Identifying microRNA panels specifically associated with hepatocellular carcinoma and its different etiologies

Abstract

Aim: Deregulation of microRNAs (miRNAs) expression has been identified in hepatocellular carcinoma (HCC), but few results are consistent. The objective of this study is to investigate “HCC tumor type specific” and “tumor common” miRNA panels.

Methods: The authors integrate and analyze clinical, etiologic and miRNA profiles data from 9 types of solid tumors in The Cancer Genome Atlas (TCGA) and HCC data from Columbia University Medical Center (CUMC).

Results: Levels of 33 miRNAs were significant different between HCC tumor and paired non-tumor tissues (over 2-fold changes) after Bonferroni correction for multiple comparisons, and most (28 miRNAs) were down-regulated in HCC tumors. Using this panel, the authors well classified HCC tumor tissues with 4 misclassifications among 48 paired tissues. Validating this panel in an additional 302 HCC tumor tissues, the authors almost perfectly distinguished tumor from non-tumor tissues with only two misclassifications (99% of HCC tissues correctly classified). Evaluating miRNA profiles in 32 independent HCC paired tissues from CUMC, the authors observed 40 miRNAs significantly deregulated in HCC with over 2-fold changes; 14 overlapped with those identified in TCGA. Subgroup analyses by HCC etiology found that 4 upregulated and 8 downregulated miRNAs were significantly associated with alcohol-related HCC. There were 7 and 4 miRNAs significantly associated with hepatitis B virus- and hepatitis C virus-related HCC, respectively. Data for the first time revealed that miR-24-1, miR-130a and miR-505 were significantly down-regulated only in HCC tumors; miR-142 and miR-455 were significantly down-regulated in HCC, but up-regulated in 5 other solid tumors; suggesting their HCC “tumor type specific” characteristics. A panel of 8 miRNAs was significant in at least 5 tumor types, including HCC, and was identified as “tumor common” marker.

Conclusion: The authors concluded that aberrant miRNA panels have HCC “tumor type specificity” and may be affected by etiologic factors.

Keywords

MicroRNA / hepatocellular carcinoma / etiologies / The Cancer Genome Atlas

References

[1] Calin GA.MicroRNA signatures in human cancers..Nat Rev Cancer2006;6:857-66

[2] Lyra-Gonzalez I,Gonzalez-Garcia I,Armendariz-Borunda J.MicroRNAs dysregulation in hepatocellular carcinoma: insights in genomic medicine..World J Hepatol2015;7:1530-40 PMCID:PMC4462691

[3] Altekruse SF,Reichman ME.Hepatocellular carcinoma incidence, mortality, and survival trends in the United States from 1975 to 2005..J Clin Oncol2009;27:1485-91 PMCID:PMC2668555

[4] Siegel RL,Jemal A.Cancer statistics, 2015..CA Cancer J Clin2015;65:5-29

[5] El Serag HB.Hepatocellular carcinoma: epidemiology and molecular carcinogenesis..Gastroenterology2007;132:2557-76

[6] Cabibbo G,Genco C,Camma C.Causes of and prevention strategies for hepatocellular carcinoma..Semin Oncol2012;39:374-83

[7] Wogan GN.Aflatoxins as risk factors for hepatocellular carcinoma in humans..Cancer Res1992;52:s2114-8

[8] Li J,Gao Y,Jing X,Wang Y.Analysis of microRNA expression profiles in human hepatitis B virus-related hepatocellular carcinoma..Clin Lab2013;59:1009-15

[9] Park KU,Lee YH,Hwang I,Nam J,Kim JY.Altered microRNA expression profile in hepatitis B virus-related hepatocellular carcinoma..Gene2015;573:278-84

[10] Diaz G,Tice A,Mishra L,Farci P.Identification of microRNAs specifically expressed in hepatitis C virus-associated hepatocellular carcinoma..Int J Cancer2013;133:816-24 PMCID:PMC3830961

