title: Discs large homolog 5 decreases formation and function of invadopodia in human hepatocellular carcinoma via Girdin and Tks5.
abstract: 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.
authors.affiliation: Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Kunming Medical University, Kunming, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Ke
authors.affiliation: Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Kunming Medical University, Kunming, China.|The Mental Health Center of Kunming Medical University, Kunming, China.
authors.forename: Tianhao
authors.initials: T
authors.lastname: Bao
authors.affiliation: Key Laboratory of Animal Models and Human Disease Mechanisms, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, China.
authors.forename: Qixin
authors.initials: Q
authors.lastname: Zhou
authors.affiliation: Department of Pathology, The Second Affiliated Hospital of Kunming Medical University, Kunming, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Kunming Medical University, Kunming, China.
authors.forename: Jiayun
authors.initials: J
authors.lastname: Ge
authors.affiliation: Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Kunming Medical University, Kunming, China.
authors.forename: Bimang
authors.initials: B
authors.lastname: Fu
authors.affiliation: Department of Gastroenterological Surgery, The Second Affiliated Hospital of Kunming Medical University, Kunming, China.
authors.forename: Xuesong
authors.initials: X
authors.lastname: Wu
authors.affiliation: Department of Gastroenterological Surgery, The Second Affiliated Hospital of Kunming Medical University, Kunming, China.
authors.forename: Haoran
authors.initials: H
authors.lastname: Tang
authors.affiliation: Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Kunming Medical University, Kunming, China.
authors.forename: Zhitian
authors.initials: Z
authors.lastname: Shi
authors.affiliation: Deparment of Medical Oncology, The Second Affiliated Hospital of Kunming Medical University, Kunming, China.
authors.forename: Xuefen
authors.initials: X
authors.lastname: Lei
authors.affiliation: Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Kunming Medical University, Kunming, China.
authors.forename: Cheng
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Kunming Medical University, Kunming, China.
authors.forename: Yuqi
authors.initials: Y
authors.lastname: Tan
authors.affiliation: Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Kunming Medical University, Kunming, China.
authors.forename: Haotian
authors.initials: H
authors.lastname: Chen
authors.affiliation: Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Kunming Medical University, Kunming, China.
authors.forename: Zhitang
authors.initials: Z
authors.lastname: Guo
authors.affiliation: Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Kunming Medical University, Kunming, China.
authors.forename: Lin
authors.identifier: 0000-0001-7383-934X
authors.initials: L
authors.lastname: Wang
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000378:metabolism*; D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000378:metabolism / Q000473:pathology*; 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 / Q000378:metabolism / Q000473:pathology*; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008840:Microfilament Proteins / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D010766:Phosphorylation; D000069261:Podosomes / Q000502:physiology*; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D033921:Vesicular Transport Proteins / Q000378:metabolism*
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; C502451:CCDC88A protein, human; C114461:DLG5 protein, human; D008565:Membrane Proteins; D008840:Microfilament Proteins; C478582:SH3PXD2A protein, human; D025521:Tumor Suppressor Proteins; D033921:Vesicular Transport Proteins
keywords: CCDC88A protein; Dlg5 protein; SH3PXD2A protein; human hepatocellular carcinoma; invadopodia