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Cited by 232MicroRNA in disease regulationHepatocellular Carcinoma Treatment and PrognosisCancer-related molecular mechanisms research

MicroRNA-based classification of hepatocellular carcinoma and oncogenic role of miR-517a

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Toffanin, Sara, Hoshida, Yujin, Lachenmayer, Anja, Villanueva, Augusto, Cabellos, Laia, Minguez, Beatriz, Savic, Radoslav, Ward, Stephen C. +12 more·2011·Gastroenterology
DOI 10.1053/j.gastro.2011.02.009PMC PMC3680790
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Abstract

BACKGROUND & AIMS: Hepatocellular carcinoma (HCC) is a heterogeneous tumor that develops via activation of multiple pathways and molecular alterations. It has been a challenge to identify molecular classes of HCC and design treatment strategies for each specific subtype. MicroRNAs (miRNAs) are involved in HCC pathogenesis, and their expression profiles have been used to classify cancers. We analyzed miRNA expression in human HCC samples to identify molecular subclasses and oncogenic miRNAs. METHODS: We performed miRNA profiling of 89 HCC samples using a ligation-mediated amplification method. Subclasses were identified by unsupervised clustering analysis. We identified molecular features specific for each subclass using expression pattern (Affymetrix U133 2.0; Affymetrix, Santa Clara, CA), DNA change (Affymetrix STY Mapping Array), mutation (CTNNB1), and immunohistochemical (phosphor[p]-protein kinase B, p-insulin growth factor-IR, p-S6, p-epidermal growth factor receptor, β-catenin) analyses. The roles of selected miRNAs were investigated in cell lines and in an orthotopic model of HCC. RESULTS: We identified 3 main clusters of HCCs: the wingless-type MMTV integration site (32 of 89; 36%), interferon-related (29 of 89; 33%), and proliferation (28 of 89; 31%) subclasses. A subset of patients with tumors in the proliferation subclass (8 of 89; 9%) overexpressed a family of poorly characterized miRNAs from chr19q13.42. Expression of miR-517a and miR-520c (from ch19q13.42) increased proliferation, migration, and invasion of HCC cells in vitro. MiR-517a promoted tumorigenesis and metastatic dissemination in vivo. CONCLUSIONS: We propose miRNA-based classification of 3 subclasses of HCC. Among the proliferation class, miR-517a is an oncogenic miRNA that promotes tumor progression. There is rationale for developing therapies that target miR-517a for patients with HCC.

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  1. [1]El-Serag HB Rudolph KL Hepatocellular carcinoma: epidemiology and molecular carcinogenesis Gastroenterology 2007 132 2557 2576 17570226
  2. [3]Llovet JM Burroughs A Bruix J Hepatocellular carcinoma Lancet 2003 362 1907 1917 14667750
  3. [5]Lang L FDA approves sorafenib for patients with inoperable liver cancer Gastroenterology 2008 134 379 18242200
  4. [6]Villanueva A Newell P Chiang DY Genomics and signaling pathways in hepatocellular carcinoma Semin Liver Dis 2007 27 55 76 17295177
  5. [7]Zucman-Rossi J Laurent-Puig P Genetic diversity of hepatocellular carcinomas and its potential impact on targeted therapies Pharmacogenomics 2007 8 997 1003 17716233
  6. [8]Hoshida Y Toffanin S Lachenmayer A Molecular classification and novel targets in hepatocellular carcinoma: recent advancements Semin Liver Dis 2010 30 35 51 20175032 PMC3668687
  7. [9]Villanueva A Chiang DY Newell P Pivotal role of mTOR signaling in hepatocellular carcinoma Gastroenterology 2008 135 1972 1983 18929564 PMC2678688