[11] Edge SB.The American Joint Committee on Cancer: the 7th edition of the AJCC cancer staging manual and the future of TNM..Ann Surg Oncol2010;17:1471-4

[12] Chu A,Brooks D,Birol I,Ma Y,Marra MA.Large-scale profiling of microRNAs for The Cancer Genome Atlas..Nucleic Acids Res2016;44:e3

[13] Barrett T,Wilhite SE,Rudnev D,Kim IF,Tomashevsky M,Phillippy KH,Muertter RN.NCBI GEO: archive for high-throughput functional genomic data..Nucleic Acids Res2009;37:D885-90

[14] Schmittgen TD.Analyzing real-time PCR data by the comparative C(T) method..Nat Protoc2008;3:1101-8

[15] Eminaga S,Vigneault F,Seidman JG.Quantification of microRNA expression with next-generation sequencing.Curr Protoc Mol Biol2013;Chapter 4:Unit.:

[16] Rice J,Burton J,States V,Galandiuk S.Assay reproducibility in clinical studies of plasma miRNA..PLoS One2015;10:e0121948

[17] Tibshirani R,Narasimhan B.Diagnosis of multiple cancer types by shrunken centroids of gene expression..Proc Natl Acad Sci U S A2002;99:6567-72 PMCID:PMC124443

[18] Simon R,Li MC,Menenzes S.Analysis of gene expression data using BRB-ArrayTools..Cancer Inform2007;3:11-7 PMCID:PMC2675854

[19] Lu TP,Tsai MH,Hsiao CK,Chuang EY.miRSystem: an integrated system for characterizing enriched functions and pathways of microRNA targets..PLoS One2012;7:e42390

[20] Chen J,Aronow BJ.ToppGene Suite for gene list enrichment analysis and candidate gene prioritization..Nucleic Acids Res2009;37:W305-11

[21] Lee L,Li G,Wang Y,Sun S,Bhak J,Lee KH,Yeom YI,Hwang S.Liverome: a curated database of liver cancer-related gene signatures with self-contained context information..BMC Genomics2011;12 Suppl 3:S3

[22] Hou W.Non-coding RNAs in hepatitis C-induced hepatocellular carcinoma: dysregulation and implications for early detection, diagnosis and therapy..World J Gastroenterol2013;19:7836-45 PMCID:PMC3848131

[23] Pogribny IP.Role of epigenetic aberrations in the development and progression of human hepatocellular carcinoma..Cancer Lett2014;342:223-30 PMCID:PMC3971756

[24] Salvi A,Portolani N,De Petro G.Human hepatocellular carcinoma cell-specific miRNAs reveal the differential expression of miR-24 and miR-27a in cirrhotic/non-cirrhotic HCC..Int J Oncol2013;42:391-402 PMCID:PMC3583619

[25] Li B,Qiu J,Hong J.MicroRNA-130a is down-regulated in hepatocellular carcinoma and associates with poor prognosis..Med Oncol2014;31:230

[26] Zhang X,Armistead D,Kottilil S.MicroRNA expression profiling in HCV-infected human hepatoma cells identifies potential anti-viral targets induced by interferon-alpha..PLoS One2013;8:e55733

[27] Liu C,Zhang Y,Xing X,Zeng X,Fan Q,Chen W.Upregulation of miR-34a-5p antagonizes AFB1-induced genotoxicity in F344 rat liver..Toxicon2015;106:46-56

[28] Tsang FH,Wei L,Lee JM,Ng IO.MicroRNA-142-3p and microRNA-142-5p are downregulated in hepatocellular carcinoma and exhibit synergistic effects on cell motility..Front Med2015;9:331-43

[29] Wu L,Wang X,Li X.MicroRNA-142-3p, a new regulator of RAC1, suppresses the migration and invasion of hepatocellular carcinoma cells..FEBS Lett2011;585:1322-30

