Renal cell carcinoma (RCC) is a relatively rare malignancy of the urinary tract system. RCC is a heterogenous disease in terms of underlying histology and its associated underlying pathobiology, prognosis and treatment schedule. The most prevalent histological RCC subtype is clear-cell renal cell carcinoma (ccRCC), accounting for about 70-80% of all RCCs. Though the pathobiology and treatment schedule for ccRCC are well-established, non-ccRCC subtypes account for 20%-30% of RCC altogether, and their underlying molecular biology and treatment options are poorly defined. The class of non-coding RNAs-molecules that are generally not translated into proteins-are new cancer drivers and suppressors in all types of cancer. Of these, small non-coding microRNAs (miRNAs) contribute to carcinogenesis by regulating posttranscriptional gene silencing. Additionally, a growing body of evidence supports the role of long non-coding RNAs (lncRNAs) in cancer development and progression. Most studies on non-coding RNAs in RCC focus on clear-cell histology, and there is a relatively limited number of studies on non-ccRCC subtypes. The aim of this review is to give an overview of the current knowledge regarding the role of non-coding RNAs (including short and long non-coding RNAs) in non-ccRCC and to highlight possible implications as diagnostic, prognostic and predictive biomarkers.

Central European Institute of Technology Masaryk University 62500 Brno Czech Republic

Department of Comprehensive Cancer Care Masaryk Memorial Cancer Institute 62500 Brno Czech Republic

Department of Experimental Therapeutics The University of Texas MD Anderson Cancer Center Houston TX 77030 USA

Research Centre for Functional Genomics and Translational Medicine Iuliu Hatieganu University of Medicine and Pharmacy 40015 Cluj Napoca Romania

Research Unit of Non Coding RNAs and Genome Editing Division of Clinical Oncology Department of Medicine Comprehensive Cancer Center Graz Medical University of Graz 8036 Graz Austria

Zobrazit více v PubMed

Siegel R.L., Miller K.D., Jemal A. Cancer statistics, 2019. CA Cancer J. Clin. 2019;69:7–34. doi: 10.3322/caac.21551. PubMed DOI

Ferlay J., Soerjomataram I., Dikshit R., Eser S., Mathers C., Rebelo M., Parkin D.M., Forman M., Bray F. Cancer incidence and mortality worldwide: Sources, methods and major patterns in GLOBOCAN 2012. Int. J. Cancer. 2015;136:E359–E386. doi: 10.1002/ijc.29210. PubMed DOI

Znaor A., Lortet-Tieulent J., Laversanne M., Jemal A., Bray F. International Variations and Trends in Renal Cell Carcinoma Incidence and Mortality. Eur. Urol. 2015;67:519–530. doi: 10.1016/j.eururo.2014.10.002. PubMed DOI

Pichler M., Hutterer G.C., Chromecki T.F., Jesche J., Kampel-Kettner K., Pummer K., Zigeuner R. Renal cell carcinoma stage migration in a single European centre over 25 years: Effects on 5- and 10-year metastasis-free survival. Int. Urol. Nephrol. 2012;44:997–1004. doi: 10.1007/s11255-012-0165-5. PubMed DOI

Moch H., Cubilla A.L., Humphrey P.A., Reuter V.E., Ulbright T.M. The 2016 WHO Classification of Tumours of the Urinary System and Male Genital Organs—Part A: Renal, Penile, and Testicular Tumours. Eur. Urol. 2016;70:93–105. doi: 10.1016/j.eururo.2016.02.029. PubMed DOI

Rini B.I., Campbell S.C., Escudier B. Renal cell carcinoma. Lancet. 2009;373:1119–1132. doi: 10.1016/S0140-6736(09)60229-4. PubMed DOI

Pichler M., Hutterer G.C., Stojakovic T., Mannweiler S., Pummer K., Zigeuner R. High plasma fibrinogen level represents an independent negative prognostic factor regarding cancer-specific, metastasis-free, as well as overall survival in a European cohort of non-metastatic renal cell carcinoma patients. Br. J. Cancer. 2013;109:1123–1129. doi: 10.1038/bjc.2013.443. PubMed DOI PMC

Pichler M., Hutterer G.C., Stoeckigt C., Chromecki T.F., Stojakovic T., Golbeck S., Eberhard K., Gerger A., Mannweiler S., Pummer K., Zigeuner R. Validation of the pre-treatment neutrophil–lymphocyte ratio as a prognostic factor in a large European cohort of renal cell carcinoma patients. Br. J. Cancer. 2013;108:901–907. doi: 10.1038/bjc.2013.28. PubMed DOI PMC

Pichler M., Hutterer G.C., Chromecki T.F., Pummer K., Mannweiler S., Zigeuner R. Presence and extent of histological tumour necrosis is an adverse prognostic factor in papillary type 1 but not in papillary type 2 renal cell carcinoma. Histopathology. 2013;62:219–228. doi: 10.1111/j.1365-2559.2012.04328.x. PubMed DOI

Hutterer G.C., Chromecki T.F., Jesche J., Kampel-Kettner K., Rehak P., Pummer K., Pichler M., Zigeuner R. Histologic Tumor Necrosis Is an Independent Prognostic Indicator for Clear Cell and Papillary Renal Cell Carcinoma. Am. J. Clin. Pathol. 2012;137:283–289. PubMed

Pichler M., Hutterer G.C., Chromecki T.F., Jesche J., Kampel-Kettner K., Groselj-Strele A., Pummer K., Zigeuner R. Predictive ability of the 2002 and 2010 versions of the Tumour-Node-Metastasis classification system regarding metastasis-free, cancer-specific and overall survival in a European renal cell carcinoma single-centre series. BJU Int. 2013;111:E191–E195. doi: 10.1111/j.1464-410X.2012.11584.x. PubMed DOI

Pichler M., Hutterer G.C., Chromecki T.F., Jesche J., Groselj-Strele A., Kampel-Kettner K., Pummer K., Zigeuner R. Prognostic Value of the Leibovich Prognosis Score Supplemented by Vascular Invasion for Clear Cell Renal Cell Carcinoma. J. Urol. 2012;187:834–839. doi: 10.1016/j.juro.2011.10.155. PubMed DOI

