Tsai Wei-Chih, Hsu Paul Wei-Che, Lai Tsung-Ching, Chau Gar-Yang, Lin Ching-Wen, Chen Chun-Ming, Lin Chien-Der, Liao Yu-Lun, Wang Jui-Ling, Chau Yat-Pang, Hsu Ming-Ta, Hsiao Michael, Huang Hsien-Da, Tsou Ann-Ping
Department of Biotechnology and Laboratory Science in Medicine, National Yang-Ming University, Taipei, Taiwan, Republic of China.
Hepatology. 2009 May;49(5):1571-82. doi: 10.1002/hep.22806.
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.
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.
微小RNA（miRNA）是基因表达的抑制剂，参与多种生物学功能和致癌过程。在本研究中，我们发现肝脏特异性微小RNA-122（miR-122）在伴有肝内转移的肝癌中显著下调，并对肿瘤发生起负向调节作用。在转移性Mahlavu和SK-HEP-1细胞中恢复miR-122的表达，可显著降低体外迁移、侵袭和非锚定依赖性生长，以及在原位肝癌模型中的体内肿瘤发生、血管生成和肝内转移。由于miRNA与其靶基因之间通常存在反向表达模式，我们采用计算方法，从两个独立的表达微阵列数据集中鉴定出多个miR-122候选靶基因。通过实验验证了32个靶基因，并且这组基因富含调节细胞运动、细胞形态、细胞间信号传导和转录的基因。我们进一步表明，miR-122的靶标之一ADAM17（一种解整合素和金属蛋白酶17）参与转移。沉默ADAM17导致体外迁移、侵袭、体内肿瘤发生、血管生成以及裸鼠肝脏局部侵袭显著减少，这与恢复miR-122的表达所产生的效果相似。
我们的研究表明，miR-122是一种肿瘤抑制性微小RNA，通过抑制血管生成影响肝细胞癌肝内转移，其部分作用是通过调节ADAM17发挥的。恢复miR-122的表达对细胞具有深远影响。通过同时下调其靶标，包括ADAM17，基于miR-122的合理治疗策略可能对肝细胞癌患者有益。