[30] Chiu LY,Chuang TP,Liu CY,Koeberl D,Boyette K,Murphy E,Chen YT.Identification of differentially expressed microRNAs in human hepatocellular adenoma associated with type I glycogen storage disease: a potential utility as biomarkers..J Gastroenterol2014;49:1274-84

[31] Du M,Yuan L,Chu H,Yin C,Wang M.Circulating miR-497 and miR-663b in plasma are potential novel biomarkers for bladder cancer..Sci Rep2015;5:10437 PMCID:PMC4444850

[32] Matamala N,Gonzalez-Campora R,Arias JI,Andrés-León E,Yanowsky K,Inglada-Pérez L,Benítez J.Tumor microRNA expression profiling identifies circulating microRNAs for early breast cancer detection..Clin Chem2015;61:1098-106

[33] Jiang H,Wang LL.miR-130a acts as a potential diagnostic biomarker and promotes gastric cancer migration, invasion and proliferation by targeting RUNX3..Oncol Rep2015;34:1153-61 PMCID:PMC4530930

[34] Li N,Wang H,Jia X,Xu P.MiR-130a and MiR-374a function as novel regulators of cisplatin resistance in human ovarian cancer A2780 cells..PLoS One2015;10:e0128886

[35] Liu L,Chen L,Du X,Tang Y.The oncogenic role of microRNA-130a/301a/454 in human colorectal cancer via targeting Smad4 expression..PLoS One2013;8:e55532

[36] Acunzo M,Romano G,Lovat F,Bottoni A,Gasparini P,Chiariello M.miR-130a targets MET and induces TRAIL-sensitivity in NSCLC by downregulating miR-221 and 222..Oncogene2012;31:634-42 PMCID:PMC3719419

[37] El-Halawany MS,Zeeneldin AA,Tantawy M,Hamed I.Investigating the pretreatment miRNA expression patterns of advanced hepatocellular carcinoma patients in association with response to TACE treatment..Biomed Res Int2015;2015:649750 PMCID:PMC4355598

[38] Liu YX,Xi ZF,Huang XY,Wang C,Xia Q.MicroRNA-24 modulates aflatoxin B1-related hepatocellular carcinoma prognosis and tumorigenesis..Biomed Res Int2014;2014:482926

[39] Meng FL,Jia WD.Diagnostic and prognostic significance of serum miR-24-3p in HBV-related hepatocellular carcinoma..Med Oncol2014;31:177

[40] Oksuz Z,Kaplan E,Tezcan S,Emekdas G,Altintas E.Serum microRNAs; miR-30c-5p, miR-223-3p, miR-302c-3p and miR-17-5p could be used as novel non-invasive biomarkers for HCV-positive cirrhosis and hepatocellular carcinoma..Mol Biol Rep2015;42:713-20

[41] Lin XJ,Guo ZW,Yang XJ,Li SP,Yuan Y,Jia WH,Chen MS,Fang JH,Zhang Y,Wu Y,Zheng L.A serum microRNA classifier for early detection of hepatocellular carcinoma: a multicentre, retrospective, longitudinal biomarker identification study with a nested case-control study..Lancet Oncol2015;16:804-15

[42] Chowdhury JB,Steele R,Ray R.Hepatitis C virus infection modulates expression of interferon stimulatory gene IFITM1 by upregulating miR-130A..J Virol2012;86:10221-5 PMCID:PMC3446586

[43] Boll K,Kasack K,Kretzschmar AK,Verhaegh G,von Bergen M,Hackermüller J.MiR-130a, miR-203 and miR-205 jointly repress key oncogenic pathways and are downregulated in prostate carcinoma..Oncogene2013;32:277-85

[44] Qiu SW,Hu D,Tan Y.Interactions of miR-323/miR-326/miR-329 and miR-130a/miR-155/miR-210 as prognostic indicators for clinical outcome of glioblastoma patients..J Transl Med2013;11:10 PMCID:PMC3551827