  8. [10]Newell P Toffanin S Villanueva A Ras pathway activation in hepatocellular carcinoma and anti-tumoral effect of combined sorafenib and rapamycin in vivo J Hepatol 2009 51 725 733 19665249 PMC2970800
  9. [11]Tovar V Alsinet C Villanueva A IGF activation in a molecular subclass of hepatocellular carcinoma and pre-clinical efficacy of IGF-1R blockage J Hepatol 2010 52 550 559 20206398 PMC3662876
  10. [12]Bartel DP MicroRNAs: genomics, biogenesis, mechanism, and function Cell 2004 116 281 297 14744438
  11. [13]Lewis BP Shih IH Jones-Rhoades MW Prediction of mammalian microRNA targets Cell 2003 115 787 798 14697198
  12. [14]Calin GA Sevignani C Dumitru CD Human microRNA genes are frequently located at fragile sites and genomic regions involved in cancers Proc Natl Acad Sci U S A 2004 101 2999 3004 14973191 PMC365734
  13. [15]Chen CZ MicroRNAs as oncogenes and tumor suppressors N Engl J Med 2005 353 1768 1771 16251533
  14. [16]Meng F Henson R Wehbe-Janek H MicroRNA-21 regulates expression of the PTEN tumor suppressor gene in human hepatocellular cancer Gastroenterology 2007 133 647 658 17681183 PMC4285346
  15. [17]Pineau P Volinia S McJunkin K miR-221 overexpression contributes to liver tumorigenesis Proc Natl Acad Sci U S A 2010 107 264 269 20018759 PMC2806773
  16. [18]Ding J Huang S Wu S Gain of miR-151 on chromosome 8q24. 3 facilitates tumour cell migration and spreading through downregulating RhoGDIA Nat Cell Biol 2010 12 390 399 20305651
  17. [19]Viswanathan SR Powers JT Einhorn W Lin28 promotes transformation and is associated with advanced human malignancies Nat Genet 2009 41 843 848 19483683 PMC2757943
  18. [20]Xiong Y Fang JH Yun JP Effects of microRNA-29 on apoptosis, tumorigenicity, and prognosis of hepatocellular carcinoma Hepatology 2010 51 836 845 20041405
  19. [21]Coulouarn C Factor VM Andersen JB Loss of miR-122 expression in liver cancer correlates with suppression of the hepatic phenotype and gain of metastatic properties Oncogene 2009 28 3526 3536 19617899 PMC3492882
  20. [22]Ji J Shi J Budhu A MicroRNA expression, survival, and response to interferon in liver cancer N Engl J Med 2009 361 1437 1447 19812400 PMC2786938
  21. [23]Lu J Getz G Miska EA MicroRNA expression profiles classify human cancers Nature 2005 435 834 838 15944708
  22. [24]Rosenfeld N Aharonov R Meiri E MicroRNAs accurately identify cancer tissue origin Nat Biotechnol 2008 26 462 469 18362881
  23. [25]Murakami Y Yasuda T Saigo K Comprehensive analysis of microRNA expression patterns in hepatocellular carcinoma and non-tumorous tissues Oncogene 2006 25 2537 2545 16331254
  24. [26]Ladeiro Y Couchy G Balabaud C MicroRNA profiling in hepatocellular tumors is associated with clinical features and oncogene/tumor suppressor gene mutations Hepatology 2008 47 1955 1963 18433021
  25. [27]Chiang DY Villanueva A Hoshida Y Focal gains of VEGFA and molecular classification of hepatocellular carcinoma Cancer Res 2008 68 6779 6788 18701503 PMC2587454
  26. [28]Hoshida Y Villanueva A Kobayashi M Gene expression in fixed tissues and outcome in hepatocellular carcinoma N Engl J Med 2008 359 1995 2004 18923165 PMC2963075
  27. [29]Mi S Lu J Sun M MicroRNA expression signatures accurately discriminate acute lymphoblastic leukemia from acute myeloid leukemia Proc Natl Acad Sci U S A 2007 104 19971 19976 18056805 PMC2148407
  28. [30]Fan JB Yeakley JM Bibikova M A versatile assay for high-throughput gene expression profiling on universal array matrices Genome Res 2004 14 878 885 15123585 PMC479115
