In silico Study of Clinical Prognosis Associated MicroRNAs for Patients with Metastasis in Clear Cell Renal Carcinoma
- Authors: Wijaya E.B.1, Mekala V.R.1, Zaenudin E.1, Ng K.1
-
Affiliations:
- Bioinformatics and Medical Engineering, Asia University
- Issue: Vol 19, No 2 (2024)
- Pages: 174-192
- Section: Life Sciences
- URL: https://jdigitaldiagnostics.com/1574-8936/article/view/643803
- DOI: https://doi.org/10.2174/1574893618666230905154441
- ID: 643803
Cite item
Full Text
Abstract
Background:Metastasis involves multiple stages and various genetic and epigenetic alterations. MicroRNA has been investigated as a biomarker and prognostic tool in various cancer types and stages. Nevertheless, exploring the role of miRNA in kidney cancer remains a significant challenge, given the ability of a single miRNA to target multiple genes within biological networks and pathways.
Objective:This study aims to propose a computational research framework that hypothesizes that a set of miRNAs functions as key regulators in modulating gene expression networks of kidney cancer survival.
Methods:We retrieved the NGS data from the TCGA-KIRC extracted from UCSC Xena. A set of prognostic miRNAs was acquired through multiple Cox regression analyses. We adopted machine learning approaches to evaluate miRNA prognosis's classification performance between normal, primary (M0), and metastasis (M1) samples. The molecular mechanism between primary cancer and metastasis was investigated by identifying the regulatory networks of miRNA's target genes.
Results:A total of 14 miRNAs were identified as potential prognostic indicators. A combination of high-expression miRNAs was associated with survival probability. Machine learning achieved an average accuracy of 95% in distinguishing primary cancer from normal tissue and 79% in predicting the metastasis from primary tissue. Correlation analysis of miRNA prognostics with target genes unveiled regulatory network disparities between metastatic and primary tissues.
Conclusion:This study has identified 14 miRNAs that could potentially serve as vital biomarkers for diagnosing and prognosing ccRCC. Differential regulatory networks between metastatic and primary tissues in this study provide the molecular basis for assessment and therapeutic treatment for ccRCC patients.
About the authors
Ezra B. Wijaya
Bioinformatics and Medical Engineering, Asia University
Email: info@benthamscience.net
Venugopala Reddy Mekala
Bioinformatics and Medical Engineering, Asia University
Email: info@benthamscience.net
Efendi Zaenudin
Bioinformatics and Medical Engineering, Asia University
Email: info@benthamscience.net
Ka-Lok Ng
Bioinformatics and Medical Engineering, Asia University
Author for correspondence.
Email: info@benthamscience.net
References
- Welch DR, Hurst DR. Defining the Hallmarks of Metastasis. Cancer Res 2019; 79(12): 3011-27. doi: 10.1158/0008-5472.CAN-19-0458 PMID: 31053634
- Fares J, Fares MY, Khachfe HH, Salhab HA, Fares Y. Molecular principles of metastasis: A hallmark of cancer revisited. Signal Transduct Target Ther 2020; 5(1): 28. doi: 10.1038/s41392-020-0134-x PMID: 32296047
- Nwabo KAH, Takam KP, Tagne SR, et al. Developmental pathways associated with cancer metastasis: Notch, Wnt, and Hedgehog. Cancer Biol Med 2017; 14(2): 109-20. doi: 10.20892/j.issn.2095-3941.2016.0032 PMID: 28607802
