title: Dynamin2 downregulation delays EGFR endocytic trafficking and promotes EGFR signaling and invasion in hepatocellular carcinoma.
abstract: Dysregulation of endocytosis was viewed as an emerging feature of cancer development and progression. A large GTPase dynamin2 plays a significant role in receptor tyrosine kinases (RTKs) endocytosis. The study was designed to investigate its roles in hepatocellular carcinoma (HCC) metastasis and its underlying mechanism. Dynamin2 expression in cancer tissues from HCC patients was assessed by immunohistochemistry and its prognostic significance for the patients was conducted using univariate and multivariate analysis. Its role in tumor invasion and metastasis was evaluated in vitro by gene silence using siRNA-mediated approach and the small molecule inhibitor of Dynasore. EGFR expression in HCC cell lines and EGFR downstream signaling ERK1/2 was evaluated by Western-blot and immunofluorescence analyses after Dynamin2 inhibition. Our data indicated that low expression of dynamin2 was well correlated with invasion characteristics and shorter overall survival. HCC cell migration, colony formation and invasion were significantly increased after the inhibition of dynamin2 in HCC cells. Internalization of EGFR was markedly reduced when dynamin2 was knock down or inhibition. In addition, we observed that dynamin2 regulated EGF mediated EGFR downstream Ras/ERK1/2 signaling and p-ERK1/2 accumulation in nucleus. The results demonstrate a possible mechanism of dynamin involved EGFR endocytosis and modulation of metastasis in HCC. Dynamin2 inhibits the invasion and metastasis of HCC cells by the promotion of EGFR endocytosis and downregulation of ERK1/2 phosphorylation.
authors.affiliation: Liver Cancer Institute, Zhongshan Hospital, Fudan University Shanghai 200032 ; Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education Shanghai 200032.
authors.forename: Chaojie
authors.initials: C
authors.lastname: Gong
authors.affiliation: Liver Cancer Institute, Zhongshan Hospital, Fudan University Shanghai 200032 ; Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education Shanghai 200032.
authors.forename: Jubo
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Liver Cancer Institute, Zhongshan Hospital, Fudan University Shanghai 200032 ; Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education Shanghai 200032.
authors.forename: Lan
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Liver Cancer Institute, Zhongshan Hospital, Fudan University Shanghai 200032 ; Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education Shanghai 200032.
authors.forename: Yingcong
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Liver Cancer Institute, Zhongshan Hospital, Fudan University Shanghai 200032 ; Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education Shanghai 200032.
authors.forename: Hui
authors.initials: H
authors.lastname: Ma
authors.affiliation: Liver Cancer Institute, Zhongshan Hospital, Fudan University Shanghai 200032 ; Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education Shanghai 200032.
authors.forename: Weizhong
authors.initials: W
authors.lastname: Wu
authors.affiliation: Liver Cancer Institute, Zhongshan Hospital, Fudan University Shanghai 200032 ; Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education Shanghai 200032.
authors.forename: Jiefeng
authors.initials: J
authors.lastname: Cui
authors.affiliation: Liver Cancer Institute, Zhongshan Hospital, Fudan University Shanghai 200032 ; Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education Shanghai 200032.
authors.forename: Yanhong
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Liver Cancer Institute, Zhongshan Hospital, Fudan University Shanghai 200032 ; Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education Shanghai 200032.
authors.forename: Zhenggang
authors.initials: Z
authors.lastname: Ren
keywords: Dynamin2; EGFR; ERK1/2; endocytosis; hepatocellular carcinoma