Pichler M., Hutterer G.C., Chromecki T.F., Jesche J., Kampel-Kettner K., Rehak P., Pummer K., Zigeuner R. External Validation of the Leibovich Prognosis Score for Nonmetastatic Clear Cell Renal Cell Carcinoma at a Single European Center Applying Routine Pathology. J. Urol. 2011;186:1773–1778. doi: 10.1016/j.juro.2011.07.034. PubMed DOI

Lieder A., Guenzel T., Lebentrau S., Schneider C., Franzen A. Diagnostic relevance of metastatic renal cell carcinoma in the head and neck: An evaluation of 22 cases in 671 patients. Int. Braz. J. Urol. 2017;43:202–208. doi: 10.1590/s1677-5538.ibju.2015.0665. PubMed DOI PMC

Heng D.Y.C., Xie W., Regan M.M., Harshman L.C., Bjarnason G.A., Vaishampayan U.N., MacKenzie M., Wood L., Donskov F., Tan M.-H., 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. 2013;14:141–148. doi: 10.1016/S1470-2045(12)70559-4. PubMed DOI PMC

Powles T., Albiges L., Staehler M., Bensalah K., Dabestani S., Giles R.H. Updated European Association of Urology Guidelines Recommendations for the Treatment of First-line Metastatic Clear Cell Renal Cancer. Eur. Urol. 2017;73:311–315. doi: 10.1016/j.eururo.2017.11.016. PubMed DOI

Cella D., Grunwald V., Escudier B., Hammers H.J., George S., Nathan P. Patient-reported outcomes of patients with advanced renal cell carcinoma treated with nivolumab plus ipilimumab versus sunitinib (CheckMate 214): A randomised, phase 3 trial. Lancet Oncol. 2019;20:297–310. doi: 10.1016/S1470-2045(18)30778-2. PubMed DOI PMC

Motzer R.J., Escudier B., McDermott D.F., George S., Hammers H.J., Srinivas S. Nivolumab versus Everolimus in Advanced Renal-Cell Carcinoma. N. Engl. J. Med. 2015;373:1803–1813. doi: 10.1056/NEJMoa1510665. PubMed DOI PMC

Motzer R.J., Tannir N.M., McDermott D.F., Aren Frontera O., Melichar B., Choueiri T.K. Nivolumab plus Ipilimumab versus Sunitinib in Advanced Renal-Cell Carcinoma. N. Engl. J. Med. 2018;378:1277–1290. doi: 10.1056/NEJMoa1712126. PubMed DOI PMC

Rini B.I., Plimack E.R., Stus V., Gafanov R., Hawkins R., Nosov D. Pembrolizumab plus Axitinib versus Sunitinib for Advanced Renal-Cell Carcinoma. N. Engl. J. Med. 2019;380:1116–1127. doi: 10.1056/NEJMoa1816714. PubMed DOI

Bartel D.P. MicroRNAs: Genomics, biogenesis, mechanism, and function. Cell. 2004;116:116–281. doi: 10.1016/S0092-8674(04)00045-5. PubMed DOI

Brennecke J., Stärk A., Russell R.B., Cohen S.M. Principles of microRNA-target recognition. PLoS Boil. 2005;3:e85. doi: 10.1371/journal.pbio.0030085. PubMed DOI PMC

Pichler M., Winter E., Ress A.L., Bauernhofer T., Gerger A., Kiesslich T. miR-181a is associated with poor clinical outcome in patients with colorectal cancer treated with EGFR inhibitor. J. Clin. Pathol. 2014;67:198–203. doi: 10.1136/jclinpath-2013-201904. PubMed DOI

Strubberg A.M., Madison B.B. MicroRNAs in the etiology of colorectal cancer: Pathways and clinical implications. Dis. Model. Mech. 2017;10:197–214. doi: 10.1242/dmm.027441. PubMed DOI PMC

Pichler M., Stiegelbauer V., Vychytilova-Faltejskova P., Ivan C., Ling H., Winter E. Genome-Wide miRNA Analysis Identifies miR-188-3p as a Novel Prognostic Marker and Molecular Factor Involved in Colorectal Carcinogenesis. Clin. Cancer Res. 2017;23:1323–1333. doi: 10.1158/1078-0432.CCR-16-0497. PubMed DOI PMC

Dieckmann K.-P., Radtke A., Geczi L., Matthies C., Anheuser P., Eckardt U., Sommer J., Zengerling F., Trenti E., Pichler R., et al. Serum Levels of MicroRNA-371a-3p (M371 Test) as a New Biomarker of Testicular Germ Cell Tumors: Results of a Prospective Multicentric Study. J. Clin. Oncol. 2019;37:1412–1423. doi: 10.1200/JCO.18.01480. PubMed DOI PMC

Terbuch A., Adiprasito J.B., Stiegelbauer V., Seles M., Klec C., Pichler G.P., Resel M., Posch F., Lembeck A.L., Stöger H., et al. MiR-371a-3p Serum Levels Are Increased in Recurrence of Testicular Germ Cell Tumor Patients. Int. J. Mol. Sci. 2018;19:3130. doi: 10.3390/ijms19103130. PubMed DOI PMC

Troppan K., Wenzl K., Pichler M., Pursche B., Schwarzenbacher D., Feichtinger J., Thallinger G.G., Beham-Schmid C., Neumeister P., Deutsch A. miR-199a and miR-497 Are Associated with Better Overall Survival due to Increased Chemosensitivity in Diffuse Large B-Cell Lymphoma Patients. Int. J. Mol. Sci. 2015;16:18077–18095. doi: 10.3390/ijms160818077. PubMed DOI PMC

Schwarzenbacher D., Klec C., Pasculli B., Cerk S., Rinner B., Karbiener M., Ivan C., Barbano R., Ling H., Wulf-Goldenberg A., et al. MiR-1287-5p inhibits triple negative breast cancer growth by interaction with phosphoinositide 3-kinase CB, thereby sensitizing cells for PI3Kinase inhibitors. Breast Cancer Res. 2019;21:20. doi: 10.1186/s13058-019-1104-5. PubMed DOI PMC