- Ljungberg B, Albiges L, Abu-Ghanem Y, et al. European association of urology guidelines on renal cell carcinoma: The 2019 update. Eur Urol 2019; 75(5): 799-810. doi: 10.1016/j.eururo.2019.02.011 PMID: 30803729
- Capitanio U, Bensalah K, Bex A, et al. Epidemiology of renal cell carcinoma. Eur Urol 2019; 75(1): 74-84. doi: 10.1016/j.eururo.2018.08.036 PMID: 30243799
- Janzen NK, Kim HL, Figlin RA, Belldegrun AS. Surveillance after radical or partial nephrectomy for localized renal cell carcinoma and management of recurrent disease. Urol Clin North Am 2003; 30(4): 843-52. doi: 10.1016/S0094-0143(03)00056-9 PMID: 14680319
- Survival Rates for Kidney Cancer. 2023. Available from: https://www.cancer.org/cancer/kidney-cancer/detection-diagnosis-staging/survival-rates.html
- Zhang L, Lu Q, Chang C. Epigenetics in health and disease. Adv Exp Med Biol 2020; 1253: 3-55. doi: 10.1007/978-981-15-3449-2_1
- Takeshima H, Ushijima T. Accumulation of genetic and epigenetic alterations in normal cells and cancer risk. NPJ Precis Oncol 2019; 3(1): 7. doi: 10.1038/s41698-019-0079-0 PMID: 30854468
- Jeffrey SS. Cancer biomarker profiling with microRNAs. Nat Biotechnol 2008; 26(4): 400-1. doi: 10.1038/nbt0408-400 PMID: 18392022
- Galvão-Lima LJ, Morais AHF, Valentim RAM, Barreto EJSS. miRNAs as biomarkers for early cancer detection and their application in the development of new diagnostic tools. Biomed Eng Online 2021; 20(1): 21. doi: 10.1186/s12938-021-00857-9 PMID: 33593374
- Condrat CE, Thompson DC, Barbu MG, et al. miRNAs as biomarkers in disease: Latest findings regarding their role in diagnosis and prognosis. Cells 2020; 9(2): 276. doi: 10.3390/cells9020276 PMID: 31979244
- Zhang S, Cheng Z, Wang Y, Han T. The risks of miRNA therapeutics: In a drug target perspective. Drug Des Devel Ther 2021; 15: 721-33. doi: 10.2147/DDDT.S288859 PMID: 33654378
- Tehrani SS, Zaboli E, Sadeghi F, et al. MicroRNA-26a-5p as a potential predictive factor for determining the effectiveness of trastuzumab therapy in HER-2 positive breast cancer patients. Biomedicine 2021; 11(2): 30-9. PMID: 35223402
- Chang LC, Yu YL. Dietary components as epigenetic-regulating agents against cancer. Biomedicine 2016; 6(1): 2. doi: 10.7603/s40681-016-0002-8 PMID: 26872811
- Lopez-Camarillo C, Marchat LA, Arechaga-Ocampo E, et al. MetastamiRs: Non-coding MicroRNAs driving cancer invasion and metasta-sis. Int J Mol Sci 2012; 13(2): 1347-79. doi: 10.3390/ijms13021347 PMID: 22408395
- Khatri NI, Rathi MN, Baradia DP, Trehan S, Misra A. In vivo delivery aspects of miRNA, shRNA and siRNA. Crit Rev Ther Drug Carrier Syst 2012; 29(6): 487-527. doi: 10.1615/CritRevTherDrugCarrierSyst.v29.i6.20 PMID: 23176057
- Grzywa TM, Klicka K, Rak B, et al. Lineage-dependent role of miR-410-3p as oncomiR in gonadotroph and corticotroph pituitary adeno-mas or tumor suppressor miR in somatotroph adenomas via MAPK, PTEN/AKT, and STAT3 signaling pathways. Endocrine 2019; 65(3): 646-55. doi: 10.1007/s12020-019-01960-7 PMID: 31165412
- Youssef RF, Cost NG, Darwish OM, Margulis V. Prognostic markers in renal cell carcinoma: A focus on the mammalian target of ra-pamycin pathway. Arab J Urol 2012; 10(2): 110-7. doi: 10.1016/j.aju.2012.02.005 PMID: 26558012
- Pajak M, Simpson TI. miRNA tap: miRNA tap: microRNA Targets - Aggregated Predictions. In: R package version. 2023.
