ARHGEF11 promotes proliferation and epithelial-mesenchymal transition of hepatocellular carcinoma through activation of β-catenin pathway

Abstract

Rho guanine nucleotide exchange factor 11 (ARHGEF11) has been proved to promote tumor metastasis in glioblastoma and ovarian carcinoma. However, the role of ARHGEF11 in hepatocellular carcinoma (HCC) progression is largely unknown. Here, we found that ARHGEF11 was upregulated in HCC samples and highly metastatic hepatoma cell lines. Knockdown of ARHGEFF11 inhibited the cell proliferation and invasion in both HCCLM3 and SKHEP1 cell lines. Subsequent mechanistic investigation showed that downregulation of ARHGEF11 significantly attenuated β-catenin nuclear translocation, thereafter repressed the expression of ZEB1 and cyclinD1, finally contributing to inhibition of epithelial-mesenchymal transition (EMT) and cell cycle arrest. Moreover, high levels of ARHGEF11 were found to be associated with shorter disease free and overall survival. A prognostic nomogram model that integrated ARHGEF11, tumor size and BCLC classification showed good performance in predicting clinical outcomes of HCC patients. Overall, this study demonstrated that ARHGEF11 could promote proliferation and metastasis of HCC via activating β-catenin pathway, suggesting that ARHGEF11 might serve as a potential prognostic biomarker for HCC.

Wnt/β-Catenin Signaling as a Driver of Hepatocellular Carcinoma Progression: An Emphasis on Molecular Pathways

“…Rho guanine nucleotide exchange factor 11 (ARHGEF11) stimulates nuclear translocation of β-catenin to enhance expression level of ZEB1, resulting in EMT induction and enhanced metastasis of HCC cells. 148 Furthermore, PI3K/Akt signaling mediates nuclear translocation of β-catenin via mediating GSK-3β degradation, resulting in Snail overexpression and EMT induction in HCC. Silencing PI3K/Akt axis results in GSK-3β overexpression, subsequent inhibition of β-catenin and prevents Snail/EMT in HCC.…”

Using biological constraints to improve prediction in precision oncology

“…While the role ARHGEF11 in bladder cancer is not well-defined, it was found to be associated with the invasiveness of progression of glioblastoma 38 and hepatocellular carcinoma. 39 Across all mechanistic pairs, the transcriptional repressor EZH2 was prominent as a progression voting gene being present in 41 unique TSPs in which its expression relative to the second gene determines the vote given by the TSP (progression if EZH2 is more expressed than gene2). This is consistent with existing evidence linking EZH2 to progression and poor prognosis in several cancers including BLCA.…”

Control of cell retraction and protrusion with a single protein

“…Given that FRET measurements that are sensing GEFs activity report RhoA activity at protruding front 11 and biosensors of RhoA-GTP report activity at the retracting back 25 , our results might solve this paradox: PRG would activate Cdc42 at the front meanwhile activating RhoA at the back. PRG is also known for being prometastatic and is overexpressed in different cancers favoring migration and epithelial to mesenchymal transition [33][34][35] . In these pathological cases, PRG was studied as a promoter of RhoA activity.…”