Ye X., Wei W., Zhang Z., He C., Yang R., Zhang J., Wu Z., Huang Q., Jiang Q. Identification of microRNAs associated with glioma diagnosis and prognosis. Oncotarget. 2017;8:26394–26403. doi: 10.18632/oncotarget.14445. PubMed DOI PMC

Yan Z., Che S., Wang J., Jiao Y., Wang C., Meng Q. miR-155 contributes to the progression of glioma by enhancing Wnt/beta-catenin pathway. Tumour. Biol. 2015;36:5323–5331. doi: 10.1007/s13277-015-3193-9. PubMed DOI

Zhang R., Pang B., Xin T., Guo H., Xing Y., Xu S., Feng B., Liu B., Pang Q. Plasma miR-221/222 Family as Novel Descriptive and Prognostic Biomarkers for Glioma. Mol. Neurobiol. 2016;53:1452–1460. doi: 10.1007/s12035-014-9079-9. PubMed DOI

Koller K., Koch K., Zandl M., Stiegelbauer V., Guertl B., Pichler M., Leuschner I., Hoefler G. Nephroblastomas Show Low Expression of MicroR-204 and High Expression of its Target, the Oncogenic Transcription Factor MEIS1. Pediatr. Dev. Pathol. 2014;17:169–175. doi: 10.2350/13-01-1288-OA.1. PubMed DOI

Yonemori K., Kurahara H., Maemura K., Natsugoe S. MicroRNA in pancreatic cancer. J. Hum. Genet. 2017;62:33–40. doi: 10.1038/jhg.2016.59. PubMed DOI

Zebisch A., Hatzl S., Pichler M., Wölfler A., Sill H. Therapeutic Resistance in Acute Myeloid Leukemia: The Role of Non-Coding RNAs. Int. J. Mol. Sci. 2016;17:2080. doi: 10.3390/ijms17122080. PubMed DOI PMC

Hatzl S., Geiger O., Kuepper M.K., Caraffini V., Seime T., Furlan T., Nussbaumer E., Wieser R., Pichler M., Scheideler M., et al. Increased Expression of miR-23a Mediates a Loss of Expression in the RAF Kinase Inhibitor Protein RKIP. Cancer Res. 2016;76:3644–3654. doi: 10.1158/0008-5472.CAN-15-3049. PubMed DOI PMC

Di Leva G., Garofalo M., Croce C.M. MicroRNAs in cancer. Ann. Rev. Pathol. 2014;9:287–314. doi: 10.1146/annurev-pathol-012513-104715. PubMed DOI PMC

Van Roosbroeck K., Calin G.A. Cancer Hallmarks and MicroRNAs: The Therapeutic Connection. Adv. Cancer. Res. 2017;135:119–149. PubMed

Ma L., Bajic V.B., Zhang Z. On the classification of long non-coding RNAs. RNA Boil. 2013;10:925–933. doi: 10.4161/rna.24604. PubMed DOI PMC

Lennox K.A., Behlke M.A. Cellular localization of long non-coding RNAs affects silencing by RNAi more than by antisense oligonucleotides. Nucleic Acids Res. 2016;44:863–877. doi: 10.1093/nar/gkv1206. PubMed DOI PMC

Martianov I., Ramadass A., Barros A.S., Chow N., Akoulitchev A. Repression of the human dihydrofolate reductase gene by a non-coding interfering transcript. Nature. 2007;445:666–670. doi: 10.1038/nature05519. PubMed DOI

Wang K.C., Chang H.Y. Molecular mechanisms of long noncoding RNAs. Mol. Cell. 2011;43:904–914. doi: 10.1016/j.molcel.2011.08.018. PubMed DOI PMC

Lee J.T. Lessons from X-chromosome inactivation: Long ncRNA as guides and tethers to the epigenome. Genome Res. 2009;23:1831–1842. doi: 10.1101/gad.1811209. PubMed DOI PMC

Tsai M.-C., Manor O., Wan Y., Mosammaparast N., Wang J.K., Lan F., Shi Y., Segal E., Chang H.Y. Long noncoding RNA as modular scaffold of histone modification complexes. Science. 2010;329:689–693. doi: 10.1126/science.1192002. PubMed DOI PMC

Rigoutsos I., Kil Lee S., Nam S.Y., Anfossi S., Pasculli B., Pichler M., Jing Y., Rodriguez-Aguayo C., Telonis A.G., Rossi S., et al. N-BLR, a primate-specific non-coding transcript leads to colorectal cancer invasion and migration. Genome Boil. 2017;18:98. doi: 10.1186/s13059-017-1224-0. PubMed DOI PMC

Ohtsuka M., Ling H., Ivan C., Pichler M., Matsushita D., Goblirsch M., Stiegelbauer V., Shigeyasu K., Zhang X., Chen M., et al. H19 Noncoding RNA, an Independent Prognostic Factor, Regulates Essential Rb-E2F and CDK8-beta-Catenin Signaling in Colorectal Cancer. EBioMedicine. 2016;13:113–124. doi: 10.1016/j.ebiom.2016.10.026. PubMed DOI PMC

Storkel S., Berg E.V.D. Morphological classification of renal cancer. World J. Urol. 1995;13:153–158. doi: 10.1007/BF00184870. PubMed DOI

Hutterer G.C., Pichler M., Chromecki T.F., Strini K.A., Klatte T., Pummer K., Remzi M., Mannweiler S., Zigeuner R. Tumour-associated macrophages might represent a favourable prognostic indicator in patients with papillary renal cell carcinoma. Histopathology. 2013;63:309–315. doi: 10.1111/his.12163. PubMed DOI

Delahunt B., Eble J.N. Papillary renal cell carcinoma: A clinicopathologic and immunohistochemical study of 105 tumors. Mod. Pathol. 1997;10:537. PubMed