- Ulgen E, Ozisik O, Sezerman OU. pathfindR: An R package for comprehensive identification of enriched pathways in omics data through active subnetworks. Front Genet 2019; 10: 858. doi: 10.3389/fgene.2019.00858 PMID: 31608109
- Luo W, Brouwer C. Pathview: An R/Bioconductor package for pathway-based data integration and visualization. Bioinformatics 2013; 29(14): 1830-1. doi: 10.1093/bioinformatics/btt285 PMID: 23740750
- Fan B, Jin Y, Zhang H, et al. MicroRNA 21 contributes to renal cell carcinoma cell invasiveness and angiogenesis via the PDCD4/c Jun (AP 1) signalling pathway. Int J Oncol 2020; 56(1): 178-92. PMID: 31789394
- Lv L, Huang F, Mao H, et al. MicroRNA-21 is overexpressed in renal cell carcinoma. Int J Biol Markers 2013; 28(2): 201-7. doi: 10.5301/JBM.2013.10831 PMID: 23558936
- Dey N, Das F, Ghosh-Choudhury N, et al. microRNA-21 governs TORC1 activation in renal cancer cell proliferation and invasion. PLoS One 2012; 7(6): e37366. doi: 10.1371/journal.pone.0037366 PMID: 22685542
- Meng K, Li Z, Cui X. Three LHPP gene‐targeting co‐expressed microRNAs (microRNA‐765, microRNA‐21, and microRNA‐144) promote proliferation, epithelial‐mesenchymal transition, invasion, and are independent prognostic biomarkers in renal cell carcinomas patients. J Clin Lab Anal 2021; 35(12): e24077. doi: 10.1002/jcla.24077 PMID: 34699621
- Chen J, Gu Y, Shen W. MicroRNA-21 functions as an oncogene and promotes cell proliferation and invasion via TIMP3 in renal cancer. Eur Rev Med Pharmacol Sci 2017; 21(20): 4566-76. PMID: 29131259
- Bera A, Das F, Ghosh-Choudhury N, Kasinath BS, Abboud HE, Choudhury GG. microRNA-21-induced dissociation of PDCD4 from rictor contributes to Akt-IKKβ-mTORC1 axis to regulate renal cancer cell invasion. Exp Cell Res 2014; 328(1): 99-117. doi: 10.1016/j.yexcr.2014.06.022 PMID: 25016284
- Cao J, Liu J, Xu R, Zhu X, Liu L, Zhao X. MicroRNA-21 stimulates epithelial-to-mesenchymal transition and tumorigenesis in clear cell renal cells. Mol Med Rep 2016; 13(1): 75-82. doi: 10.3892/mmr.2015.4568 PMID: 26572589
- Okato A, Arai T, Yamada Y, et al. Dual strands of pre-miR-149 inhibit cancer cell migration and invasion through targeting FOXM1 in renal cell carcinoma. Int J Mol Sci 2017; 18(9): 1969. doi: 10.3390/ijms18091969 PMID: 28902136
- Liu Z, Zhang J, Hu X, Ge Q, Xiao J, Novalinda Ginting C. Expression of miR-410 in peripheral blood of patients with clear cell renal cell carcinoma and its effect on proliferation and invasion of Caki-2 cells. J BUON 2021; 26(5): 2059-66. PMID: 34761617
- Niu S, Ma X, Zhang Y, et al. Expression of miR-223 in clear cell renal cell carcinoma and its significance. Nan Fang Yi Ke Da Xue Xue Bao 2015; 35(3): 338-42. PMID: 25818776
- Dong X, Kong C, Liu X, et al. GAS5 functions as a ceRNA to regulate hZIP1 expression by sponging miR-223 in clear cell renal cell car-cinoma. Am J Cancer Res 2018; 8(8): 1414-26. PMID: 30210913
- Zhang RL, Aimudula A, Dai JH, Bao YX. RASA1 inhibits the progression of renal cell carcinoma by decreasing the expression of miR-223-3p and promoting the expression of FBXW7. Biosci Rep 2020; 40(7): BSR20194143. doi: 10.1042/BSR20194143 PMID: 32588875
- Li Y, Guan B, Liu J, et al. MicroRNA-200b is downregulated and suppresses metastasis by targeting LAMA4 in renal cell carcinoma. EBioMedicine 2019; 44: 439-51. doi: 10.1016/j.ebiom.2019.05.041 PMID: 31130475
