Abstract
Hepatocellular carcinoma (HCC) can be derived from malignant transformed adult hepatic progenitor cells. However, the regulatory factors and molecular mechanisms underlying the process are not well defined. Our previous microRNA (miRNA) microarray analysis revealed a significant decrease of miR-200a level in F344 rat HCC side population (SP) fraction cells versus their normal counterparts. In the present study, we further investigated the effect of miR-200a on hepatic oval cell (HOC) phenotypes. We first confirmed downregulated miR-200a levels in rat hepatoma cells compared with WB-F344 cells. Next, by lentivirus-mediated loss-of-function studies, we showed that stable knockdown of miR-200a confers a mesenchymal phenotype to WB-F344 cells, including an elongated cell morphology, enhanced cell migration ability and expression of epithelial mesenchymal transition (EMT)-representative markers. Concomitantly, several cancer stem cell (CSC)-like traits appeared in these cells, which exhibit enhanced spheroid-forming capacity, express putative hepatic CSC markers and display superior resistance to chemotherapeutic drugs in vitro. Furthermore, bioinformatics analysis, luciferase assays and western blot analysis identified β-catenin (CTNNB1) as a direct and functional target of miR-200a. Knockdown of miR-200a partially activated Wnt/β-catenin signaling, and silencing of β-catenin functionally attenuated anti-miR-200a effects in vitro in WB-F344 cells. At length, in vivo xenograft assay demonstrated the acquisition of tumorigenicity of WB-F344 cells after miR-200a siliencing. Collectively, our findings indicate that miR-200a may function as an important regulatory factor in neoplastic transition of HOCs by targeting the β-catenin pathway.
Highlights
Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer, which accounts for the third most frequent cause of cancer-related death worldwide [1]
There is evidence demonstrating that dysregulated hepatic progenitor cells (HPCs)/hepatic oval cell (HOC) possess tumor-initiating ability in vivo [12,13]. These findings suggest that HPCs/HOCs might be involved in the genesis of hepatic cancer stem cell (CSC)
Our results demonstrated that miR-200a expression was much higher in WB cells than in hepatoma cells (Figure 1A), indicating that downregulated miR-200a may be associated with HCC malignant phenotypes
Summary
Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer, which accounts for the third most frequent cause of cancer-related death worldwide [1]. CSCs might originate from normal stem/progenitor cells in certain pathological processes [5,6]. Certain hepatic CSCs emerging during chronic liver injury share many common signaling pathways, including transforming growth factor beta (TGF-b) [9], b-catenin [10] and surface markers [11], with normal hepatic progenitor cells (HPCs) or hepatic oval cells (HOCs). There is evidence demonstrating that dysregulated HPCs/HOCs possess tumor-initiating ability in vivo [12,13]. These findings suggest that HPCs/HOCs might be involved in the genesis of hepatic CSCs. the specific molecular mechanism(s) remain(s) to be determined
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