  29. [31]April C Klotzle B Royce T Whole-genome gene expression profiling of formalin-fixed, paraffin-embedded tissue samples PLoS One 2009 4 e8162 19997620 PMC2780295
  30. [32]Llovet JM Chen Y Wurmbach E A molecular signature to discriminate dysplastic nodules from early hepatocellular carcinoma in HCV cirrhosis Gastroenterology 2006 131 1758 1767 17087938
  31. [33]Huang Q Gumireddy K Schrier M The microRNAs miR-373 and miR-520c promote tumour invasion and metastasis Nat Cell Biol 2008 10 202 210 18193036
  32. [35]Hoshida Y Brunet JP Tamayo P Subclass mapping: identifying common subtypes in independent disease data sets PLoS ONE 2007 2 e1195 18030330 PMC2065909
  33. [37]Reich M Liefeld T Gould J GenePattern 2. 0 Nat Genet 2006 38 500 501 16642009
  34. [38]Baldi P Long AD A Bayesian framework for the analysis of microarray expression data: regularized t-test and statistical inferences of gene changes Bioinformatics 2001 17 509 519 11395427
  35. [39]Boyault S Rickman DS de Reynies A Transcriptome classification of HCC is related to gene alterations and to new therapeutic targets Hepatology 2007 45 42 52 17187432
  36. [40]Hoshida Y Nijman SM Kobayashi M Integrative transcriptome analysis reveals common molecular subclasses of human hepatocellular carcinoma Cancer Res 2009 69 7385 7392 19723656 PMC3549578
  37. [41]Lee JS Chu IS Heo J Classification and prediction of survival in hepatocellular carcinoma by gene expression profiling Hepatology 2004 40 667 676 15349906
  38. [42]Bentwich I Avniel A Karov Y Identification of hundreds of conserved and nonconserved human microRNAs Nat Genet 2005 37 766 770 15965474
  39. [43]Glazov EA McWilliam S Barris WC Origin, evolution, and biological role of miRNA cluster in DLK-DIO3 genomic region in placental mammals Mol Biol Evol 2008 25 939 948 18281269
  40. [44]Kaposi-Novak P Lee JS Gomez-Quiroz L Met-regulated expression signature defines a subset of human hepatocellular carcinomas with poor prognosis and aggressive phenotype J Clin Invest 2006 116 1582 1595 16710476 PMC1462944
  41. [45]Yamashita T Forgues M Wang W EpCAM and alpha-fetoprotein expression defines novel prognostic subtypes of hepatocellular carcinoma Cancer Res 2008 68 1451 1461 18316609
  42. [46]Nakabayashi H Taketa K Miyano K Growth of human hepatoma cells lines with differentiated functions in chemically defined medium Cancer Res 1982 42 3858 3863 6286115
  43. [47]Bar M Wyman SK Fritz BR MicroRNA discovery and profiling in human embryonic stem cells by deep sequencing of small RNA libraries Stem Cells 2008 26 2496 2505 18583537 PMC2847579
  44. [48]Laurent LC Chen J Ulitsky I Comprehensive microRNA profiling reveals a unique human embryonic stem cell signature dominated by a single seed sequence Stem Cells 2008 26 1506 1516 18403753
  45. [49]Ren J Jin P Wang E MicroRNA and gene expression patterns in the differentiation of human embryonic stem cells J Transl Med 2009 7 20 19309508 PMC2669448
  46. [50]Li M Lee KF Lu Y Frequent amplification of a chr19q13. 41 microRNA polycistron in aggressive primitive neuroectodermal brain tumors Cancer Cell 2009 16 533 546 19962671 PMC3431561
  47. [51]Rippe V Dittberner L Lorenz VN The two stem cell MicroRNA gene clusters C19MC and miR-371-3 are activated by specific chromosomal rearrangements in a subgroup of thyroid adenomas PLoS One 2010 5 e9485 20209130 PMC2831057
  48. [52]Tsai KW Kao HW Chen HC Epigenetic control of the expression of a primate-specific microRNA cluster in human cancer cells Epigenetics 2009 4 587 592 19923923
