Renal cell carcinoma (RCC) is one of the most frequently occurring tumors worldwide. Herein, we established a microRNA (miRNA) predicting signature to assess the prognosis of papillary-type RCC (PRCC) patients. miR-1293, miR-34a, miR-551b, miR-937, miR-299, and miR-3199-2 were used in building the overall survival (OS)-related signature, whereas miR-7156, miR-211, and miR-301b were used to construct the formula of recurrence-free survival (RFS) with the help of LASSO Cox regression analysis. The Kaplan–Meier and receiver operating characteristic curves indicated good discrimination and efficiency of the two signatures. Functional annotation for the downstream genes of the OS/RFS-related miRNAs exposed the potential mechanisms of PRCC. Notably, the multivariate analyses suggested that the two signatures were independent risk factors for PRCC patients and had better prognostic capacity than any other classifier. In addition, the nomogram indicated synthesis effects and showed better predictive performance than clinicopathologic features and our signatures. We validated the OS and RFS prediction formulas in clinical samples and met our expectations. Finally, we established two novel miRNA-based OS and RFS predicting signatures for PRCC, which are reliable tools for assessing the prognosis of PRCC patients.
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References
1.
AgarwalV., BellG.W., NamJ.W., and BartelD.P. (2015). Predicting effective microRNA target sites in mammalian mRNAs. eLife 4,e05005.
2.
BaltimoreD., BoldinM.P., O'ConnellR.M., RaoD.S., and TaganovK.D. (2008). MicroRNAs: new regulators of immune cell development and function. Nat Immunol, 9, 839–845.
3.
BetelD., KoppalA., AgiusP., SanderC., and LeslieC. (2010). Comprehensive modeling of microRNA targets predicts functional non-conserved and non-canonical sites. Genome Biol 11,R90.
4.
BreenD.J., KingA.J., PatelN., LockyerR., and HayesM. (2018). Image-guided cryoablation for sporadic renal cell carcinoma: three- and 5-year outcomes in 220 patients with biopsy-proven renal cell carcinoma. Radiology, 289, 554–561.
5.
DieckmannK.P., RadtkeA., GecziL., MatthiesC, AnheuserP, EckardtU, et al. (2019). 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, 37, 1412–1423.
6.
DyG.W., GoreJ.L., ForouzanfarM.H., NaghaviM., and FitzmauriceC. (2017). Global burden of urologic cancers, 1990–2013. Eur Urol, 71, 437–446.
7.
EllingerJ., HollD., NuhnP., KahlP., HasekeN., StaehlerM., et al. (2011). DNA hypermethylation in papillary renal cell carcinoma. BJU Int, 107, 664–669.
8.
FaragallaH., YoussefY.M., ScorilasA., KhalilB., WhiteN.M., Mejia-GuerreroS., et al. (2012). The clinical utility of miR-21 as a diagnostic and prognostic marker for renal cell carcinoma. J Mol Diagn, 14, 385–392.
9.
FicarraV., BrunelliM., ChengL., KirkaliZ., Lopez-BeltranA., MartignoniG., et al. (2010). Prognostic and therapeutic impact of the histopathologic definition of parenchymal epithelial renal tumors. Eur Urol, 58, 655–668.
10.
GoldmanM.J., CraftB., HastieM., RepečkaK., McDadeF., KamathA., et al. (2020). Visualizing and interpreting cancer genomics data via the Xena platform. Nat Biotechnol, 38, 675–678.
11.
GrabowskaB., UlvskogE., CarlssonJ., FiorentinoM., GiunchiF., LindbladP., et al. (2018). Clinical outcome and time trends of surgically treated renal cell carcinoma between 1986 and 2010: results from a single centre in Sweden. Scand J Urol, 52, 206–212.
12.
GuoQ., ZhangC., GuoX., TaoF., XuY., FengG., et al. (2018). Incidence of bone metastasis and factors contributing to its development and prognosis in newly diagnosed renal cell carcinoma: a population-based study. Cancer Manag Res, 10, 2935–2944.
13.
HeK., LiW.X., GuanD., GongM., YeS., FangZ., et al. (2019). Regulatory network reconstruction of five essential microRNAs for survival analysis in breast cancer by integrating miRNA and mRNA expression datasets. Funct Integr Genomics, 19, 645–658.
14.
HuangJ., YaoX., ZhangJ., DongB., ChenQ., XueW., et al. (2013). Hypoxia-induced downregulation of miR-30c promotes epithelial-mesenchymal transition in human renal cell carcinoma. Cancer Sci, 104, 1609–1617.
15.
JiangL., and HermekingH. (2017). miR-34a and miR-34b/c Suppress Intestinal Tumorigenesis. Cancer Res, 77, 2746–2758.
16.
JonaschE., GaoJ., and RathmellW.K. (2014). Renal cell carcinoma. BMJ (Clin Res Ed) 349,g4797.
17.
KarrichJ.J., JachimowskiL.C., LiboubanM., IyerA., BrandwijkK., Taanman-KueterE.W., et al. (2013). MicroRNA-146a regulates survival and maturation of human plasmacytoid dendritic cells. Blood, 122, 3001–3009.
18.
KimM., SohnM., ShimM., ChoiS.K., ParkM., KimE., et al. (2017). Prognostic value of vascular endothelial growth factor (VEGF), VEGF receptor 2, platelet-derived growth factor-β (PDGF-β), and PDGF-β receptor expression in papillary renal cell carcinoma. Hum Pathol, 61, 78–89.
19.
