EDIL3 is a novel regulator of epithelial-mesenchymal transition controlling early recurrence of hepatocellular carcinoma.

Patients with advanced hepatocellular carcinoma (HCC) continue to have a dismal prognosis. Early recurrence, metastases and angiogenesis are the major obstacles to improve the outcome of HCC. Epithelial-mesenchymal transition (EMT) is a key contributor to cancer metastasis and recurrence, which are the major obstacles to improve prognosis of HCC. Combining gene expression profiles of HCC samples with or without early recurrence and established cell lines with epithelial or mesenchymal phenotype, EDIL3 was identified as a novel regulator of EMT. The expression of EDIL3 was evaluated by quantitative PCR, Western blotting or immunohistochemistry. The effects of EDIL3 on the angiogenesis and metastasis of HCC cells were examined by wound healing, Matrigel invasion and tube formation assay in vitro and orthotopic xenograft mouse model of HCC in vivo. The signaling pathways of EDIL3 mediated were investigated through microarray and Western blotting analysis. EDIL3 was identified as a novel regulator of EMT, which contributes to angiogenesis, metastasis and recurrence of HCC. EDIL3 induces EMT and promotes HCC migration, invasion and angiogenesis in vitro. Mechanistically, overexpression of EDIL3, which was regulated by the downregulation of miR-137 in HCC, triggered the activation of ERK and TGF-β signaling through interactions with αvβ3 integrin. Blocking ERK and TGF-β signaling overcomes EDIL3 induced angiogenesis and invasion. Using the orthotopic xenograft mouse model of HCC, we demonstrated that EDIL3 enhanced the tumorigenic, metastatic and angiogenesis potential of HCC in vivo. EDIL3-mediated activation of TGF-β and ERK signaling could provide therapeutic implications for HCC.

Xia H ，Chen J ，Shi M ，Gao H ，Sekar K ，Seshachalam VP ，Ooi LL ，Hui KM ... -  《-》

MicroRNA-216a/217-induced epithelial-mesenchymal transition targets PTEN and SMAD7 to promote drug resistance and recurrence of liver cancer.

Tumor recurrence and metastases are the major obstacles to improving the prognosis of patients with hepatocellular carcinoma (HCC). To identify novel risk factors associated with HCC recurrence and metastases, we have established a panel of recurrence-associated microRNAs (miRNAs) by comparing miRNA expression in recurrent and nonrecurrent human HCC tissue samples using microarrays (recurrence is defined as recurrent disease occurring within a 2-year time point of the original treatment). Among the panel, expression of the miR-216a/217 cluster was consistently and significantly up-regulated in HCC tissue samples and cell lines associated with early tumor recurrence, poor disease-free survival, and an epithelial-mesenchymal transition (EMT) phenotype. Stable overexpression of miR-216a/217-induced EMT increased the stem-like cell population, migration, and metastatic ability of epithelial HCC cells. Phosphatase and tensin homolog (PTEN) and mothers against decapentaplegic homolog 7 (SMAD7) were subsequently identified as two functional targets of miR-216a/217, and both PTEN and SMAD7 were down-regulated in HCC. Ectopic expression of PTEN or SMAD7 partially rescued miR-216a/217-mediated EMT, cell migration, and stem-like properties of HCC cells. Previously, SMAD7 was shown to be a transforming growth factor beta (TGF-β) type 1 receptor antagonist. Here, we further demonstrated that overexpression of miR-216a/217 acted as a positive feedback regulator for the TGF-β pathway and the canonical pathway involved in the activation of phosphoinositide 3-kinase/protein kinase K (PI3K/Akt) signaling in HCC cells. Additionally, activation of the TGF-β- and PI3K/Akt-signaling pathways in HCC cells resulted in an acquired resistance to sorafenib, whereas blocking activation of the TGF-β pathway overcame miR-216a/217-induced sorafenib resistance and prevented tumor metastases in HCC. Overexpression of miR-216a/217 activates the PI3K/Akt and TGF-β pathways by targeting PTEN and SMAD7, contributing to hepatocarcinogenesis and tumor recurrence in HCC.

Xia H ，Ooi LL ，Hui KM 《-》

Role of IQGAP3 in metastasis and epithelial-mesenchymal transition in human hepatocellular carcinoma.

Shi Y ，Qin N ，Zhou Q ，Chen Y ，Huang S ，Chen B ，Shen G ，Jia H ... -  《Journal of Translational Medicine》

Activation of phosphatidylinositol 3-kinase/Akt signaling mediates sorafenib-induced invasion and metastasis in hepatocellular carcinoma.

Wang H ，Xu L ，Zhu X ，Wang P ，Chi H ，Meng Z ... -  《-》

HCC-derived exosomes elicit HCC progression and recurrence by epithelial-mesenchymal transition through MAPK/ERK signalling pathway.

Chen L ，Guo P ，He Y ，Chen Z ，Chen L ，Luo Y ，Qi L ，Liu Y ，Wu Q ，Cui Y ，Fang F ，Zhang X ，Song T ，Guo H ... -  《Cell Death & Disease》