Genome-Wide Screening Identified That miR-134 Acts as a Metastasis Suppressor by Targeting Integrin β1 in Hepatocellular Carcinoma

Abstract

MicroRNAs (miRNAs) are small, single-stranded, non-coding RNAs that play pivotal roles in human cancer development and progression, such as tumor metastasis. Here, we identified the miRNAs that regulate hepatocellular carcinoma (HCC) cell migration by a high-throughput screening method using the classical wound-healing assay with time-lapse video microscopy and validation with a transwell migration assay. Eleven miRNAs (miR-134, -146b-3p, -188-3p, -525-3p, -661, -767-5p, -891a, -891b, -1244, -1247 and miR-1471) were found to promote or inhibit HCC cell migration. Further investigation revealed that miR-134 suppressed the invasion and metastasis of HCC cells in vitro and in vivo, and integrin beta 1 (ITGB1) was a direct and functional target gene of miR-134. Moreover, miR-134 inhibited the phosphorylation of focal adhesion kinase (FAK) and the activation of RhoA downstream of the ITGB1 pathway, thereby decreasing stress fiber formation and cell adhesion in HCC cells. In conclusion, we demonstrated that miR-134 is a novel metastasis suppressor in HCC and could be a potential therapeutic target for the treatment of HCC.

Decreased miR-134 expression and its tumor-suppressive function in human osteosarcoma

“…Overexpression of miR-134 in HCC cells arrested cell growth and decreased cell migration and invasion by downregulating the oncoprotein KRAS. Zha et al (2014) also revealed that miR-134 suppressed the invasion and metastasis of HCC cells in vitro and in vivo, and integrin beta 1 was a direct and functional target gene of miR-134 (Zha, et al, 2014). In non-small cell lung cancer, miR-134 inhibits the invasive potential and epithelial-to-mesenchymal transition phenotype of tumor cells, and directly targets FOXM1 (Li et al, 2012), a potential metastasis promoter.…”

MicroRNA-134 targets KRAS to suppress breast cancer cell proliferation, migration and invasion

“…In hepatocellular carcinoma, miR-134 suppressed cell metastasis by regulating the expression of integrin β1 (19). In glioma, the downregulation of miR-134 expression is typical, and cell growth, migration and invasion was inhibited by the upregulation of miR-134; miR-134 overexpression also enhanced cell apoptosis in human glioma cells (20).…”

“…miR-134 has been previously demonstrated to function as a tumor suppressor in several types of tumors (18)(19)(20). In hepatocellular carcinoma, miR-134 suppressed cell metastasis by regulating the expression of integrin β1 (19).…”

“…However, to the best of our knowledge, this is the first study of miR-134 in human breast cancer (18)(19)(20).…”

MicroRNAs in the Occurrence and Development of Primary Hepatocellular Carcinoma

“…More and more upstream regulator genes related to tumor metastasis, such as pre-transfer microRNA and anti-metastatic microRNA, are found to have an important role in the invasion and metastasis of HCC. Genome-wide screening has identified that miR-134 acts as a metastasis suppressor by targeting integrin beta 1 in hepatocellular carcinoma [26]. microRNA-21, which can change the focal adhesion kinase (FAK) expression and phosphorylation of MMP2 and MMP9 matrix metalloproteinase, together with the downstream regulator of PTEN, participate in the metastasis and invasion of tumor cells.…”