauer K, Merseburger AS, Kuczyk MA, Grünwald V, Serth J. DNA methylation biomarkers predict progression-free and overall survival of metastatic renal cell cancer (mRCC) treated with antiangiogenic therapies. PLoS One. 2014;9:e91440.
Dubrowinskaja N, Gebauer K, Peters I, 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. 2014;3:300–9.
Motzer RJ, Hutson TE, Hudes GR, 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. 2014;74:739–50.
Cancer Genome Atlas Research Network. Comprehensive molecular characterization of papillary renal cell carcinoma. N Engl J Med. 2016;374:135–45.
Ljungberg B, Bensalah K, Canfield S, Dabestani S, Hofmann F, Hora M, et al. EAU guidelines on renal cell carcinoma:2014 update. Eur Urol. 2015;67:913–24.
Weins A, Schwarz K, Faul C, Barisoni L, Linke WA, Mundel P. Differentiation- and stress-dependent nuclear cytoplasmic redistribution of myopodin, a novel actin-bundling protein. J Cell Biol. 2001;155:393–404.
Van Impe K, De Corte V, Eichinger L, Bruyneel E, Mareel M, Vandekerckhove J, et al. The nucleo-cytoplasmic actin-binding protein CapG lacks a nuclear export sequence present in structurally related proteins. J Biol Chem. 2003;278:17945–52.
Faul C, Hüttelmaier S, Oh J, Hachet V, Singer RH, Mundel P. Promotion of import alpha-mediated nuclear import by the phophorylation-dependent binding of cargo protein to 14-3-3. J Cell Biol. 2005;169:415–24.
De Ganck A, Hubert T, Van Impe K, Geelen D, Vandekerckhove J, De Corte V, et al. A monopartite nuclear localization sequence regulates nuclear targeting of the actin binding protein myopodin. FEBS Lett. 2005;579:6673–80.
Faul C, Dhume A, Schecter AD, Mundel P. Protein kinase A, Ca2+/calmodulin-dependent kinase II, and calcineurin regulate the intracellular trafficking of myopodin between the Z-disc and the nucleus of cardiac myocytes. Mol Cell Biol. 2007;27:8215–27.
Liang J, Ke G, You W, Peng Z, Lan J, Kalesse M, et al. Interaction between importin 13 and myopodin suggests a nuclear import pathway for myopodin. Mol Cell Biochem. 2008;307:93–100.
Lin F, YP Y, Woods J, Cieply K, Gooding B, Finkelstein P, et al. Myopodin, a synaptopodin homologue, is frequently deleted in invasive prostate cancers. Am J Pathol. 2001;159:1603–12.
Jing L, Liu L, YP Y, Dhir R, Acquafondada M, Landsittel D, et al. Expression of myopodin induces suppression of tumor growth and metastasis. Am J Pathol. 2004;164:1799–806.
Yu YP, Luo JH. Myopodin-mediated suppression of prostate cancer cell migration involves interaction with zyxin. Cancer Res. 2006;66:7414–9.
Yu YP, Tseng GC, Luo JH. Inactivation of myopodin expression associated with prostate cancer relapse. Urology. 2006;68:578–82.
Sanchez-Carbayo M, Schwarz K, Charytonowicz E, Cordon-Cardo C, Mundel P. Tumor suppressor role for myopodin in bladder cancer: loss of nuclear expression of myopodin is cell-cycle dependent and predicts clinical outcome. Oncogene. 2003;22:5298–305.
Cebrian V, Alvarez M, Aleman A, Palou J, Bellmunt J, Gonzalez-Peramato P, Cordón-Cardo C, García J, Piulats JM, Sánchez-Carbayo M. Discovery of myopodin methylation in bladder cancer. J Pathol. 2008;216:111–9.
Alvarez-Múgica M, Cebrian V, Fernández-Gómez JM, Fresno F, Escaf S, Sánchez-Carbayo M. Myopodin methylation is associated with clinical outcome in patients with T1G3 bladder cancer. J Urol. 2010;184:1507–13.
Esteban S, Moya P, Fernandez-Suarez A, Vidaurreta M, González-Peramato P, Sánchez-Carbayo M. Diagnostic and prognostic utility of methylation and protein expression patterns of myopodin in colon cancer. Tumour Biol. 2012;33:337–46.
Dawson-Saunders B, Trapp RG. Basic & clinical biostatistics. 2nd ed. Norwalk: Appleton & Lange; 1994.
Acknowledgments
The study was supported by a grant (SAF2012-40206) from the Spanish Ministry of Economy and Innovation (to Dr. Sánchez-Carbayo). The authors would like to thank all the members of his laboratory at the Translational Oncology Lab, and those at the previous Tumor Markers Group at the Spanish National Cancer Center for their technical support and constructive suggestions in the preparation of this manuscript. Finally, we would like to acknowledge the members of our clinical collaborators at the different institutions involved in this study, for their support in facilitating the tumor specimens as well as the clinical follow-up of the bladder cancer cases analyzed in this study.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflicts of interest
None
Electronic supplementary material
Supplementary Table 1
(DOC 30 kb)
About this article
Cite this article
Pompas-Veganzones, N., Sandonis, V., Perez-Lanzac, A. et al. Myopodin methylation is a prognostic biomarker and predicts antiangiogenic response in advanced kidney cancer. Tumor Biol. 37, 14301–14310 (2016). https://doi.org/10.1007/s13277-016-5267-8
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s13277-016-5267-8