- Liu P, Chen S, Huang Y, et al. LINC00667 promotes Wilms tumor metastasis and stemness by sponging miR‐200b/c/429 family to regulate IKK‐β. Cell Biol Int 2020; 44(6): 1382-93. doi: 10.1002/cbin.11334 PMID: 32129525
- Oliveira RC, Ivanovic RF, Leite KRM, et al. Expression of micro-RNAs and genes related to angiogenesis in ccRCC and associations with tumor characteristics. BMC Urol 2017; 17(1): 113. doi: 10.1186/s12894-017-0306-3 PMID: 29202733
- Saleeb R, Kim SS, Ding Q, et al. The miR-200 family as prognostic markers in clear cell renal cell carcinoma. Urol Oncol 2019; 37(12): 955-63. doi: 10.1016/j.urolonc.2019.08.008 PMID: 31635993
- Yu Y, Bai F, Qin N, et al. Non-proximal renal tubule-derived urinary exosomal mir-200b as a biomarker of renal fibrosis. Nephron J 2018; 139(3): 269-82. doi: 10.1159/000487104 PMID: 29539618
- Yoshino H, Enokida H, Itesako T, et al. Epithelialmesenchymal transition-related microRNA-200s regulate molecular targets and path-ways in renal cell carcinoma. J Hum Genet 2013; 58(8): 508-16. doi: 10.1038/jhg.2013.31 PMID: 23635949
- Wang C, Uemura M, Tomiyama E, et al. MicroRNA‐92b‐3p is a prognostic oncomiR that targets TSC1 in clear cell renal cell carcinoma. Cancer Sci 2020; 111(4): 1146-55. doi: 10.1111/cas.14325 PMID: 31975504
- He C, Chen ZY, Li Y, et al. miR-10b suppresses cell invasion and metastasis through targeting HOXA3 regulated by FAK/YAP signaling pathway in clear-cell renal cell carcinoma. BMC Nephrol 2019; 20(1): 127. doi: 10.1186/s12882-019-1322-1 PMID: 30975094
- White NMA, Khella HWZ, Grigull J, et al. miRNA profiling in metastatic renal cell carcinoma reveals a tumour-suppressor effect for miR-215. Br J Cancer 2011; 105(11): 1741-9. doi: 10.1038/bjc.2011.401 PMID: 22033272
- Li Y, Chen D, 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 2016; 35(4): 1967-78. doi: 10.3892/or.2016.4579 PMID: 26796749
- Lin T, Yang Y, Ye X, Yao J, Zhou H. Low expression of miR-99b promotes progression of clear cell renal cell carcinoma by up-regulating IGF1R/Akt/mTOR signaling. Int J Clin Exp Pathol 2020; 13(12): 3083-91. PMID: 33425108
- Lukamowicz-Rajska M, Mittmann C, Prummer M, et al. MiR-99b-5p expression and response to tyrosine kinase inhibitor treatment in clear cell renal cell carcinoma patients. Oncotarget 2016; 7(48): 78433-47. doi: 10.18632/oncotarget.12618 PMID: 27738339
- 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 2015; 34(2): 739-46. doi: 10.3892/or.2015.4041 PMID: 26058752
- Niu S, Ma X, Zhang Y, et al. MicroRNA-19a and microRNA-19b promote the malignancy of clear cell renal cell carcinoma through target-ing the tumor suppressor RhoB. PLoS One 2018; 13(2): e0192790. doi: 10.1371/journal.pone.0192790 PMID: 29474434
- Ma Q, Peng Z, Wang L, et al. miR-19a correlates with poor prognosis of clear cell renal cell carcinoma patients via promoting cell prolifer-ation and suppressing PTEN/SMAD4 expression. Int J Oncol 2016; 49(6): 2589-99. doi: 10.3892/ijo.2016.3746 PMID: 27779660
- Dong Y, Gao Y, Xie T, Liu H, Zhan X, Xu Y. miR-101-3p serves as a tumor suppressor for renal cell carcinoma and inhibits its invasion and metastasis by targeting EZH2. BioMed Res Int 2021; 2021: 1-12. doi: 10.1155/2021/9950749 PMID: 34307682
