title: Numb downregulation suppresses cell growth and is associated with a poor prognosis of human hepatocellular carcinoma.
abstract: Numb, an endocytic adaptor, is a known cell fate determinant that participates in asymmetric cell division. The present study aimed to explore the potential roles of Numb in hepatocarcinogenesis. Numb expression was investigated in hepatocellular carcinomas (HCC) with reverse transcription‑quantitative polymerase chain reaction and immunohistochemical examination; its association with the prognosis of HCC patients was analyzed. In addition, the effects of Numb deletion on proliferation of HCC cells and its relevant molecules were evaluated in Huh7 and HepG2 cells. Numb overexpression was observed in 62% of adjacent non‑tumor tissues and 46% of tumor tissues. Overexpression of Numb in HCC was associated with histological grade, portal vein invasion and the number of tumors (P=0.001, 0.022 and 0.034 respectively). Multivariate analysis revealed that Numb expression was an independent prognostic indicator of HCC patients. Methylation of the Numb promoter contributed to hepatocarcinogenesis. In vitro assays demonstrated that Numb silencing resulted in inhibition of cell proliferation, induction of apoptosis, downregulation of cyclin‑dependent protein kinase 4 (CDK4) and S‑phase kinase‑associated protein 2 (SKP2), and upregulation of Bcl‑2 homologous antagonist/killer (BAK) and cyclin‑dependent kinase inhibitor 1 (p21). The present study suggests that downregulation of Numb inhibits colony formation and cell proliferation, induces apoptosis of HCC cells and independently predicts the poor prognosis of HCC patients. Thus, Numb has a potential role in the development and progression of HCC.
authors.affiliation: Division of Hepatobiliary‑Pancreatic Surgery, Department of Surgery, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, P.R. China.
authors.forename: Chengzhi
authors.initials: C
authors.lastname: Xie
authors.affiliation: Department of Hepatobiliary Surgery, General Hospital of Ningxia Medical University, Yinchuan, Ningxia Hui Autonomous Region 750004, P.R. China.
authors.forename: Zhenhui
authors.initials: Z
authors.lastname: Lu
authors.affiliation: Division of Hepatobiliary‑Pancreatic Surgery, Department of Surgery, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, P.R. China.
authors.forename: Guoxing
authors.initials: G
authors.lastname: Liu
authors.affiliation: Division of Hepatobiliary‑Pancreatic Surgery, Department of Surgery, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, P.R. China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Fang
authors.affiliation: Division of Hepatobiliary‑Pancreatic Surgery, Department of Surgery, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, P.R. China.
authors.forename: Jiefeng
authors.initials: J
authors.lastname: Liu
authors.affiliation: Division of Hepatobiliary‑Pancreatic Surgery, Department of Surgery, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, P.R. China.
authors.forename: Zhao
authors.initials: Z
authors.lastname: Huang
authors.affiliation: Division of Hepatobiliary‑Pancreatic Surgery, Department of Surgery, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, P.R. China.
authors.forename: Fusheng
authors.initials: F
authors.lastname: Wang
authors.affiliation: Division of Hepatobiliary‑Pancreatic Surgery, Department of Surgery, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, P.R. China.
authors.forename: Xiaolong
authors.initials: X
authors.lastname: Wu
authors.affiliation: Division of Hepatobiliary‑Pancreatic Surgery, Department of Surgery, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, P.R. China.
authors.forename: Xiaohua
authors.initials: X
authors.lastname: Lei
authors.affiliation: Division of Hepatobiliary‑Pancreatic Surgery, Department of Surgery, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, P.R. China.
authors.forename: Xiaocheng
authors.initials: X
authors.lastname: Li
authors.affiliation: Division of Hepatobiliary‑Pancreatic Surgery, Department of Surgery, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, P.R. China.
authors.forename: Yueming
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Division of Hepatobiliary‑Pancreatic Surgery, Department of Surgery, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, P.R. China.
authors.forename: Zecheng
authors.initials: Z
authors.lastname: Hu
authors.affiliation: Division of Hepatobiliary‑Pancreatic Surgery, Department of Surgery, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, P.R. China.
authors.forename: Ke
authors.initials: K
authors.lastname: Qian
authors.affiliation: Division of Hepatobiliary‑Pancreatic Surgery, Department of Surgery, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, P.R. China.
authors.forename: Jixiong
authors.initials: J
authors.lastname: Hu
authors.affiliation: Division of Hepatobiliary‑Pancreatic Surgery, Department of Surgery, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, P.R. China.
authors.forename: Shengfu
authors.initials: S
authors.lastname: Huang
authors.affiliation: Division of Hepatobiliary‑Pancreatic Surgery, Department of Surgery, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, P.R. China.
authors.forename: Dewu
authors.initials: D
authors.lastname: Zhong
authors.affiliation: Division of Hepatobiliary‑Pancreatic Surgery, Department of Surgery, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, P.R. China.
authors.forename: Xundi
authors.initials: X
authors.lastname: Xu
mesh_terms: D000328:Adult; D000368:Aged; D017209:Apoptosis; D006528:Carcinoma, Hepatocellular / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D019175:DNA Methylation; D015536:Down-Regulation; D005260:Female; D017353:Gene Deletion; D015972:Gene Expression Regulation, Neoplastic; D056945:Hep G2 Cells; D006801:Humans; D008099:Liver / Q000378:metabolism / Q000473:pathology*; D008113:Liver Neoplasms / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000235:genetics*; D011379:Prognosis; D011401:Promoter Regions, Genetic
chemical_list: D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; C113026:NUMB protein, human