Integrative analysis of dysregulated microRNAs and mRNAs in multiple recurrent synchronized renal tumors from patients with von Hippel-Lindau disease

Gattolliat,Charles-Henry; Couvé,Sophie; Meurice,Guillaume; Oréar,Cédric; Droin,Nathalie; Chiquet,Mathieu; Ferlicot,Sophie; Verkarre,Virginie; Vasiliu,Viorel; Molinié,Vincent; Méjean,Arnaud; Dessen,Philippe; Giraud,Sophie; Bressac-De-Paillerets,Brigitte; Gardie,Betty; Tean Teh,Bin; Richard,Stéphane; Gad,Sophie

doi:10.3892/ijo.2018.4490

Integrative analysis of dysregulated microRNAs and mRNAs in multiple recurrent synchronized renal tumors from patients with von Hippel-Lindau disease

Authors:
- Charles-Henry Gattolliat
- Sophie Couvé
- Guillaume Meurice
- Cédric Oréar
- Nathalie Droin
- Mathieu Chiquet
- Sophie Ferlicot
- Virginie Verkarre
- Viorel Vasiliu
- Vincent Molinié
- Arnaud Méjean
- Philippe Dessen
- Sophie Giraud
- Brigitte Bressac-De-Paillerets
- Betty Gardie
- Bin Tean Teh
- Stéphane Richard
- Sophie Gad
View Affiliations

Affiliations: Oncogenetics Laboratory, EPHE, PSL Research University, 75014 Paris, France, Bioinformatic Platform, 94800 Villejuif, France, Genomic Platform, Gustave Roussy, 94800 Villejuif, France, INSERM, UMR 1186, Gustave Roussy, Paris-Sud University, Paris-Saclay University, 94800 Villejuif, France, PREDIR INCa, Department of Urology, AP-HP, Bicêtre Hospital, 94270 Le Kremlin-Bicêtre, France, Department of Pathological Anatomy, Necker Hospital, 75015 Paris, France, Department of Pathological Anatomy and Cytology, Saint Joseph Hospital, 75014 Paris, France, National Cancer Centre, Duke Graduate Medical School, Cancer Science Institute of Singapore, Institute of Molecular and Cellular Biology, Singapore 138673, Singapore
Published online on: July 19, 2018 https://doi.org/10.3892/ijo.2018.4490
Pages: 1455-1468
Copyright: © Gattolliat et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Von Hippel-Lindau (VHL) disease is a rare autosomal dominant syndrome that is the main cause of inherited clear-cell renal cell carcinoma (ccRCC), which generally occurs in the form of multiple recurrent synchronized tumors. Affected patients are carriers of a germline mutation in the VHL tumor suppressor gene. Somatic mutations of this gene are also found in sporadic ccRCC and numerous pan-genomic studies have reported a dysregulation of microRNA (miRNA) expression in these sporadic tumors. In order to investigate the molecular mechanisms underlying the pathogenesis of VHL-associated ccRCC, particularly in the context of multiple tumors, the present study characterized the mRNA and miRNA transcriptome through an integrative analysis compared with sporadic renal tumors. In the present study, two series of ccRCC samples were used. The first set consisted of several samples from different tumors occurring in the same patient, for two independent patients affected with VHL disease. The second set consisted of 12 VHL-associated tumors and 22 sporadic ccRCC tumors compared with a pool of normal renal tissue. For each sample series, an expression analysis of miRNAs and mRNAs was conducted using microarrays. The results indicated that multiple tumors within the kidney of a patient with VHL disease featured a similar pattern of miRNA and gene expression. In addition, the expression levels of miRNA were able to distinguish VHL-associated tumors from sporadic ccRCC, and it was identified that 103 miRNAs and 2,474 genes were differentially expressed in the ccRCC series compared with in normal renal tissue. The majority of dysregulated genes were implicated in ‘immunity’ and ‘metabolism’ pathways. Taken together, these results allow a better understanding of the occurrence of ccRCC in patients with VHL disease, by providing insights into dysregulated miRNA and mRNA. In the set of patients with VHL disease, there were few differences in miRNA and mRNA expression, thus indicating a similar molecular evolution of these synchronous tumors and suggesting that the same molecular mechanisms underlie the pathogenesis of these hereditary tumors.