- Li LY. EZH2: Novel therapeutic target for human cancer. Biomedicine 2014; 4(1): 1. doi: 10.7603/s40681-014-0001-6 PMID: 25520914
- Yamada Y, Nohata N, Uchida A, et al. Replisome genes regulation by antitumor miR‐101‐5p in clear cell renal cell carcinoma. Cancer Sci 2020; 111(4): 1392-406. doi: 10.1111/cas.14327 PMID: 31975570
- Welch DR. Preface. Cancer Metastasis Rev 2012; 31(3-4): 417-8. doi: 10.1007/s10555-012-9386-4 PMID: 22695772
- Grzywa TM, Klicka K, Włodarski PK. Regulators at every stephow micrornas drive tumor cell invasiveness and metastasis. Cancers 2020; 12(12): 3709. doi: 10.3390/cancers12123709 PMID: 33321819
- Chiang AC, Massagué J. Molecular basis of metastasis. N Engl J Med 2008; 359(26): 2814-23. doi: 10.1056/NEJMra0805239 PMID: 19109576
- Dessie EY, Tsai JJP, Chang JG, Ng KL. A novel miRNA-based classification model of risks and stages for clear cell renal cell carcinoma patients. BMC Bioinformatics 2021; 22(S10): 270. doi: 10.1186/s12859-021-04189-2 PMID: 34058987
- Zhan Y, Zhang R, Li C, et al. A microRNA‐clinical prognosis model to predict the overall survival for kidney renal clear cell carcinoma. Cancer Med 2021; 10(17): 6128-39. doi: 10.1002/cam4.4148 PMID: 34288551
- Yang T, Miao X, Bai Z, et al. A novel mRNA-miRNA regulatory sub-network associated with prognosis of metastatic clear cell renal cell carcinoma. Front Oncol 2021; 10: 593601. doi: 10.3389/fonc.2020.593601 PMID: 33542901
- Zhao E, Li X, You B, Wang J, Hou W, Wu Q. Identification of a Five-miRNA signature for diagnosis of kidney renal clear cell carcinoma. Front Genet 2022; 13: 857411. doi: 10.3389/fgene.2022.857411 PMID: 35528546
- Zhang Z, Xing T, Chen Y, Xiao J. Exosome-mediated miR-200b promotes colorectal cancer proliferation upon TGF-β1 exposure. Biomed Pharmacother 2018; 106: 1135-43. doi: 10.1016/j.biopha.2018.07.042 PMID: 30119180
- Fang W, Song L, Li Z, Meng P, Zuo S, Liu S. Effect of miRNA-200b on the proliferation of liver cancer cells via targeting SMYD2/p53 signaling pathway. Zhong Nan Da Xue Xue Bao Yi Xue Ban 2022; 47(10): 1303-14. PMID: 36411681
- Tang O, Chen XM, Shen S, Hahn M, Pollock CA. MiRNA-200b represses transforming growth factor-β1-induced EMT and fibronectin expression in kidney proximal tubular cells. Am J Physiol Renal Physiol 2013; 304(10): F1266-73. doi: 10.1152/ajprenal.00302.2012 PMID: 23408168
- Xie M, Lv Y, Liu Z, et al. Identification and validation of a four-miRNA(miRNA-21-5p, miRNA-9-5p, miR-149-5p, and miRNA-30b-5p) prognosis signature in clear cell renal cell carcinoma. Cancer Manag Res 2018; 10: 5759-66. doi: 10.2147/CMAR.S187109 PMID: 30532596
- Yu L, Xiang L, Feng J, et al. miRNA-21 and miRNA-223 expression signature as a predictor for lymph node metastasis, distant metastasis and survival in kidney renal clear cell carcinoma. J Cancer 2018; 9(20): 3651-9. doi: 10.7150/jca.27117 PMID: 30405833
- Guo Y, Li X, Zheng J, Fang J, Pan G, Chen Z. Identification of a novel immune-related microRNA prognostic model in clear cell renal cell carcinoma. Transl Androl Urol 2021; 10(2): 888-99. doi: 10.21037/tau-20-1495 PMID: 33718090
- Khella HWZ, Daniel N, Youssef L, et al. miR-10b is a prognostic marker in clear cell renal cell carcinoma. J Clin Pathol 2017; 70(10): 854-9. doi: 10.1136/jclinpath-2017-204341 PMID: 28360191