Cancer Genome Atlas Research Network. Linehan W.M., Spellman P.T., Ricketts C.J., Creighton C.J., Fei S.S., Davis C., Wheeler D.A., Murray B.A., Schmidt L., et al. Comprehensive Molecular Characterization of Papillary Renal-Cell Carcinoma. N. Engl. J. Med. 2016;374:135–145. PubMed PMC

Steffens S., Janssen M., Roos F.C., Becker F., Schumacher S., Seidel C., Wegener G., Thüroff J.W., Hofmann R., Stöckle M., et al. Incidence and long-term prognosis of papillary compared to clear cell renal cell carcinoma – A multicentre study. Eur. J. Cancer. 2012;48:2347–2352. doi: 10.1016/j.ejca.2012.05.002. PubMed DOI

Pignot G., Elie C., Conquy S., Vieillefond A., Flam T., Zerbib M., Debre B., Amsellem-Ouazana D. Survival Analysis of 130 Patients with Papillary Renal Cell Carcinoma: Prognostic Utility of Type 1 and Type 2 Subclassification. Urology. 2007;69:230–235. doi: 10.1016/j.urology.2006.09.052. PubMed DOI

Faragalla H., Youssef Y.M., Scorilas A., Khalil B., White N.M., Mejia-Guerrero S., Khella H., Jewett M.A., Evans A., Lichner Z., et al. The Clinical Utility of miR-21 as a Diagnostic and Prognostic Marker for Renal Cell Carcinoma. J. Mol. Diagn. 2012;14:385–392. doi: 10.1016/j.jmoldx.2012.02.003. PubMed DOI

Silva-Santos R.M., Costa-Pinheiro P., Luis A., Antunes L., Lobo F., Oliveira J., Henrique R., Jeronimo C. MicroRNA profile: A promising ancillary tool for accurate renal cell tumour diagnosis. Br. J. Cancer. 2013;109:2646–2653. doi: 10.1038/bjc.2013.552. PubMed DOI PMC

White N.M., Fatoohi E., Metias M., Jung K., Stephan C., Yousef G.M. Metastamirs: A stepping stone towards improved cancer management. Nat. Rev. Clin. Oncol. 2011;8:75–84. doi: 10.1038/nrclinonc.2010.173. PubMed DOI

Powers M.P., Alvarez K., Kim H.-J., Monzon F.A. Molecular Classification of Adult Renal Epithelial Neoplasms Using MicroRNA Expression and Virtual Karyotyping. Diagn. Mol. Pathol. 2011;20:63–70. doi: 10.1097/PDM.0b013e3181efe2a9. PubMed DOI

Di Meo A., Saleeb R., Wala S.J., Khella H.W., Ding Q., Zhai H., Krishan K., Krizova A., Gabril M., Evans A., et al. A miRNA-based classification of renal cell carcinoma subtypes by PCR and in situ hybridization. Oncotarget. 2017;9:2092–2104. PubMed PMC

Liu B., Peng X.-C., Zheng X.-L., Wang J., Qin Y.-W. MiR-126 restoration down-regulate VEGF and inhibit the growth of lung cancer cell lines in vitro and in vivo. Lung Cancer. 2009;66:169–175. doi: 10.1016/j.lungcan.2009.01.010. PubMed DOI

Sun Y., Bai Y., Zhang F., Wang Y., Guo Y., Guo L. miR-126 inhibits non-small cell lung cancer cells proliferation by targeting EGFL7. Biochem. Biophys. Res. Commun. 2010;391:1483–1489. doi: 10.1016/j.bbrc.2009.12.098. PubMed DOI

Qu Y., Wu J., Deng J.-X., Zhang Y.-P., Liang W.-Y., Jiang Z.-L., Yu Q.-H., Li J. MicroRNA-126 affects rheumatoid arthritis synovial fibroblast proliferation and apoptosis by targeting PIK3R2 and regulating PI3K-AKT signal pathway. Oncotarget. 2016;7:74217–74226. doi: 10.18632/oncotarget.12487. PubMed DOI PMC

Wach S., Nolte E., Theil A., Stöhr C., Rau T.T., Hartmann A., Ekici A., Keck B., Taubert H., Wullich B. MicroRNA profiles classify papillary renal cell carcinoma subtypes. Br. J. Cancer. 2013;109:714–722. doi: 10.1038/bjc.2013.313. PubMed DOI PMC

Bavelloni A., Ramazzotti G., Poli A., Piazzi M., Focaccia E., Blalock W., Faenza I. MiRNA-210: A Current Overview. Anticancer Res. 2017;37:6511–6521. PubMed

Chang W., Lee C.Y., Park J.-H., Park M.-S., Maeng L.-S., Yoon C.S., Lee M.Y., Hwang K.-C., Chung Y.-A. Survival of hypoxic human mesenchymal stem cells is enhanced by a positive feedback loop involving miR-210 and hypoxia-inducible factor 1. J. Veter Sci. 2013;14:69–76. doi: 10.4142/jvs.2013.14.1.69. PubMed DOI PMC

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. 2010;8:64. doi: 10.1186/1741-7015-8-64. PubMed DOI PMC

Juan D., Alexe G., Antes T., Liu H., Madabhushi A., DeLisi C., Ganesan S., Bhanot G., Liou L.S. Identification of a MicroRNA Panel for Clear-cell Kidney Cancer. Urology. 2010;75:835–841. doi: 10.1016/j.urology.2009.10.033. PubMed DOI

Wang W., Qu A., Liu W., Liu Y., Zheng G., Du L., Zhang X., Yang Y., Wang C., Chen X., et al. Circulating miR-210 as a diagnostic and prognostic biomarker for colorectal cancer. Eur. J. Cancer Care. 2017;26 doi: 10.1111/ecc.12448. PubMed DOI

Petrozza V., Pastore A.L., Palleschi G., Tito C., Porta N., Ricci S., Marigliano C., Costantini M., Simone G., Di Carlo A., et al. Secreted miR-210-3p as non-invasive biomarker in clear cell renal cell carcinoma. Oncotarget. 2017;8:69551–69558. doi: 10.18632/oncotarget.18449. PubMed DOI PMC