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1	Richard S, Gardie B, Couvé S and Gad S: Von Hippel-Lindau: How a rare disease illuminates cancer biology. Semin Cancer Biol. 23:26–37. 2013. View Article : Google Scholar
2	Fuhrman SA, Lasky LC and Limas C: Prognostic significance of morphologic parameters in renal cell carcinoma. Am J Surg Pathol. 6:655–663. 1982. View Article : Google Scholar : PubMed/NCBI
3	Sato Y, Yoshizato T, Shiraishi Y, Maekawa S, Okuno Y, Kamura T, Shimamura T, Sato-Otsubo A, Nagae G, Suzuki H, et al: Integrated molecular analysis of clear-cell renal cell carcinoma. Nat Genet. 45:860–867. 2013. View Article : Google Scholar : PubMed/NCBI
4	Wu P, Liu JL, Pei SM, Wu CP, Yang K, Wang SP and Wu S: Integrated genomic analysis identifies clinically relevant subtypes of renal clear cell carcinoma. BMC Cancer. 18:2872018. View Article : Google Scholar : PubMed/NCBI
5	Thiesen HJ, Steinbeck F, Maruschke M, Koczan D, Ziems B and Hakenberg OW: Stratification of clear cell renal cell carcinoma (ccRCC) genomes by gene-directed copy number alteration (CNA) analysis. PLoS One. 12:e01766592017. View Article : Google Scholar : PubMed/NCBI
6	Gerlinger M, Horswell S, Larkin J, Rowan AJ, Salm MP, Varela I, Fisher R, McGranahan N, Matthews N, Santos CR, et al: Genomic architecture and evolution of clear cell renal cell carcinomas defined by multiregion sequencing. Nat Genet. 46:225–233. 2014. View Article : Google Scholar : PubMed/NCBI
7	Cancer Genome Atlas and Research Network: Comprehensive molecular characterization of clear cell renal cell carcinoma. Nature. 499:43–49. 2013. View Article : Google Scholar
8	Beroukhim R, Brunet JP, Di Napoli A, Mertz KD, Seeley A, Pires MM, Linhart D, Worrell RA, Moch H, Rubin MA, et al: Patterns of gene expression and copy-number alterations in von-hippel lindau disease-associated and sporadic clear cell carcinoma of the kidney. Cancer Res. 69:4674–4681. 2009. View Article : Google Scholar : PubMed/NCBI
9	Shuib S, Wei W, Sur H, Morris MR, McMullan D, Rattenberry E, Meyer E, Maxwell PH, Kishida T, Yao M, et al: Copy number profiling in von Hippel-Lindau disease renal cell carcinoma. Genes Chromosomes Cancer. 50:479–488. 2011. View Article : Google Scholar : PubMed/NCBI
10	Fisher R, Horswell S, Rowan A, Salm MP, de Bruin EC, Gulati S, McGranahan N, Stares M, Gerlinger M, Varela I, et al: Development of synchronous VHL syndrome tumors reveals contingencies and constraints to tumor evolution. Genome Biol. 15:4332014. View Article : Google Scholar : PubMed/NCBI
11	Bartel DP: MicroRNAs: Genomics, biogenesis, mechanism, and function. Cell. 116:281–297. 2004. View Article : Google Scholar : PubMed/NCBI
12	Iorio MV and Croce CM: Causes and consequences of microRNA dysregulation. Cancer J. 18:215–222. 2012. View Article : Google Scholar : PubMed/NCBI
13	Lewis BP, Burge CB and Bartel DP: Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets. Cell. 120:15–20. 2005. View Article : Google Scholar : PubMed/NCBI
14	Juan D, Alexe G, Antes T, Liu H, Madabhushi A, Delisi C, Ganesan S, Bhanot G and Liou LS: Identification of a microRNA panel for clear-cell kidney cancer. Urology. 75:835–841. 2010. View Article : Google Scholar
15	Neal CS, Michael MZ, Rawlings LH, Van der Hoek MB and Gleadle JM: The VHL-dependent regulation of microRNAs in renal cancer. BMC Med. 8:642010. View Article : Google Scholar : PubMed/NCBI
16	Messai Y, Gad S, Noman MZ, Le Teuff G, Couve S, Janji B, Kammerer SF, Rioux-Leclerc N, Hasmim M, Ferlicot S, et al: Renal cell carcinoma programmed death-ligand 1, a new direct target of hypoxia-inducible factor-2 alpha, is regulated by von Hippel-Lindau gene mutation status. Eur Urol. 70:623–632. 2016. View Article : Google Scholar