- Qin J, Zhou J, Teng L, Han Y. MicroRNA-10b promotes apoptosis via JNK pathway in clear cell renal cell carcinoma. Nephron J 2018; 139(2): 172-80. doi: 10.1159/000486017 PMID: 29672315
- Fritz HKM, Lindgren D, Ljungberg B, Axelson H, Dahlbäck B. The miR21/10b ratio as a prognostic marker in clear cell renal cell carcinoma. Eur J Cancer 2014; 50(10): 1758-65. doi: 10.1016/j.ejca.2014.03.281 PMID: 24793999
- Zaidi NE, Shazali NAH, Leow TC, Osman MA, Ibrahim K, Rahman NMANA. Crosstalk between fatty acid metabolism and tumour-associated macrophages in cancer progression. Biomedicine 2022; 12(4): 9-19. doi: 10.37796/2211-8039.1381 PMID: 36816174
- Fingleton B. Matrix metalloproteinases: Roles in cancer and metastasis. Front Biosci 2006; 11(1): 479-91. doi: 10.2741/1811 PMID: 16146745
- Allavena P, Sica A, Garlanda C, Mantovani A. The Yin-Yang of tumor-associated macrophages in neoplastic progression and immune surveillance. Immunol Rev 2008; 222(1): 155-61. doi: 10.1111/j.1600-065X.2008.00607.x PMID: 18364000
- Flavahan WA, Gaskell E, Bernstein BE. Epigenetic plasticity and the hallmarks of cancer. Science 2017; 357(6348): eaal2380. doi: 10.1126/science.aal2380 PMID: 28729483
- Khan I, Steeg PS. Metastasis suppressors: Functional pathways. Lab Invest 2018; 98(2): 198-210. doi: 10.1038/labinvest.2017.104 PMID: 28967874
- Xu P, Wu Q, Yu J, et al. A systematic way to infer the regulation relations of mirnas on target genes and critical mirnas in cancers. Front Genet 2020; 11: 278. doi: 10.3389/fgene.2020.00278 PMID: 32296462
- Deshmukh AP, Vasaikar SV, Tomczak K, et al. Identification of EMT signaling cross-talk and gene regulatory networks by single-cell RNA sequencing. Proc Natl Acad Sci 2021; 118(19): e2102050118. doi: 10.1073/pnas.2102050118 PMID: 33941680
- Chen HF, Wu KJ. Epigenetics, TET proteins, and hypoxia in epithelial-mesenchymal transition and tumorigenesis. Biomedicine 2016; 6(1): 1. doi: 10.7603/s40681-016-0001-9 PMID: 26869355
- Patel SA, Rodrigues P, Wesolowski L, Vanharanta S. Genomic control of metastasis. Br J Cancer 2021; 124(1): 3-12. doi: 10.1038/s41416-020-01127-6 PMID: 33144692
- Parolia A, Cieslik M, Chu SC, et al. Distinct structural classes of activating FOXA1 alterations in advanced prostate cancer. Nature 2019; 571(7765): 413-8. doi: 10.1038/s41586-019-1347-4 PMID: 31243372
- Babaei K, Khaksar R, Zeinali T, et al. Epigenetic profiling of MUTYH, KLF6, WNT1 and KLF4 genes in carcinogenesis and tumorigenesis of colorectal cancer. Biomedicine 2019; 9(4): 22. doi: 10.1051/bmdcn/2019090422 PMID: 31724937
- Heinzelmann J, Arndt M, Pleyers R, et al. 4-miRNA score predicts the individual metastatic risk of renal cell carcinoma patients. Ann Surg Oncol 2019; 26(11): 3765-73. doi: 10.1245/s10434-019-07578-3 PMID: 31270716
- Adjei AA. Blocking oncogenic Ras signaling for cancer therapy. J Natl Cancer Inst 2001; 93(14): 1062-74. doi: 10.1093/jnci/93.14.1062 PMID: 11459867
- Peng XS, Yang JP, Qiang YY, et al. PTPN3 inhibits the growth and metastasis of clear cell renal cell carcinoma via inhibition of PI3K/AKT signaling. Mol Cancer Res 2020; 18(6): 903-12. doi: 10.1158/1541-7786.MCR-19-1142 PMID: 32169891
Supplementary files
