Microrna-30D Promotes Tumor Invasion and Metastasis by Targeting Galphai2 in Hepatocellular Carcinoma

Abstract

The pathological relevance and significance of microRNAs (miRNAs) in hepatocarcinogenesis have attracted much attention in recent years; however, little is known about the underlying molecular mechanisms through which miRNAs are involved in the development and progression of hepatocellular carcinoma (HCC). In this study, we demonstrate that miR-30d is frequently up-regulated in HCC and that its expression is highly associated with the intrahepatic metastasis of HCC. Furthermore, the enhanced expression of miR-30d could promote HCC cell migration and invasion in vitro and intrahepatic and distal pulmonary metastasis in vivo, while silencing its expression resulted in a reduced migration and invasion. Galphai2 (GNAI2) was identified as the direct and functional target of miR-30d with integrated bioinformatics analysis and messenger RNA array assay. This regulation was further confirmed by luciferase reporter assays. In addition, our results, for the first time, showed that GNAI2 was frequently suppressed in HCC by way of quantitative reverse-transcription polymerase chain reaction and immunohistochemical staining assays. The increase of the GNAI2 expression significantly inhibits, whereas knockdown of the GNAI2 expression remarkably enhances HCC cell migration and invasion, indicating that H epatocellular carcinoma (HCC) is one of the most prevalent malignancies and leading causes of death from cancer worldwide, especially in East Asia and South Africa. 1 The pathogenesis of HCC is a multistage process that is usually associated with preneoplastic liver lesions, chronic inflammation, and/or cirrhosis. Despite great advances in the treatment of the disease, relapse or metastasis is frequently observed in clinics, and the 5-year survival rate is still quite low among patients with HCC. 2 In past decades, studies have been performed to investigate the genes and proteins that underlie the development and progression of HCC. Several factors involved in the pathogenesis of this malignancy, including wnt/catenin, p53, Rb, and Ras/MAPK, 3 have been identified. However, the roles and significances of nonprotein coding genes with a particular focus on a class of endogenous tiny RNA molecules termed microRNA (miRNA) remain to be established in the pathogenic processes of HCC.miRNAs are approximately 21-to 25-nucleotide noncoding RNA molecules that are highly conserved in a variety of eukaryotic organisms. Since their initial discovery in Caenorhabditis elegans, 4 miRNAs have become widely accepted as posttranscriptional regulators of gene expression through directly degrading messenger RNA (mRNA) or indirectly repressing protein translation. 5 Recent progress suggests that deregulation of miRNAs is involved in a wide range of human diseases, including

miR-612 suppresses the invasive-metastatic cascade in hepatocellular carcinoma

“…2 A). These findings demonstrate Zhang et al, 2009;Ding et al, 2010;Liang et al, 2010;Tan et al, 2010;Yao et al, 2010;Wong et al, 2011;Zhou and Wang, 2011). However, it remains unclear whether other miRNAs are also involved in the process of HCC invasivemetastatic cascade.…”

Absent expression of miR‑30a promotes the growth of lung cancer cells by targeting MEF2D

“…In addition, miR-30 family members are frequently found to be downregulated in these types of tumor tissue. Several studies have revealed that miR-30d and miR-30a are antimetastatic factors in tumors (5,6), and interfere with the epithelial-mesenchymal transition (EMT) (7). Certain miR-30 family members have been identified to abrogate chemoresistance and promote cancer cell apoptosis (7)(8)(9)(10)(11)(12).…”

Amplification of MPZL1/PZR promotes tumor cell migration through Src-mediated phosphorylation of cortactin in hepatocellular carcinoma

“…Recently, a number of cancer genes have been reported to be associated with the tumor metastasis in HCC, including CLU, KAI1, ROCK2 and TWIST [1][2][3][4]. Furthermore, we have previously identified several microRNAs that play critical roles in HCC metastasis, such as miR-30D, miR-151 and miR-210 [5][6][7]. Additionally, many signaling pathways have also been implicated in the process of HCC metastasis, including RAF/MEK/ERK pathway, WNT/ β-catenin pathway, insulin-like growth factor pathway, hepatocyte growth factor/c-MET pathway and growth factor-regulated angiogenic signaling [8].…”