17	Gentleman RC, Carey VJ, Bates DM, Bolstad B, Dettling M, Dudoit S, Ellis B, Gautier L, Ge Y, Gentry J, et al: Bioconductor: Open software development for computational biology and bioinformatics. Genome Biol. 5:R802004. View Article : Google Scholar : PubMed/NCBI
18	Ritchie ME, Phipson B, Wu D, Hu Y, Law CW, Shi W and Smyth GK: limma powers differential expression analyses for RNA-sequencing and microarray studies. Nucleic Acids Res. 43:e472015. View Article : Google Scholar : PubMed/NCBI
19	Silva-Santos RM, Costa-Pinheiro P, Luis A, Antunes L, Lobo F, Oliveira J, Henrique R and Jerónimo C: MicroRNA profile: A promising ancillary tool for accurate renal cell tumour diagnosis. Br J Cancer. 109:2646–2653. 2013. View Article : Google Scholar : PubMed/NCBI
20	Christinat Y and Krek W: Integrated genomic analysis identifies subclasses and prognosis signatures of kidney cancer. Oncotarget. 6:10521–10531. 2015. View Article : Google Scholar : PubMed/NCBI
21	Gowrishankar B, Ibragimova I, Zhou Y, Slifker MJ, Devarajan K, Al-Saleem T, Uzzo RG and Cairns P: MicroRNA expression signatures of stage, grade, and progression in clear cell RCC. Cancer Biol Ther. 15:329–341. 2014. View Article : Google Scholar :
22	Miko E, Czimmerer Z, Csánky E, Boros G, Buslig J, Dezso B and Scholtz B: Differentially expressed microRNAs in small cell lung cancer. Exp Lung Res. 35:646–664. 2009. View Article : Google Scholar : PubMed/NCBI
23	Chan SY and Loscalzo J: MicroRNA-210: A unique and pleiotropic hypoxamir. Cell Cycle. 9:1072–1083. 2010. View Article : Google Scholar : PubMed/NCBI
24	Puisségur MP, Mazure NM, Bertero T, Pradelli L, Grosso S, Robbe-Sermesant K, Maurin T, Lebrigand K, Cardinaud B, Hofman V, et al: miR-210 is overexpressed in late stages of lung cancer and mediates mitochondrial alterations associated with modulation of HIF-1 activity. Cell Death Differ. 18:465–478. 2011. View Article : Google Scholar :
25	Couvé S, Ladroue C, Laine E, Mahtouk K, Guégan J, Gad S, Le Jeune H, Le Gentil M, Nuel G, Kim WY, et al: Genetic evidence of a precisely tuned dysregulation in the hypoxia signaling pathway during oncogenesis. Cancer Res. 74:6554–6564. 2014. View Article : Google Scholar : PubMed/NCBI
26	Kulshreshtha R, Davuluri RV, Calin GA and Ivan M: A microRNA component of the hypoxic response. Cell Death Differ. 15:667–671. 2008. View Article : Google Scholar : PubMed/NCBI
27	Chen D, Cabay RJ, Jin Y, Wang A, Lu Y, Shah-Khan M and Zhou X: MicroRNA deregulations in head and neck squamous cell carcinomas. J Oral Maxillofac Res. 4:e22013. View Article : Google Scholar
28	Kong W, He L, Richards EJ, Challa S, Xu CX, Permuth-Wey J, Lancaster JM, Coppola D, Sellers TA, Djeu JY, 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. View Article : Google Scholar :
29	Bruning U, Cerone L, Neufeld Z, Fitzpatrick SF, Cheong A, Scholz CC, Simpson DA, Leonard MO, Tambuwala MM, Cummins EP, et al: MicroRNA-155 promotes resolution of hypoxia-inducible factor 1alpha activity during prolonged hypoxia. Mol Cell Biol. 31:4087–4096. 2011. View Article : Google Scholar : PubMed/NCBI
30	Hell MP, Thoma CR, Fankhauser N, Christinat Y, Weber TC and Krek W: miR-28-5p promotes chromosomal instability in VHL-associated cancers by inhibiting Mad2 translation. Cancer Res. 74:2432–2443. 2014. View Article : Google Scholar : PubMed/NCBI
31	Mathew LK, Lee SS, Skuli N, Rao S, Keith B, Nathanson KL, Lal P and Simon MC: Restricted expression of miR-30c-2-3p and miR-30a-3p in clear cell renal cell carcinomas enhances HIF2α activity. Cancer Discov. 4:53–60. 2014. View Article : Google Scholar
32	Favier J, Brière JJ, Burnichon N, Rivière J, Vescovo L, Benit P, Giscos-Douriez I, De Reyniès A, Bertherat J, Badoual C, et al: The Warburg effect is genetically determined in inherited pheochromocytomas. PLoS One. 4:e70942009. View Article : Google Scholar : PubMed/NCBI