Furge K.A., Chen J., Koeman J., Swiatek P., Dykema K., Lucin K., Kahnoski R., Yang X.J., Teh B.T. Detection of DNA Copy Number Changes and Oncogenic Signaling Abnormalities from Gene Expression Data Reveals MYC Activation in High-Grade Papillary Renal Cell Carcinoma. Cancer Res. 2007;67:3171–3176. doi: 10.1158/0008-5472.CAN-06-4571. PubMed DOI

Bellut J., Bertz S., Nolte E., Stöhr C., Polifka I., Lieb V., Herrmann E., Jung R., Hartmann A., Wullich B., et al. Differential prognostic value of MYC immunohistochemistry in subtypes of papillary renal cell carcinoma. Sci. Rep. 2017;7:16424. doi: 10.1038/s41598-017-16144-4. PubMed DOI PMC

Peng J., Liu H., Liu C. MiR-155 Promotes Uveal Melanoma Cell Proliferation and Invasion by Regulating NDFIP1 Expression. Technol. Cancer Res. Treat. 2017;16:1160–1167. doi: 10.1177/1533034617737923. PubMed DOI PMC

Que W.-C., Qiu H.-Q., Cheng Y., Liu M.-B., Wu C.-Y., Chen Y. PTEN in kidney cancer: A review and meta-analysis. Clin. Chim. Acta. 2018;480:92–98. doi: 10.1016/j.cca.2018.01.031. PubMed DOI

Fu X., Wen H., Jing L., Yang Y., Wang W., Liang X., Nan K., Yao Y., Tian T. MicroRNA-155-5p promotes hepatocellular carcinoma progression by suppressing PTEN through the PI3K/Akt pathway. Cancer Sci. 2017;108:620–631. doi: 10.1111/cas.13177. PubMed DOI PMC

Peng Y., Dong W., Lin T.-X., Zhong G.-Z., Liao B., Wang B., Gu P., Huang L., Xie Y., Lu F.-D., et al. MicroRNA-155 promotes bladder cancer growth by repressing the tumor suppressor DMTF1. Oncotarget. 2015;6:16043–16058. doi: 10.18632/oncotarget.3755. PubMed DOI PMC

Lu L., Mao X., Shi P., He B., Xu K., Zhang S., et al. MicroRNAs in the prognosis of triple-negative breast cancer: A systematic review and meta-analysis. Medicine. 2017;96:e7085. doi: 10.1097/MD.0000000000007085. PubMed DOI PMC

Casanova-Salas I., Rubio-Briones J., Calatrava A., Mancarella C., Masiá E., Casanova J., Fernandez-Serra A., Rubio L., Ramírez-Backhaus M., Armiñán A., et al. Identification of miR-187 and miR-182 as Biomarkers of Early Diagnosis and Prognosis in Patients with Prostate Cancer Treated with Radical Prostatectomy. J. Urol. 2014;192:252–259. doi: 10.1016/j.juro.2014.01.107. PubMed DOI

Vychytilova-Faltejskova P., Radova L., Sachlova M., Kosarova Z., Slaba K., Fabian P., Grolich T., Prochazka V., Kala Z., Svoboda M., et al. Serum-based microRNA signatures in early diagnosis and prognosis prediction of colon cancer. Carcinogenesis. 2016;37:941–950. doi: 10.1093/carcin/bgw078. PubMed DOI

Shekari N., Baradaran B., Shanehbandi D., Kazemi T. Circulating MicroRNAs: Valuable Biomarkers for the Diagnosis and Prognosis of Gastric Cancer. Curr. Med. Chem. 2018;25:698–714. doi: 10.2174/0929867324666171003123425. PubMed DOI

Ge Y.Z., Xu L.W., Xu Z., Wu R., Xin H., Zhu M., Lu T.Z., Genf L.-G., Liu H., Zhou C.-C., et al. Expression Profiles and Clinical Significance of MicroRNAs in Papillary Renal Cell Carcinoma: A STROBE-Compliant Observational Study. Medicine. 2015;94:e767. doi: 10.1097/MD.0000000000000767. PubMed DOI PMC

Luo W., Wang L., Luo M.-H., Huang Y.-Z., Yang H., Zhou Y., Jia H.-T., Wang X.-X. hsa-mir-3199-2 and hsa-mir-1293 as Novel Prognostic Biomarkers of Papillary Renal Cell Carcinoma by COX Ratio Risk Regression Model Screening. J. Cell. Biochem. 2017;118:3488–3494. doi: 10.1002/jcb.26008. PubMed DOI

Huang C., Yuan N., Wu L., Wang X., Dai J., Song P., Li F., Xu C., Zhao X. An integrated analysis for long noncoding RNAs and microRNAs with the mediated competing endogenous RNA network in papillary renal cell carcinoma. OncoTargets Ther. 2017;10:4037–4050. doi: 10.2147/OTT.S141951. PubMed DOI PMC

Ge Y.-Z., Xin H., Lu T.-Z., Xu Z., Yu P., Zhao Y.-C., Li M.-H., Zhao Y., Zhong B., Xu X., et al. MicroRNA expression profiles predict clinical phenotypes and prognosis in chromophobe renal cell carcinoma. Sci. Rep. 2015;5:10328. doi: 10.1038/srep10328. PubMed DOI PMC

Feng X., Wang Z., Fillmore R., Xi Y. MiR-200, a new star miRNA in human cancer. Cancer Lett. 2014;344:166–173. doi: 10.1016/j.canlet.2013.11.004. PubMed DOI PMC

Zhang L., Liao Y., Tang L. MicroRNA-34 family: A potential tumor suppressor and therapeutic candidate in cancer. J. Exp. Clin. Cancer Res. 2019;38:53. doi: 10.1186/s13046-019-1059-5. PubMed DOI PMC

