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

Sara Toffanin, Yujin Hoshida, Anja Lachenmayer, Augusto Villanueva, Laia Cabellos, Beatriz Minguez, Radoslav Savic, Stephen C. Ward, Swan Thung, Derek Y. Chiang, Clara Alsinet, Victoria Tovar, Sasan Roayaie, Myron Schwartz, Jordi Bruix, Samuel Waxman, Scott L. Friedman, Todd Golub, Vincenzo Mazzaferro, Josep M. Llovet

Research output: Contribution to journalArticle

158 Citations (Scopus)

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, pinsulin growth factorIR, p-S6, pepidermal 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.

Original languageEnglish (US)
Pages (from-to)1618-1628.e16
JournalGastroenterology
Volume140
Issue number5
DOIs
StatePublished - May 2011
Externally publishedYes

Fingerprint

MicroRNAs
Hepatocellular Carcinoma
Neoplasms
S 6
Catenins
Proto-Oncogene Proteins c-akt
Growth Factor Receptors
Interferons
Ligation
Cluster Analysis
Carcinogenesis
Cell Line
Mutation
DNA
Therapeutics
Growth

Keywords

  • Liver Cancer
  • Oncogenesis
  • OncomiR
  • Tumor Profiling

ASJC Scopus subject areas

  • Hepatology
  • Gastroenterology

Cite this

Toffanin, S., Hoshida, Y., Lachenmayer, A., Villanueva, A., Cabellos, L., Minguez, B., ... Llovet, J. M. (2011). MicroRNA-based classification of hepatocellular carcinoma and oncogenic role of miR-517a. Gastroenterology, 140(5), 1618-1628.e16. https://doi.org/10.1053/j.gastro.2011.02.009

MicroRNA-based classification of hepatocellular carcinoma and oncogenic role of miR-517a. / Toffanin, Sara; Hoshida, Yujin; Lachenmayer, Anja; Villanueva, Augusto; Cabellos, Laia; Minguez, Beatriz; Savic, Radoslav; Ward, Stephen C.; Thung, Swan; Chiang, Derek Y.; Alsinet, Clara; Tovar, Victoria; Roayaie, Sasan; Schwartz, Myron; Bruix, Jordi; Waxman, Samuel; Friedman, Scott L.; Golub, Todd; Mazzaferro, Vincenzo; Llovet, Josep M.

In: Gastroenterology, Vol. 140, No. 5, 05.2011, p. 1618-1628.e16.

Research output: Contribution to journalArticle

Toffanin, S, Hoshida, Y, Lachenmayer, A, Villanueva, A, Cabellos, L, Minguez, B, Savic, R, Ward, SC, Thung, S, Chiang, DY, Alsinet, C, Tovar, V, Roayaie, S, Schwartz, M, Bruix, J, Waxman, S, Friedman, SL, Golub, T, Mazzaferro, V & Llovet, JM 2011, 'MicroRNA-based classification of hepatocellular carcinoma and oncogenic role of miR-517a', Gastroenterology, vol. 140, no. 5, pp. 1618-1628.e16. https://doi.org/10.1053/j.gastro.2011.02.009
Toffanin, Sara ; Hoshida, Yujin ; Lachenmayer, Anja ; Villanueva, Augusto ; Cabellos, Laia ; Minguez, Beatriz ; Savic, Radoslav ; Ward, Stephen C. ; Thung, Swan ; Chiang, Derek Y. ; Alsinet, Clara ; Tovar, Victoria ; Roayaie, Sasan ; Schwartz, Myron ; Bruix, Jordi ; Waxman, Samuel ; Friedman, Scott L. ; Golub, Todd ; Mazzaferro, Vincenzo ; Llovet, Josep M. / MicroRNA-based classification of hepatocellular carcinoma and oncogenic role of miR-517a. In: Gastroenterology. 2011 ; Vol. 140, No. 5. pp. 1618-1628.e16.
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AU - Toffanin, Sara

AU - Hoshida, Yujin

AU - Lachenmayer, Anja

AU - Villanueva, Augusto

AU - Cabellos, Laia

AU - Minguez, Beatriz

AU - Savic, Radoslav

AU - Ward, Stephen C.

AU - Thung, Swan

AU - Chiang, Derek Y.

AU - Alsinet, Clara

AU - Tovar, Victoria

AU - Roayaie, Sasan

AU - Schwartz, Myron

AU - Bruix, Jordi

AU - Waxman, Samuel

AU - Friedman, Scott L.

AU - Golub, Todd

AU - Mazzaferro, Vincenzo

AU - Llovet, Josep M.

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N2 - 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, pinsulin growth factorIR, p-S6, pepidermal 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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