Abstract
Hepatocellular carcinoma (HCC) is one of the most malignant and lethal human cancers. Epithelial-mesenchymal transition (EMT) enhances the carcinogenesis of HCC, and therapies targeting EMT appear to be promising treatments. We have previously shown that Krüppel-like Factor 4 (KLF4) suppressed EMT of HCC cells through downregulating EMT-associated proteins. Here, we examined the roles of microRNAs (miRNAs) in KLF4-regulated EMT in HCC cells. KLF4 induced expression of 3 miRNAs (miR-153, miR-506 and miR-200b) that targeted 3′-UTR of Snail1, Slug and ZEB1 mRNAs, respectively, to inhibit protein translation in HCC cells, which was confirmed by promoter luciferase assay. Expression of either miRNA significantly inhibited HCC cell growth and invasiveness, while the effect of combined expression of all 3 miRNAs was more pronounced. Furthermore, overexpression of antisense of all 3 miRNAs abolished the inhibitory effect of KLF4 on HCC cell growth and invasiveness. Together, our data suggest that KLF4 inhibits EMT-enhanced HCC growth and invasion, possibly through reducing EMT-related proteins Snail1, Slug and ZEB1 via increasing miR-153, miR-506 and miR-200b.
Highlights
The malignancy of hepatocellular carcinoma (HCC) largely results from its aggressive characteristics [1,2,3,4,5,6]
Expression of Krüppel-like Factor 4 (KLF4) in Hepatocellular carcinoma (HCC) cells sensitizes them to the anti-proliferative effects of VD3, possibly through regulation of epithelial-mesenchymal transition (EMT)-associated events related to cell metastases and growth [18]
We have previously reported that KLF4 suppressed the levels of Epithelial-mesenchymal transition (EMT)-related proteins, Snail1, Slug and ZEB1, in HCC cells
Summary
The malignancy of hepatocellular carcinoma (HCC) largely results from its aggressive characteristics [1,2,3,4,5,6]. The zinc finger protein Krüppel-like Factor 4 (KLF4) regulates gene transcription and cell fate in a context-dependent manner, and has been shown to promote cell differentiation, and to suppress tumor growth stem cell and malignant progression [7,8,9]. A variety of growth-suppressive signals activate KLF4, e.g. cell-contact inhibition, serum starvation, DNA damage, and cell differentiation [7,8,9]. These in vitro results suggest KLF4 may suppress cell proliferation rates in cancer cells, including HCC [1417]. Expression of KLF4 in HCC cells sensitizes them to the anti-proliferative effects of VD3, possibly through regulation of epithelial-mesenchymal transition (EMT)-associated events related to cell metastases and growth [18]. We studied how KLF4 may regulate EMT events in HCC
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