Transcription factor 3 enhances hepatocellular carcinoma metastasis by upregulating matrix metalloproteinase-11.

Abstract

Background: Transcription factor 3 (TCF3) has a vital role in tumor occurrence and progression. However, the specific functions and underlying mechanisms of dysregulated TCF3 in hepatocellular carcinoma (HCC) have not been not thoroughly characterized. Thus, we explored the roles of TCF3 in HCC.

Aim: To explore the roles of TCF3 in HCC.

Methods: TCF3 knockdown and overexpression models were developed via lentiviral vectors in HCC cells. Transwell and in vivo metastasis experiments were performed to measure the effects of TCF3 on HCC cell metastasis. Then, reverse transcription-quantitative polymerase chain reaction, serial deletion, western blotting, site-directed mutagenesis, chromatin immunoprecipitation, and dual-luciferase reporter assays were done to determine the pathomechanisms.

Results: TCF3 levels were markedly elevated in HCC samples and correlated with poor prognosis. Furthermore, overexpression of TCF3 promoted HCC cell invasion as well as migration, while TCF3 knockdown repressed HCC cell growth. In addition, TCF3 interacted with the promoter region of matrix metalloproteinase-11 (MMP11), facilitating the transcriptional activation of MMP11 mRNA, which consequently enhanced the expression of MMP11. MMP11 knockdown repressed TCF3-associated HCC cell migration and invasion, while its overexpression attenuated the TCF3 knockdown-mediated repression of HCC growth. In human-derived HCC samples, TCF3 was positively correlated with MMP11 expression levels.

Conclusion: TCF3 was significantly upregulated in HCC. TCF3 overexpression enhanced HCC cell invasion and metastasis through transactivation of MMP11 expression. TCF3 could be a prognostic biomarker and regulator of HCC metastasis.