MiR-148b suppresses cell proliferation and invasion in hepatocellular carcinoma by targeting WNT1/β-catenin pathway

Abstract

Accumulating evidences indicate that microRNAs play a vital role in regulating tumor progression. However, the roles of miR-148b in hepatocellular carcinoma (HCC) are still largely unknown. In this study, our data showed that miR-148b was significantly downregulated in 40 pairs of human HCC tissues. Further, the deregulated miR-148b was significantly correlated with larger tumor size, more tumor number, metastasis and worse prognosis in HCC. Overexpression of miR-148b inhibited HCC HepG2 cells proliferation and tumorigenicity. Further, miR-148b induced cells apoptosis by activating caspase- 3 and caspase-9, and induced S phase arrest by regulating cyclinD1 and p21, and also inhibited cell invasion. Data from the dual-luciferase reporter gene assay showed that WNT1 was a direct target of miR-148b, and overexpressed WNT1 inversely correlated with miR-148b levels in HCC tissues. Silencing of WNT1 inhibited the growth of HCC cells, and also induced cells apoptosis and inhibited invasion, which is consistent with the effects of miR-148b overexpression. MiR-148b downregulated expression of WNT1, β-catenin and C-myc, while upregulated E-cadherin expression. We conclude that the frequently downregulated miR-148b can regulate WNT1/β-catenin signalling pathway and function as a tumor suppressor in HCC. These findings suggest that miR-148b may serve as a novel therapeutic target for HCC.

Effects of Wnt‑1 blockade in DEN‑induced hepatocellular adenomas of mice

“…Nonetheless, they had neoplastic cells with nuclear Cyclin D1 signal, which suggests that DEN-induced hepatocellular tumors of mice at the stage of adenoma do not require nuclear β-catenin for the initial stages of Cyclin D1 upregulation. On the other hand, however, the disruption of the Wnt/β-catenin pathway in the present study worked to suppress Cyclin D1 in the mouse tumors, which is similar to what has been frequently reported in studies using mouse models of HCC (4,13,20,22,36,46).…”

“…Although the role of Wnt-1, β-catenin and FLZ-1 in the early preneoplastic stages of DEN-induced liver cancer cannot be definitively excluded, our results do not confirm that Wnt-1 blockade counteracts hepatocellular tumors, by contrast to previous studies (20,22,23). It should be noted, however, that those studies base their conclusions on experiments using HCC cell cultures and tumor transplant mouse models grafted with HCC rather than hepatocellular adenoma cells (20,22,23). β-catenin which is an important downstream molecule of Wnt-1-FLZ1 binding is mutated in mice treated with DEN and phenobarbital but not in those treated with DEN alone (4,44).…”

“…In the context of hepatocellular cancer, Wnt-1 blockade testing is thus far restricted to cell culture studies (20,22,23) or studies using HCC xenograft mouse models (20,22). To the best of our knowledge, our study is the first examining the effects of blocking Wnt-1 in the mouse liver using a spontaneous HCC mouse model.…”

“…A small number of studies, however, tested the depletion of Wnt-1 on HCC cell cultures and tumor transplant mouse models grafted with HCC cells. These studies show preliminary evidence of tumor suppressive effects (20)(21)(22)(23).…”

MicroRNA‑138 targets SP1 to inhibit the proliferation, migration and invasion of hepatocellular carcinoma cells

“…At the time of writing, ~1,000 miRNAs have been identified in humans (10). miRNAs are believed to modulate more than a third of human genes (11) and therefore serve notable functions in a large number of biological processes, including cell proliferation, cell cycle, apoptosis, differentiation, metabolism, migration and invasion (12)(13)(14). Furthermore, increasing evidence has demonstrated that the abnormal expression of miRNAs contributes to the initiation and development of human malignancies, including HCC (15)(16)(17).…”