title: ShRNA-targeted MAP4K4 inhibits hepatocellular carcinoma growth.
abstract: OBJECTIVE
  Mitogen-activated protein kinase kinase kinase kinase 4 (MAP4K4) is overexpressed in many types of cancer. Herein, we aimed to investigate its expression pattern, clinical significance, and biological function in hepatocellular carcinoma (HCC).
  
  
  METHODS
  MAP4K4 expression was examined in 20 fresh HCCs and corresponding nontumor liver tissues. Immunohistochemistry for MAP4K4 was performed on additional 400 HCCs, of which 305 (76%) were positive for hepatitis B surface antigens. The clinical significance of MAP4K4 expression was analyzed. MAP4K4 downregulation was performed in HCC cell lines HepG2 and Hep3B with high abundance of MAP4K4, and the effects of MAP4K4 silencing on cell proliferation in vitro and tumor growth in vivo were evaluated. Quantitative real-time PCR arrays were employed to identify the MAP4K4-regulated signaling pathways.
  
  
  RESULTS
  MAP4K4 was aberrantly overexpressed in HCCs relative to adjacent nontumor liver tissues. This overexpression was significantly associated with larger tumor size, increased histologic grade, advanced tumor stage, and intrahepatic metastasis, as well as worse overall survival and higher early recurrence rate. Knockdown of the MAP4K4 expression reduced cell proliferation, blocked cell cycle at S phase, and increased apoptosis. The antitumor effects of MAP4K4 silencing were also observed in vivo, manifested as retarded tumor xenograft growth. Furthermore, multiple tumor progression-related signaling pathways including JNK, NFκB, and toll-like receptors were repressed by MAP4K4 downregulation.
  
  
  CONCLUSIONS
  MAP4K4 overexpression is an independent predictor of poor prognosis of HCC patients, and inhibition of its expression might be of therapeutic significance.
authors.affiliation: Department of Pathology, Yueyang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
authors.forename: An-Wen
authors.initials: AW
authors.lastname: Liu
authors.forename: Jing
authors.initials: J
authors.lastname: Cai
authors.forename: Xiang-Li
authors.initials: XL
authors.lastname: Zhao
authors.forename: Ting-Hui
authors.initials: TH
authors.lastname: Jiang
authors.forename: Tian-Feng
authors.initials: TF
authors.lastname: He
authors.forename: Hua-Qun
authors.initials: HQ
authors.lastname: Fu
authors.forename: Ming-Hua
authors.initials: MH
authors.lastname: Zhu
authors.forename: Shu-Hui
authors.initials: SH
authors.lastname: Zhang
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D006528:Carcinoma, Hepatocellular / Q000378:metabolism / Q000473:pathology*; D002453:Cell Cycle / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D005260:Female; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D053208:Kaplan-Meier Estimate; D008113:Liver Neoplasms / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008875:Middle Aged; D015999:Multivariate Analysis; D009368:Neoplasm Transplantation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics; D014183:Transplantation, Heterologous; D047368:Tumor Burden / Q000235:genetics; D015854:Up-Regulation; D055815:Young Adult
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D034741:RNA, Small Interfering; C117090:MAP4K4 protein, human; D017346:Protein Serine-Threonine Kinases