Control of mitogenic and motogenic pathways by miR-198, diminishing hepatoma cell growth and migration

Abstract

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer deaths, worldwide. MicroRNAs, inhibiting gene expression by targeting various transcripts, are involved in genomic dysregulation during hepatocellular tumorigenesis. In previous studies, microRNA-198 (miR-198) was shown to be significantly downregulated in HCV-positive hepatocellular carcinoma (HCC). Herein, the function of miR-198 in hepatocellular carcinoma cell growth and gene expression was studied. In hepatoma cell-types with low levels of liver-specific transcription factor HNF1α indicating a low differentiation grade, miR-198 expression was most downregulated. However, miR-198 treatment did not restore the expression of the liver-specific transcription factors HNF1α or HNF4α. Importantly, overexpression of miR-198 in Pop10 hepatoma cells markedly reduced cell growth. In agreement, comprehensive gene expression profiling by microarray hybridisation and real-time quantification revealed that central signal transducers of proliferation pathways were downregulated by miR-198. In contrast, genes mediating cellular adherence were highly upregulated by miR-198. Thus, the low expression of E-cadherin and claudin-1, involved in cell adhesion and cell-cell contacts, was abolished in hepatoma cells after miR-198 overexpression. This definite induction of both proteins by miR-198 was shown to be accompanied by a significantly impaired migration activity of hepatoma Pop10 cells. In conclusion, miR-198 acts as a tumor suppressor by repression of mitogenic and motogenic pathways diminishing cell growth and migration.

Lower expressed miR-198 and its potential targets in hepatocellular carcinoma: a clinicopathological and in silico study

“…Later, Tan et al13 identified the suppressing role of miR-198 in HGF/c-MET pathway that influenced migration and invasion of HCC cells. Then, Elfimova et al14 found that miR-198 was associated with the repression of mitogenic and motogenic pathways in vitro, which could negatively regulate cell growth and migration, thus classifying miR-198 as a main tumor suppressor miRNA in HCC carcinogenesis. However, no study has been reported on the relationship between miR-198 and its corresponding clinicopathological parameters in HCC in the existing literatures.…”

“…Tan et al identified the suppressing role of miR-198 in HGF/c-MET pathway that influenced migration and invasion of HCC cells 13. Elfimova et al found another pathway that was repressed by miR-198 in vitro which could negatively regulate cell growth and migration 14. However, whether miR-198 is related to clinicopathological parameters has not been studied, there still remains a mystery regarding miR-198’s role in the key processes of hepatocellular carcinogenesis.…”

Tumor suppressor function of miR-483-3p on squamous cell carcinomas due to its pro-apoptotic properties

“…Indeed, miR-203 has recently been shown to be a tumor suppressor in basal cell carcinoma, 56 and decreased miR-198 expression is observed in hepatocellular carcinomas, where it favors tumor cells growth and invasion. [57][58][59] Other opportunities for the development of replacement therapies also come from miRNAs that are dysregulated in pretumoral lesions such as chronic wounds or ulcers. This could be particularly challenging for patients suffering from recessive dystrophic epidermolysis bullosa, a genodermatosis characterized by severe erosive skin lesions with an elevated risk of invasive SCC development.…”

miR-198 functions as a tumor suppressor in breast cancer by targeting CUB domain-containing protein 1

“…miR-198 was reported to be located in the 3'UTR of follistatin-like 1 messenger RNA, which promotes keratinocyte migration, whereas miR-198 expression has the opposite effect (24). In human cancers, miR-198 was reported to be downregulated in colorectal (4), lung (5), pancreatic (6) and hepatocellular carcinoma (8,9), and generally acts as a tumor suppressor by inhibiting cancer cell growth and migration. In contrast, high expression of miR-198 was noted to be associated with a shorter disease-free survival and overall survival time in pancreatic ductal adenocarcinomas (7), with poor prognosis in esophageal cancer (11) and in high-grade prostate tumors (10).…”

“…miRNAs have been implicated in a variety of biological processes, including embryonic development, cell differentiation and diseases including human cancer (3). miR-198 has been reported to be deregulated in several human cancers, including colorectal (4), lung (5), pancreatic (6,7), hepato cellular (8,9), prostate (10) and esophageal cancer (11). However, the involvement and effects of miR-198 on breast cancer progression and the underlying mechanism remain unknown.…”