33	Mullen AR, Wheaton WW, Jin ES, Chen PH, Sullivan LB, Cheng T, Yang Y, Linehan WM, Chandel NS and DeBerardinis RJ: Reductive carboxylation supports growth in tumour cells with defective mitochondria. Nature. 481:385–388. 2011. View Article : Google Scholar : PubMed/NCBI
34	Schmidt LS and Linehan WM: Genetic predisposition to kidney cancer. Semin Oncol. 43:566–574. 2016. View Article : Google Scholar : PubMed/NCBI
35	Elsässer-Beile U, Grussenmeyer T, Gierschner D, Schmoll B, Schultze-Seemann W, Wetterauer U and Schulte Mönting J: Semiquantitative analysis of Th1 and Th2 cytokine expression in CD3⁺, CD4⁺, and CD8⁺ renal-cell-carcinoma-infiltrating lymphocytes. Cancer Immunol Immunother. 48:204–208. 1999. View Article : Google Scholar
36	Finke JH, Rayman P, Edinger M, Tubbs RR, Stanley J, Klein E and Bukowski R: Characterization of a human renal cell carcinoma specific cytotoxic CD8⁺ T cell line. J Immunother. 1991(11): 1–11. 1992. View Article : Google Scholar
37	Gaudin C, Dietrich PY, Robache S, Guillard M, Escudier B, Lacombe MJ, Kumar A, Triebel F and Caignard A: In vivo local expansion of clonal T cell subpopulations in renal cell carcinoma. Cancer Res. 55:685–690. 1995.PubMed/NCBI
38	Schwaab T, Schned AR, Heaney JA, Cole BF, Atzpodien J, Wittke F and Ernstoff MS: In vivo description of dendritic cells in human renal cell carcinoma. J Urol. 162:567–573. 1999. View Article : Google Scholar : PubMed/NCBI
39	Zagzag D, Krishnamachary B, Yee H, Okuyama H, Chiriboga L, Ali MA, Melamed J and Semenza GL: Stromal cell-derived factor-1alpha and CXCR4 expression in hemangioblastoma and clear cell-renal cell carcinoma: Von Hippel-Lindau loss-of-function induces expression of a ligand and its receptor. Cancer Res. 65:6178–6188. 2005. View Article : Google Scholar : PubMed/NCBI
40	Altuvia Y, Landgraf P, Lithwick G, Elefant N, Pfeffer S, Aravin A, Brownstein MJ, Tuschl T and Margalit H: Clustering and conservation patterns of human microRNAs. Nucleic Acids Res. 33:2697–2706. 2005. View Article : Google Scholar : PubMed/NCBI
41	Yuan X, Liu C, Yang P, He S, Liao Q, Kang S and Zhao Y: Clustered microRNAs' coordination in regulating protein-protein interaction network. BMC Syst Biol. 3:652009. View Article : Google Scholar : PubMed/NCBI
42	Kawakami T, Chano T, Minami K, Okabe H, Okada Y and Okamoto K: Imprinted DLK1 is a putative tumor suppressor gene and inactivated by epimutation at the region upstream of GTL2 in human renal cell carcinoma. Hum Mol Genet. 15:821–830. 2006. View Article : Google Scholar : PubMed/NCBI
43	Thayanithy V, Sarver AL, Kartha RV, Li L, Angstadt AY, Breen M, Steer CJ, Modiano JF and Subramanian S: Perturbation of 14q32 miRNAs-cMYC gene network in osteosarcoma. Bone. 50:171–181. 2012. View Article : Google Scholar
44	Gattolliat CH, Thomas L, Ciafrè SA, Meurice G, Le Teuff G, Job B, Richon C, Combaret V, Dessen P, Valteau-Couanet D, et al: Expression of miR-487b and miR-410 encoded by 14q32.31 locus is a prognostic marker in neuroblastoma. Br J Cancer. 105:1352–1361. 2011. View Article : Google Scholar : PubMed/NCBI
45	Gattolliat CH, Le Teuff G, Combaret V, Mussard E, Valteau-Couanet D, Busson P, Bénard J and Douc-Rasy S: Expression of two parental imprinted miRNAs improves the risk stratification of neuroblastoma patients. Cancer Med. 3:998–1009. 2014. View Article : Google Scholar : PubMed/NCBI
46	Tang SW, Chang WH, Su YC, Chen YC, Lai YH, Wu PT, Hsu CI, Lin WC, Lai MK and Lin JY: MYC pathway is activated in clear cell renal cell carcinoma and essential for proliferation of clear cell renal cell carcinoma cells. Cancer Lett. 273:35–43. 2009. View Article : Google Scholar
47	Liu Y, Zhang M, Qian J, Bao M, Meng X, Zhang S, Zhang L, Zhao R, Li S, Cao Q, et al: miR-134 functions as a tumor suppressor in cell proliferation and epithelial-to-mesenchymal Transition by targeting KRAS in renal cell carcinoma cells. DNA Cell Biol. 34:429–436. 2015. View Article : Google Scholar : PubMed/NCBI