Toraih E.A., Ibrahiem A.T., Fawzy M.S., Hussein M.H., Al-Qahtani S.A.M., Shaalan A.A.M. MicroRNA-34a: A Key Regulator in the Hallmarks of Renal Cell Carcinoma. Oxidative Med. Cell. Longev. 2017;2017:1–21. doi: 10.1155/2017/3269379. PubMed DOI PMC

Yang S., Li Y., Gao J., Zhang T., Li S., Luo A., CHhen H., Ding F., Wang X., Liu Z., et al. MicroRNA-34 suppresses breast cancer invasion and metastasis by directly targeting Fra-1. Oncogene. 2013;32:4294–4303. doi: 10.1038/onc.2012.432. PubMed DOI

Hu S., Yuan Y., Song Z., Yan D., Kong X. Expression Profiles of microRNAs in Drug-Resistant Non-Small Cell Lung Cancer Cell Lines Using microRNA Sequencing. Cell. Physiol. Biochem. 2018;51:2509–2522. doi: 10.1159/000495921. PubMed DOI

Pai A., Brunson A., Brown M., Pan C.-X., Lara P.N. Evolving Epidemiologic Trends in Nonclear Cell Renal Cell Cancer: An Analysis of the California Cancer Registry. Urology. 2013;82:840–845. doi: 10.1016/j.urology.2013.07.020. PubMed DOI

Klatte T., Han K.-R., Said J.W., Böhm M., Allhoff E.P., Kabbinavar F.F., Belldegrun A.S., Pantuck A.J. Pathobiology and prognosis of chromophobe renal cell carcinoma. Urol. Oncol. Semin. Orig. Investig. 2008;26:604–609. doi: 10.1016/j.urolonc.2007.07.015. PubMed DOI

Abrahams N.A., Tamboli P. Oncocytic renal neoplasms: Diagnostic considerations. Clin. Lab. Med. 2005;25:317–339. doi: 10.1016/j.cll.2005.01.006. PubMed DOI

Petillo Kort E.J., Anema J., Petillo D., Furge K.A., Yang X.J., Teh B.T. MicroRNA profiling of human kidney cancer subtypes. Int. J. Oncol. 2009;35:109. doi: 10.3892/ijo_00000318. PubMed DOI

Youssef Y.M., White N.M., Grigull J., Krizova A., Samy C., Mejia-Guerrero S., Evans A., Yousef G.M. Accurate Molecular Classification of Kidney Cancer Subtypes Using MicroRNA Signature. Eur. Urol. 2011;59:721–730. doi: 10.1016/j.eururo.2011.01.004. PubMed DOI

Fridman E., Dotan Z., Barshack I., Ben David M., Dov A., Tabak S., Zion O., Benjamin S., Benjamin H., Kuker H., et al. Accurate Molecular Classification of Renal Tumors Using MicroRNA Expression. J. Mol. Diagn. 2010;12:687–696. doi: 10.2353/jmoldx.2010.090187. PubMed DOI PMC

Nakada C., Matsuura K., Tsukamoto Y., Tanigawa M., Yoshimoto T., Narimatsu T., Nguyen L., Hijiya N., Uchida T., Sato F., et al. Genome-wide microRNA expression profiling in renal cell carcinoma: Significant down-regulation of miR-141 and miR-200c. J. Pathol. 2008;216:418–427. doi: 10.1002/path.2437. PubMed DOI

Iida M., Hazama S., Tsunedomi R., Tanaka H., Takenouchi H., Kanekiyo S., Tokumitsu Y., Tomochika S., Tokuhisa Y., Sakamoto K., et al. Overexpression of miR-221 and miR-222 in the cancer stroma is associated with malignant potential in colorectal cancer. Oncol. Rep. 2018;40:1621–1631. doi: 10.3892/or.2018.6575. PubMed DOI

Ning T., Zhang H., Wang X., Li S., Zhang L., Deng T., Zhou L., Wang X., Liu R., Bai M., et al. miR-221 and miR-222 synergistically regulate hepatocyte growth factor activator inhibitor type 1 to promote cell proliferation and migration in gastric cancer. Tumor Boil. 2017;39 doi: 10.1177/1010428317701636. PubMed DOI

Li B., Lu Y., Wang H., Han X., Mao J., Li J., Yu L., Wang B., Fan S., Yu X., et al. miR-221/222 enhance the tumorigenicity of human breast cancer stem cells via modulation of PTEN/Akt pathway. Biomed. Pharmacother. 2016;79:93–101. doi: 10.1016/j.biopha.2016.01.045. PubMed DOI

Goto Y., Kojima S., Nishikawa R., Kurozumi A., Kato M., Enokida H., Matsushita R., Yamazaki K., Ishida Y., Nakagawa M., et al. MicroRNA expression signature of castration-resistant prostate cancer: The microRNA-221/222 cluster functions as a tumour suppressor and disease progression marker. Br. J. Cancer. 2015;113:1055–1065. doi: 10.1038/bjc.2015.300. PubMed DOI PMC

Lu G.-J., Dong Y.-Q., Zhang Q.-M., Di W.-Y., Jiao L.-Y., Gao Q.-Z., Zhang C.-G. miRNA-221 promotes proliferation, migration and invasion by targeting TIMP2 in renal cell carcinoma. Int. J. Clin. Exp. Pathol. 2015;8:5224–5229. PubMed PMC

Khella H.W.Z., Butz H., Ding Q., Rotondo F., Evans K.R., Kupchak P., Dharsee M., Latif A., Pasic M.D., Lianidou E., et al. miR-221/222 Are Involved in Response to Sunitinib Treatment in Metastatic Renal Cell Carcinoma. Mol. Ther. 2015;23:1748–1758. doi: 10.1038/mt.2015.129. PubMed DOI PMC

Xu M., Gu M., Zhang K., Zhou J., Wang Z., Da J. miR-203 inhibition of renal cancer cell proliferation, migration and invasion by targeting of FGF2. Diagn. Pathol. 2015;10:24. doi: 10.1186/s13000-015-0255-7. PubMed DOI PMC

