MicroRNA-122, a tumor suppressor microRNA that regulates intrahepatic metastasis of hepatocellular carcinoma.
MicroRNAs (miRNAs), which are inhibitors of gene expression, participate in diverse biological functions and in carcinogenesis. In this study, we show that liver-specific microRNA-122 (miR-122) is significantly down-regulated in liver cancers with intrahepatic metastasis and negatively regulates tumorigenesis. Restoration of miR-122 in metastatic Mahlavu and SK-HEP-1 cells significantly reduced in vitro migration, invasion, and anchorage-independent growth as well as in vivo tumorigenesis, angiogenesis, and intrahepatic metastasis in an orthotopic liver cancer model. Because an inverse expression pattern is often present between an miRNA and its target genes, we used a computational approach and identified multiple miR-122 candidate target genes from two independent expression microarray datasets. Thirty-two target genes were empirically verified, and this group of genes was enriched with genes regulating cell movement, cell morphology, cell-cell signaling, and transcription. We further showed that one of the miR-122 targets, ADAM17 (a disintegrin and metalloprotease 17) is involved in metastasis. Silencing of ADAM17 resulted in a dramatic reduction of in vitro migration, invasion, in vivo tumorigenesis, angiogenesis, and local invasion in the livers of nude mice, which is similar to that which occurs with the restoration of miR-122.


CONCLUSIONS
Our study suggests that miR-122, a tumor suppressor microRNA affecting hepatocellular carcinoma intrahepatic metastasis by angiogenesis suppression, exerts some of its action via regulation of ADAM17. Restoration of miR-122 has a far-reaching effect on the cell. Using the concomitant down-regulation of its targets, including ADAM17, a rational therapeutic strategy based on miR-122 may prove to be beneficial for patients with hepatocellular carcinoma.
Tsai
Wei-Chih
WC
Department of Biotechnology and Laboratory Science in Medicine, National Yang-Ming University, Taipei, Taiwan, Republic of China.
Hsu
Paul Wei-Che
PW
Lai
Tsung-Ching
TC
Chau
Gar-Yang
GY
Lin
Ching-Wen
CW
Chen
Chun-Ming
CM
Lin
Chien-Der
CD
Liao
Yu-Lun
YL
Wang
Jui-Ling
JL
Chau
Yat-Pang
YP
Hsu
Ming-Ta
MT
Hsiao
Michael
M
Huang
Hsien-Da
HD
Tsou
Ann-Ping
AP
D020413:3' Untranslated Regions; D051722:ADAM Proteins / Q000378:metabolism*; D000072198:ADAM17 Protein; D000818:Animals; D000070416:Antagomirs; D006528:Carcinoma, Hepatocellular / Q000378:metabolism* / Q000473:pathology; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D002465:Cell Movement; D015536:Down-Regulation; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D006801:Humans; D008099:Liver / Q000473:pathology; D008113:Liver Neoplasms / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D035683:MicroRNAs / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D020411:Oligonucleotide Array Sequence Analysis; D009841:Oligonucleotides
D020413:3' Untranslated Regions; D000070416:Antagomirs; C531907:MIRN122 microRNA, human; D035683:MicroRNAs; D009841:Oligonucleotides; C520440:antagomir-122; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human; C000606463:Adam17 protein, mouse