  49. [53]Zhang L Volinia S Bonome T Genomic and epigenetic alterations deregulate microRNA expression in human epithelial ovarian cancer Proc Natl Acad Sci U S A 2008 105 7004 7009 18458333 PMC2383982
  50. [54]Labonte P Kadhim S Bowlin T Inhibition of tumor growth with doxorubicin in a new orthotopically implanted human hepatocellular carcinoma model Hepatol Res 2000 18 72 85 10838038
  51. [55]Luo SS Ishibashi O Ishikawa G Human villous trophoblasts express and secrete placenta-specific microRNAs into maternal circulation via exosomes Biol Reprod 2009 81 717 729 19494253
  52. [56]Dharmawardhane S Schurmann A Sells MA Regulation of macropinocytosis by p21-activated kinase-1 Mol Biol Cell 2000 11 3341 3352 11029040 PMC14996
  53. [57]Kota J Chivukula RR O’Donnell KA Therapeutic microRNA delivery suppresses tumorigenesis in a murine liver cancer model Cell 2009 137 1005 1017 19524505 PMC2722880
  54. [58]Toffanin S Villanueva A Llovet JM miRNA delivery: emerging therapy for hepatocellular carcinoma Gastroenterology 2010 138 1202 1204 20102759
  55. [59]Wang V Wu W MicroRNA-based therapeutics for cancer BioDrugs 2009 23 15 23 19344188

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Authors
Toffanin, S., Hoshida, Y., Lachenmayer, A., Villanueva, A., Cabellos, L., Minguez, B., Savic, R., Ward, S. C., Thung, S., Chiang, D. Y., Alsinet, C., Tovar, V., Roayaie, S., Schwartz, M., Bruix, J., Waxman, S., Friedman, S. L., Golub, T., Mazzaferro, V., & Llovet, J. M.
Affiliations
  • Tisch Cancer Institute (US)
  • Broad Institute (US)
  • Düsseldorf University Hospital (DE)
  • Hospital Clínic de Barcelona (ES)
  • University of North Carolina at Chapel Hill (US)
  • Institució Catalana de Recerca i Estudis Avançats (ES)
Corresponding author
Llovet, Josep M.
ORCID
Venue
Gastroenterology
Publisher
Elsevier BV
Published
2011-05
Volume
140
Issue
5
Pages
1618-1628.e16
ISSN
0016-5085 (ISSN-L)
DOI
10.1053/j.gastro.2011.02.009
PMC
PMC3680790
OpenAlex
W1992886217
Cited by
232
References
4
Citations by year
2026: 2 · 2025: 3 · 2024: 2 · 2023: 7 · 2022: 13 · 2021: 14 · 2020: 13 · 2019: 16 · 2018: 15 · 2017: 9 · 2016: 20 · 2015: 19 · 2014: 28 · 2013: 20 · 2012: 39
FWCI
10.78
Type
journal article
Language
en
Open access
Licence
Locations
  • Gastroenterology (publishedVersion, public-domain)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • European Commission (259744)
  • Deutsche Forschungsgemeinschaft
  • Ministerio de Ciencia e Innovación
  • European Association for the Study of the Liver
  • National Institutes of Health
  • Instituto de Salud Carlos III
  • National Cancer Institute
  • National Institute of Diabetes and Digestive and Kidney Diseases (1R01DK56621, R01DK076986, 1R01DK37340, R01DK056621, R01DK037340)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › MicroRNA in disease regulation
  • Health Sciences › Medicine › Hepatology › Hepatocellular Carcinoma Treatment and Prognosis
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer-related molecular mechanisms research
Keywords
hepatocellular carcinoma, miRNA expression profiling, molecular subtyping, oncogenic microRNA, tumor cell proliferation, metastasis, Wnt signaling, CTNNB1 mutation, β-catenin, orthotopic tumor model
MeSH terms
Carcinoma, Hepatocellular, Humans, Liver Neoplasms, RNA, Neoplasm, Tumor Cells, Cultured, Gene Expression Regulation, Neoplastic, Polymerase Chain Reaction, Disease Progression, MicroRNAs, Cell Line, Tumor, Cell Proliferation

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