Abstract
Tumor metastasis is the major cause of cancer-related death especially in human hepatocellular carcinoma (HCC). Although microRNAs have been implicated in tumor development, the roles of miR-124 in HCC metastasis are still not well understood. We conducted functional analysis in this study to investigate miR-124. We observed that miR-124 significantly retarded the wound healing and migration of HCC SMMC-7721 and BEL-7404 cells. Further analysis indicated miR-124 directly targeting the transcriptional factor Sp1 which is an important transcription factor for the integrin αV subunit gene transcription. Co-transfection of miR-124 with the luciferase reporter containing Sp1 3′ untranslated region (UTR) significantly suppressed the luciferase activities. While mutation of the binding site of miR-124 in Sp1 mRNA 3′UTR completely abrogated the suppression of miR-124. Overexpression of miR-124 resulted in robust downregulation of Sp1 and integrin αV expression at either mRNA or protein level. Ectopic expression of miR-124 in HCC dramatically repressed the wound healing and migration in vitro and tumor metastasis in mouse experiments. Our findings demonstrated that miR-124 played as an important role in regulation of integrin αV expression in HCC, and reintroduction of miR-124 might be an alternative therapeutic strategy for controlling integrin αV expression in HCC.
Highlights
Stemness of tumor cells[13,14]
We demonstrated that miR-124 was involved in the regulation of migration and metastasis of human hepatocellular carcinoma cells (SMMC-7721 and BEL-7404)
This implied that miR-124 regulation of hepatocellular carcinoma cell migration might be related with the expression of integrin αV that is important in HCC cell migration and metastasis
Summary
Stemness of tumor cells[13,14]. Integrin αVβ3 antagonists have shown encouraging anti-tumor effect on glioma in the initiatory trials[15]. Overexpressed integrin αVβ3 helps glioblastoma cells to escape senescence by activation of the cytoskeletal regulatory kinase PAK416 and promotes the migration of HCC17. The subunit of integrin αVis encoded in the gene of ITGAV. The promoter region of ITGAV gene encoding integrin αVsubunit, contains four GC-rich motifs. In our previous study[19] we observed that Sp1 bound to integrin αV subunit gene promoter and activated its transcription in the pathway of integrin αV transcription regulated by sulfatide. We tried to explore further the mechanism of sulfatide inducing integrin αV subunit gene expression on the base of our previous results. In analysis of integrin αVregulation of cell migration in HCC we identified miR-124 as a novel regulator of the pathway, targeting Sp1 directly in HCC. Overexpression of miR-124 inhibited invasion and metastasis of HCC through integrin αV subunit implicated
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