title: GAB2 promotes cell proliferation by activating the ERK signaling pathway in hepatocellular carcinoma.
abstract: Grb2-associated binding protein 2 (GAB2), a key member of the family of Gab scaffolding adaptors, is important in the phospoinositide3-kinase (PI3K) and extracellular signal-regulated kinase (ERK) signaling pathways, and is closely associated with cell proliferation, cell transformation, and tumor progression. But its role in hepatocellular carcinoma (HCC) is still unknown. In this study, we investigated the expression of GAB2 and its potential clinical and biological significances in HCC. Western bolt and immunohistochemistrical analyses revealed that GAB2 was obviously upregulated in HCC tissues. Meanwhile, GAB2 was significantly associated with histological grade, tumor size, and the proliferation marker Ki-67 through our further analysis. The Kaplan-Meier survival curves also showed that increased GAB2 expression was directly correlated with poor prognosis in HCC patients and served as an independent prognostic marker of overall survival. Moreover, serum starvation-refeeding, RNA interference, CCK-8, EDU, colony formation, and flow-cytometry analyses were all performed with the purpose of investigating GAB2's regulation of HCC cell proliferation. Our results indicated that GAB2 progressively accumulated when cells entered into S phase. Consistently, cell proliferation was distinctly hindered by small interfering RNA. More interestingly, we discovered that GAB2 promoted cell proliferation by enhancing ERK signaling and GAB2-induced cell proliferation was inhibited by the inhibition of ERK activation. Finally, GAB2 was verified to be able to confer doxorubicin resistance in HCC cells. In summary, these data demonstrated that GAB2 might promote HCC cell proliferation by enhancing ERK signaling, and all above findings provided a potential therapeutic strategy for the treatment of HCC.
authors.affiliation: Class 2, Grade 13, Clinical Medicine, Medical College, Nantong University, Nantong, Jiangsu, 226001, People's Republic of China.
authors.forename: Yuyan
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Digestion, Affiliated Hospital of Nantong University, Nantong University, Nantong, Jiangsu, 226001, People's Republic of China.
authors.forename: Qingqing
authors.initials: Q
authors.lastname: Liu
authors.affiliation: Department of Digestion, Affiliated Hospital of Nantong University, Nantong University, Nantong, Jiangsu, 226001, People's Republic of China.
authors.forename: Miaomiao
authors.initials: M
authors.lastname: Wu
authors.affiliation: Department of Digestion, Affiliated Hospital of Nantong University, Nantong University, Nantong, Jiangsu, 226001, People's Republic of China.
authors.forename: Manhua
authors.initials: M
authors.lastname: Li
authors.affiliation: Department of Digestion, Affiliated Hospital of Nantong University, Nantong University, Nantong, Jiangsu, 226001, People's Republic of China.
authors.forename: Haifang
authors.initials: H
authors.lastname: Ding
authors.affiliation: Department of Digestion, Affiliated Hospital of Nantong University, Nantong University, Nantong, Jiangsu, 226001, People's Republic of China.
authors.forename: Xiaohang
authors.initials: X
authors.lastname: Shan
authors.affiliation: Department of Digestion, Affiliated Hospital of Nantong University, Nantong University, Nantong, Jiangsu, 226001, People's Republic of China.
authors.forename: Jinxia
authors.initials: J
authors.lastname: Liu
authors.affiliation: Jiangsu Province Key Laboratory for Inflammation and Molecular Drug Target, Nantong University, 19 Qixiu Road, Nantong, 226001, Jiangsu Province, People's Republic of China.
authors.forename: Tao
authors.initials: T
authors.lastname: Tao
authors.affiliation: Department of Digestion, Affiliated Hospital of Nantong University, Nantong University, Nantong, Jiangsu, 226001, People's Republic of China. nirunzh@163.com.
authors.forename: Runzhou
authors.initials: R
authors.lastname: Ni
authors.affiliation: Department of Oncology, Affiliated Cancer Hospital of Nantong University, Nantong, 226361, Jiangsu Province, People's Republic of China. chexdong@163.com.
authors.forename: Xudong
authors.initials: X
authors.lastname: Chen
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000502:physiology*; D000328:Adult; D000368:Aged; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004317:Doxorubicin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology*; D005260:Female; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy / Q000209:etiology / Q000473:pathology*; D020935:MAP Kinase Signaling System / Q000502:physiology*; D008297:Male; D008875:Middle Aged
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C490895:GAB2 protein, human; D004317:Doxorubicin; D048049:Extracellular Signal-Regulated MAP Kinases
keywords: Cell proliferation; Doxorubicin resistance; ERK signaling; GAB2; Hepatocellular carcinoma; Prognosis