[45] Lal A,Maher CA,Yan N,Chowdhury D,Tsai P,Becker KG,Hide W.miR-24 inhibits cell proliferation by targeting E2F2, MYC, and other cell-cycle genes via binding to "seedless" 3'UTR microRNA recognition elements..Mol Cell2009;35:610-25 PMCID:PMC2757794

[46] Li YQ,Bao XM,Wu JH.MiR-24 functions as a tumor suppressor in nasopharyngeal carcinoma through targeting FSCN1..J Exp Clin Cancer Res2015;34:130 PMCID:PMC4621856

[47] Ma Y,Ming YZ.miR-24 promotes the proliferation and invasion of HCC cells by targeting SOX7..Tumour Biol2014;35:10731-6

[48] Hatziapostolou M,Aggelidou E,Poultsides GA,Ogata H,Struhl K,Iliopoulos D.An HNF4alpha-miRNA inflammatory feedback circuit regulates hepatocellular oncogenesis..Cell2011;147:1233-47 PMCID:PMC3251960

[49] Lal A,Abdelmohsen K,Pullmann RJr,Subrahmanyam R,Yang X,Navarro F,Lieberman J.p16(INK4a) translation suppressed by miR-24..PLoS One2008;3:e1864

[50] Qin W,Zhao B,Jin L,Jin Y.miR-24 regulates apoptosis by targeting the open reading frame (ORF) region of FAF1 in cancer cells..PLoS One2010;5:e9429

[51] Yan SR,Yu S.Investigation of the value of miR-21 in the diagnosis of early stage HCC and its prognosis: a meta-analysis..Genet Mol Res2015;14:11573-86

[52] Wang Y,Wei F,Yu J,Sun Q,Yan C,Ren X.Diagnostic and prognostic value of circulating miR-21 for cancer: a systematic review and meta-analysis..Gene2014;533:389-97

[53] Zhang QH,Zheng RZ,Zhang Q,Tang ZH.Meta-analysis of microRNA-183 family expression in human cancer studies comparing cancer tissues with noncancerous tissues..Gene2013;527:26-32

[54] Zhang HD,Sun DW,Tang JH.MiR-139-5p: promising biomarker for cancer..Tumour Biol2015;36:1355-65

[55] Mizuguchi Y,Yoshida H.Dysregulated microRNAs in progression of hepatocellular carcinoma: a systematic review..Hepatol Res2015;

[56] He Y,Kong D,Xu C,Etheridge A,Ding Y.Current state of circulating microRNAs as cancer biomarkers..Clin Chem2015;61:1138-55

[57] Wojcicka A,Kornasiewicz O,Maciag M,Kotlarek M,Koperski L,Krawczyk M.Next generation sequencing reveals microRNA isoforms in liver cirrhosis and hepatocellular carcinoma..Int J Biochem Cell Biol2014;53:208-17

[58] Zhang J,Chen GG.A seven-microRNA expression signature predicts survival in hepatocellular carcinoma..PLoS One2015;10:e0128628

[59] Hou J,Zhou W,Ding G,Qin L,Zheng Y,Tian W,Wang C,Zhuang SM,Liang A,Cao X.Identification of miRNomes in human liver and hepatocellular carcinoma reveals miR-199a/b-3p as therapeutic target for hepatocellular carcinoma..Cancer Cell2011;19:232-43

[60] Lopez JP,Cruceanu C,Laboissiere S,Fontaine J,Benes V,Ernst C.Biomarker discovery: quantification of microRNAs and other small non-coding RNAs using next generation sequencing..BMC Med Genomics2015;8:35 PMCID:PMC4487992

[61] Knutsen E,Ursvik A,Perander M,Seternes OM,Andreassen M.Performance comparison of digital microRNA profiling technologies applied on human breast cancer cell lines..PLoS One2013;8:e75813

[62] Pritchard CC,Tewari M.MicroRNA profiling: approaches and considerations..Nat Rev Genet2012;13:358-69 PMCID:PMC4517822