Yoshino H., Enokida H., Itesako T., Tatarano S., Kinoshita T., Fuse M., Kojima S., Nakagawa M., Seki N. Epithelial–mesenchymal transition-related microRNA-200s regulate molecular targets and pathways in renal cell carcinoma. J. Hum. Genet. 2013;58:508–516. doi: 10.1038/jhg.2013.31. PubMed DOI

Hanahan D., Weinberg R.A. Hallmarks of Cancer: The Next Generation. Cell. 2011;144:646–674. doi: 10.1016/j.cell.2011.02.013. PubMed DOI

Samaan S., Khella H.W., Girgis A., Scorilas A., Lianidou E., Gabril M., Krylov S.N., Jewett M., Bjarnason G.A., El-Said H., et al. miR-210 Is a Prognostic Marker in Clear Cell Renal Cell Carcinoma. J. Mol. Diagn. 2015;17:136–144. doi: 10.1016/j.jmoldx.2014.10.005. PubMed DOI

Banerjee I., Yadav S.S., Tomar V., Yadav S., Talreja S. Tubulocystic Renal Cell Carcinoma: A Great Imitator. Rev. Urol. 2016;18:118–121. PubMed PMC

Amin M.B., MacLennan G.T., Gupta R., Grignon D., Paraf F., Vieillefond A., Paner G., Stovsky M., MBA F., Young A.N., et al. Tubulocystic carcinoma of the kidney: Clinicopathologic analysis of 31 cases of a distinctive rare subtype of renal cell carcinoma. Am. J. Surg. Pathol. 2009;33:384–392. doi: 10.1097/PAS.0b013e3181872d3f. PubMed DOI

Bhullar J.S., Bindroo S., Varshney N., Mittal V. Tubulocystic Renal Cell Carcinoma: A Rare Renal Tumor. J. Kidney Cancer VHL. 2014;1:56–62. doi: 10.15586/jkcvhl.2014.13. PubMed DOI PMC

Lawrie C.H., Armesto M., Fernandez-Mercado M., Arestín M., Manterola L., Goicoechea I., Larrea E., Caffarel M.M., Araujo A.M., Sole C., et al. Noncoding RNA Expression and Targeted Next-Generation Sequencing Distinguish Tubulocystic Renal Cell Carcinoma (TC-RCC) from Other Renal Neoplasms. J. Mol. Diagn. 2018;20:34–45. doi: 10.1016/j.jmoldx.2017.09.002. PubMed DOI

Slabáková E., Culig Z., Remšík J., Souček K. Alternative mechanisms of miR-34a regulation in cancer. Cell Death Dis. 2017;8:e3100. doi: 10.1038/cddis.2017.495. PubMed DOI PMC

Yamamura S., Saini S., Majid S., Hirata H., Ueno K., Chang I., Tanaka Y., Gupta A., Dahiya R. MicroRNA-34a suppresses malignant transformation by targeting c-Myc transcriptional complexes in human renal cell carcinoma. Carcinogenesis. 2012;33:294–300. doi: 10.1093/carcin/bgr286. PubMed DOI PMC

Beg M.S., Brenner A.J., Sachdev J., Borad M., Kang Y.K., Stoudemire J., Stoudemire J., Smith S., Bader A.G., Kim S., et al. Phase I study of MRX34, a liposomal miR-34a mimic, administered twice weekly in patients with advanced solid tumors. Investig. New Drugs. 2017;35:180–188. doi: 10.1007/s10637-016-0407-y. PubMed DOI PMC

Zhou H., Zheng S., Truong L.D., Ro J.Y., Ayala A.G., Shen S.S. Clear cell papillary renal cell carcinoma is the fourth most common histologic type of renal cell carcinoma in 290 consecutive nephrectomies for renal cell carcinoma. Hum. Pathol. 2014;45:59–64. doi: 10.1016/j.humpath.2013.08.004. PubMed DOI

Wang K., Zarzour J., Rais-Bahrami S., Gordetsky J. Clear Cell Papillary Renal Cell Carcinoma: New Clinical and Imaging Characteristics. Urology. 2017;103:136–141. doi: 10.1016/j.urology.2016.12.002. PubMed DOI

Lawrie C.H., Larrea E., Larrinaga G., Goicoechea I., Arestin M., Fernandez-Mercado M., Hes O., Cacers F., Manterola L., Lorpze J., et al. Targeted next-generation sequencing and non-coding RNA expression analysis of clear cell papillary renal cell carcinoma suggests distinct pathological mechanisms from other renal tumour subtypes. J. Pathol. 2014;232:32–42. doi: 10.1002/path.4296. PubMed DOI

Munari E., Marchionni L., Chitre A., Hayashi M., Martignoni G., Brunelli M., Gobbo S., Argani P., Allaf M., Hoque M.O., et al. Clear cell papillary renal cell carcinoma: Micro-RNA expression profiling and comparison with clear cell renal cell carcinoma and papillary renal cell carcinoma. Hum. Pathol. 2014;45:1130–1138. doi: 10.1016/j.humpath.2014.01.013. PubMed DOI PMC

Mongroo P.S., Rustgi A.K. The role of the miR-200 family in epithelial-mesenchymal transition. Cancer Boil. Ther. 2010;10:219–222. doi: 10.4161/cbt.10.3.12548. PubMed DOI PMC

Rohan S.M., Xiao Y., Liang Y., Dudas M.E., Al-Ahmadie H.A., Fine S.W., Gopalan A., Reuter V.E., Rosenblum M.K., Russo P., et al. Clear-cell papillary renal cell carcinoma: Molecular and immunohistochemical analysis with emphasis on the von Hippel–Lindau gene and hypoxia-inducible factor pathway-related proteins. Mod. Pathol. 2011;24:1207–1220. doi: 10.1038/modpathol.2011.80. PubMed DOI

Zhou L., Chen J., Li Z., Li X., Hu X., Huang Y., Zhao X., Liang C., Wang Y., Sun L., et al. Integrated Profiling of MicroRNAs and mRNAs: MicroRNAs Located on Xq27.3 Associate with Clear Cell Renal Cell Carcinoma. PLoS ONE. 2010;5:e15224. doi: 10.1371/journal.pone.0015224. PubMed DOI PMC