KovacsG., AkhtarM., BeckwithB.J., BugertP., CooperC.S., DelahuntB., et al. (1997). The Heidelberg classification of renal cell tumours. J Pathol, 183, 131–133.
20.
LiuB., ShyrY., CaiJ., and LiuQ. (2018). Interplay between miRNAs and host genes and their role in cancer. Brief Funct Genomics, 18, 255–266.
21.
LiuK., RenY., PangL., QiY., JiaW., TaoL., et al. (2015). Papillary renal cell carcinoma: a clinicopathological and whole-genome exon sequencing study. Int J Clin Exp Pathol, 8, 8311–8335.
22.
LiuW., and WangX. (2019). Prediction of functional microRNA targets by integrative modeling of microRNA binding and target expression data. Genome Biol 20,18.
23.
LiuX.L., PanW.G., LiK.L., MaoY.J., LiuS.D., and ZhangR.M. (2020). miR-1293 suppresses tumor malignancy by targeting hydrocyanic oxidase 2: therapeutic potential of a miR-1293/hydrocyanic oxidase 2 axis in renal cell carcinoma. Cancer Biother Radiopharm, 35, 377–386.
24.
LovatF., ValeriN., and CroceC.M. (2011). MicroRNAs in the pathogenesis of cancer. Semin Oncol, 38, 724–733.
25.
LuoW., WangL., LuoM.H., HuangY.Z., YangH., ZhouY., et al. (2017). 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, 118, 3488–3494.
26.
MateiD.V., RoccoB., VarelaR., VerweijF., ScardinoE., RenneG., et al. (2005). Synchronous collecting duct carcinoma and papillary renal cell carcinoma: a case report and review of the literature. Anticancer Res, 25, 579–586.
27.
MontironiR., ChengL., ScarpelliM., and Lopez-BeltranA. (2016). Pathology and genetics: tumours of the Urinary System and Male Genital System: clinical implications of the 4th Edition of the WHO Classification and Beyond. Eur Urol, 70, 120–123.
28.
MoyaL., MeijerJ., SchubertS., MatinF., and BatraJ. (2019). Assessment of miR-98-5p, miR-152-3p, miR-326 and miR-4289 expression as biomarker for prostate cancer diagnosis. Int J Mol Sci 20,1154.
29.
NassarF.J., NasrR., and TalhoukR. (2017). MicroRNAs as biomarkers for early breast cancer diagnosis, prognosis and therapy prediction. Pharmacol Therap, 172, 34–49.
30.
PalS.K., AliS.M., YakirevichE., GeynismanD.M., KaramJ.A., ElvinJ.A., et al. (2018). Characterization of clinical cases of advanced papillary renal cell carcinoma via comprehensive genomic profiling. Eur Urol, 73, 71–78.
31.
PatardJ.J., LerayE., Rioux-LeclercqN., CindoloL., FicarraV., ZismanA., et al. (2005). Prognostic value of histologic subtypes in renal cell carcinoma: a multicenter experience. J Clin Oncol, 23, 2763–2771.
32.
SaliminejadK., Khorram KhorshidH.R., Soleymani FardS., and GhaffariS.H. (2019). An overview of microRNAs: biology, functions, therapeutics, and analysis methods. J Cell Physiol, 234, 5451–5465.
33.
SchullerA.G., BarryE.R., JonesR.D., HenryR.E., FrigaultM.M., BeranG., et al. (2015). The MET Inhibitor AZD6094 (Savolitinib, HMPL-504) induces regression in papillary renal cell carcinoma patient-derived xenograft models. Clin Cancer Res, 21, 2811–2819.
34.
SongG., ZhangH., ChenC., GongL., ChenB., ZhaoS., et al. (2017). miR-551b regulates epithelial-mesenchymal transition and metastasis of gastric cancer by inhibiting ERBB4 expression. Oncotarget, 8, 45725–45735.
35.
SunH.Y., QuZ.C., LiuD.M., ZhangW., LiuG., and ZhuL. (2019). Decreased expression of miR-551b predicts poor prognosis and promotes tumorigenesis by targeting PTP4A3 in human colorectal cancer. Eur Rev Med Pharm Sci, 23, 5741–5751.
36.
XiaoW., WangX., WangT., and XingJ. (2019). MiR-223-3p promotes cell proliferation and metastasis by downregulating SLC4A4 in clear cell renal cell carcinoma. Aging, 11, 615–633.
37.
XuR.H., WeiW., KrawczykM., WangW., LuoH., FlaggK., et al. (2017). Circulating tumour DNA methylation markers for diagnosis and prognosis of hepatocellular carcinoma. Nat Mat, 16, 1155–1161.
38.
XuX., WuJ., LiS., HuZ., XuX., ZhuY., et al. (2014). Downregulation of microRNA-182-5p contributes to renal cell carcinoma proliferation via activating the AKT/FOXO3a signaling pathway. Mol Cancer 13,109.
39.
YoussefY.M., WhiteN.M., GrigullJ., KrizovaA., SamyC., Mejia-GuerreroS., et al. (2011). Accurate molecular classification of kidney cancer subtypes using microRNA signature. Eur Urol, 59, 721–730.
40.
ZhuJ., ZhuD.Q., ZhangY., LiuQ.M., WangP.C., LiH.Z., et al. (2019). MicroRNA-363 inhibits angiogenesis, proliferation, invasion, and migration of renal cell carcinoma via inactivation of the Janus tyrosine kinases 2-signal transducers and activators of transcription 3 axis by suppressing growth hormone receptor gene. J Cell Physiol, 234, 2581–2592.
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