Discs large homolog 5 decreases formation and function of invadopodia in human hepatocellular carcinoma via Girdin and Tks5.
Invadopodium formation is a crucial early event of invasion and metastasis of hepatocellular carcinoma (HCC). However, the molecular mechanisms underlying regulation of invadopodia remain elusive. This study aimed to investigate the potential role of discs large homolog 5 (Dlg5) in invadopodium formation and function in HCC. We found that Dlg5 expression was significantly lower in human HCC tissues and cell lines than adjacent nontumor tissues and liver cells. Lower Dlg5 expression was associated with advanced stages of HCC, and poor overall and disease-free survival of HCC patients. Dlg5-silencing promoted epithelial-mesenchymal transition, invadopodium formation, gelatin degradation function, and invadopodium-associated invasion of HepG2 cells. In contrast, Dlg5 overexpression inhibited epithelial-mesenchymal transition, functional invadopodium formation, and invasion of SK-Hep1 cells. Both Girdin and Tks5, but not the Tks5 nonphosphorylatable mutant, were responsible for the enhanced invadopodium formation and invasion of Dlg5-silenced HepG2 cells. Furthermore, Dlg5 interacted with Girdin and interfered with the interaction of Girdin and Tks5. Dlg5 silencing promoted Girdin and Tks5 phosphorylation, which was abrogated by Girdin silencing and rescued by inducing shRNA-resistant Girdin expression. Moreover, Dlg5 overexpression significantly inhibited HCC intrahepatic and lung metastasis in vivo. Taken together, our data indicate that Dlg5 acts as a novel regulator of invadopodium-associated invasion via Girdin and by interfering with the interaction between Girdin and Tks5, which might be important for Tks5 phosphorylation in HCC cells. Conceivably, Dlg5 may act as a new biomarker for prognosis of HCC patients.
['Ke|Yang|Y|', 'Bao|Tianhao|T|', 'Zhou|Qixin|Q|', 'Wang|Yan|Y|', 'Ge|Jiayun|J|', 'Fu|Bimang|B|', 'Wu|Xuesong|X|', 'Tang|Haoran|H|', 'Shi|Zhitian|Z|', 'Lei|Xuefen|X|', 'Zhang|Cheng|C|', 'Tan|Yuqi|Y|', 'Chen|Haotian|H|', 'Guo|Zhitang|Z|', 'Wang|Lin|L|0000-0001-7383-934X']
D033942:Adaptor Proteins, Vesicular Transport D000818:Animals D006528:Carcinoma, Hepatocellular D045744:Cell Line, Tumor D015536:Down-Regulation D058750:Epithelial-Mesenchymal Transition D005260:Female D015972:Gene Expression Regulation, Neoplastic D056945:Hep G2 Cells D006801:Humans D008113:Liver Neoplasms D008297:Male D008565:Membrane Proteins D051379:Mice D008840:Microfilament Proteins D009361:Neoplasm Invasiveness D009362:Neoplasm Metastasis D009368:Neoplasm Transplantation D010766:Phosphorylation D000069261:Podosomes D025521:Tumor Suppressor Proteins D033921:Vesicular Transport Proteins
invadopodia human hepatocellular carcinoma CCDC88A protein Dlg5 protein SH3PXD2A protein