Nie W., Ni D., Ma X., Zhang Y., Gao Y., Peng C., Zhang X. [Corrigendum] miR-122 promotes proliferation and invasion of clear cell renal cell carcinoma by suppressing Forkhead box O3. Int. J. Oncol. 2019;54:1496. doi: 10.3892/ijo.2019.4694. PubMed DOI PMC

Han Z., Zhao C., Tan R., Wang Z., Qin C., Zhang J., Tao J., Cao Q., Zhou W., Xu Z., et al. MiR-122 promotes renal cancer cell proliferation by targeting Sprouty2. Tumor Boil. 2017;39 PubMed

Fan Y., Ma X., Li H., Gao Y., Huang Q., Zhang Y., Bao X., Du Q., Luo G., Liu K., et al. miR-122 promotes metastasis of clear-cell renal cell carcinoma by downregulating Dicer. Int. J. Cancer. 2018;142:547–560. doi: 10.1002/ijc.31050. PubMed DOI

Ross H., Edelman M., Argani P. Xp11 Translocation Renal Cell Carcinoma. Pathol. Case Rev. 2010;15:3–6. doi: 10.1097/PCR.0b013e3181d2cfc2. PubMed DOI

Marchionni L., Hayashi M., Guida E., Ooki A., Munari E., Jabboure F.J., Dinalankara W., Raza A., Netto G.J., Hoque M.O., et al. MicroRNA expression profiling of Xp11 renal cell carcinoma. Hum. Pathol. 2017;67:18–29. doi: 10.1016/j.humpath.2017.03.011. PubMed DOI PMC

Li S., Shuch B.M., Gerstein M.B. Whole-genome analysis of papillary kidney cancer finds significant noncoding alterations. PLoS Genet. 2017;13:1006685. doi: 10.1371/journal.pgen.1006685. PubMed DOI PMC

Klec C., Prinz F., Pichler M. Involvement of the long noncoding RNA NEAT1 in carcinogenesis. Mol. Oncol. 2019;13:46–60. doi: 10.1002/1878-0261.12404. PubMed DOI PMC

Liu F., Chen N., Gong Y., Xiao R., Wang W., Pan Z. The long non-coding RNA NEAT1 enhances epithelial-to-mesenchymal transition and chemoresistance via the miR-34a/c-Met axis in renal cell carcinoma. Oncotarget. 2017;8:62927–62938. doi: 10.18632/oncotarget.17757. PubMed DOI PMC

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. 2015;36:2947–2955. doi: 10.1007/s13277-014-2925-6. PubMed DOI

Xiao H., Tang K., Liu P., Chen K., Hu J., Zeng J., Xiao W., Yu G., Yao W., Zhou 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. 2015;6:38005–38015. doi: 10.18632/oncotarget.5357. PubMed DOI PMC

Luo Q., Cui M., Deng Q., Liu J. Comprehensive analysis of differentially expressed profiles and reconstruction of a competing endogenous RNA network in papillary renal cell carcinoma. Mol. Med. Rep. 2019;19:4685–4696. doi: 10.3892/mmr.2019.10138. PubMed DOI PMC

Gu L., Zhang J., Shi M., Zhan Q., Shen B., Peng C. lncRNA MEG3 had anti-cancer effects to suppress pancreatic cancer activity. Biomed. Pharmacother. 2017;89:1269–1276. doi: 10.1016/j.biopha.2017.02.041. PubMed DOI

Zhang C.-Y., Yu M.-S., Li X., Zhang Z., Han C.-R., Yan B. Overexpression of long non-coding RNA MEG3 suppresses breast cancer cell proliferation, invasion, and angiogenesis through AKT pathway. Tumor Boil. 2017;39 doi: 10.1177/1010428317701311. PubMed DOI

Dong Z., Zhang A., Liu S., Lu F., Guo Y., Zhang G., Xu F., Shi Y., Shen S., Liang J., et al. Aberrant Methylation-mediated Silencing of lncRNA MEG3 Functions as a ceRNA in Esophageal Cancer. Mol. Cancer Res. 2017;15:800–810. doi: 10.1158/1541-7786.MCR-16-0385. PubMed DOI

Wei G.-H., Wang X. lncRNA MEG3 inhibit proliferation and metastasis of gastric cancer via p53 signaling pathway. Eur. Rev. Med. Pharmacol. Sci. 2017;21:3850–3856. PubMed

He H., Dai J., Zhuo R., Zhao J., Wang H., Sun F., Zhu Y., Xu D. Study on the mechanism behind lncRNA MEG3 affecting clear cell renal cell carcinoma by regulating miR-7/RASL11B signaling. J. Cell. Physiol. 2018;233:9503–9515. doi: 10.1002/jcp.26849. PubMed DOI

Lan H., Zeng J., Chen G., Huang H. Survival prediction of kidney renal papillary cell carcinoma by comprehensive LncRNA characterization. Oncotarget. 2017;8:110811–110829. doi: 10.18632/oncotarget.22732. PubMed DOI PMC

Zuo S., Wang L., Wen Y., Dai G. Identification of a universal 6-lncRNA prognostic signature for three pathologic subtypes of renal cell carcinoma. J. Cell Biochem. 2018;120:7375–7385. doi: 10.1002/jcb.28012. PubMed DOI

He H.-T., Xu M., Kuang Y., Han X.-Y., Wang M.-Q., Yang Q. Biomarker and competing endogenous RNA potential of tumor-specific long noncoding RNA in chromophobe renal cell carcinoma. OncoTargets Ther. 2016;9:6399–6406. doi: 10.2147/OTT.S116392. PubMed DOI PMC

Circulating Non-coding RNAs in Renal Cell Carcinoma-Pathogenesis and Potential Implications as Clinical Biomarkers

Long Non-Coding RNA PANTR1 is Associated with Poor Prognosis and Influences Angiogenesis and Apoptosis in Clear-Cell Renal Cell Cancer