title: HDGF-related protein-3 is required for anchorage-independent survival and chemoresistance in hepatocellular carcinomas.
abstract: OBJECTIVE
  Hepatoma-derived growth factor (HDGF)-related proteins (HRPs) comprise a family of six members and are characterised by a conserved HATH domain. Among the family members, HDGF was the first to be identified as a mitogenic factor and shown to play an important role in hepatocellular carcinoma pathogenesis. The aim of the present study is to examine the relevance of HDGF-related protein-3 (HRP-3), another member of the HRP family in hepatocellular carcinoma (HCC).
  
  
  METHODS
  HRP-3 expression in HCC tissues was measured by quantitative reverse transcriptase PCR, western blot and immunohistochemistry analysis. The biological consequences of overexpression and knockdown of HRP-3 in HCC cell lines were studied in vitro and in vivo.
  
  
  RESULTS
  Expression of HRP-3 mRNA and protein was shown to be highly upregulated in HCC tissues. While knockdown of HRP-3 by small interference RNAs failed to affect anchorage-dependent growth of HCC cells, it inhibited anchorage-independent growth of HCC cells in vitro and xenograft tumour growth in vivo. Further, knockdown of HRP-3 was shown to sensitise HCC cells to anoikis. Moreover, HRP-3 specifically activated the extracellular-signal-regulated kinase (ERK) pathway without affecting c-Jun N-terminal kinase (JNK), p38, AKT and signal transducer and activator of transcription 3 (STAT3). Importantly, inhibition of the ERK pathway diminished HRP-3-mediated protection of HCC cells from anoikis. Finally, knockdown of HRP-3 was shown to enhance apoptosis of HCC cells induced by multiple chemotherapeutic drugs.
  
  
  CONCLUSIONS
  These findings indicate that HRP-3 plays an essential role in HCC pathogenesis and suggest that it may serve as a novel prognostic marker and molecular target for development of drugs for treatment of HCC.
authors.affiliation: The State Key Laboratory of Genetic Engineering, Fudan University, 220 Handan Road, Shanghai 200433, People's Republic of China.
authors.forename: Qianyi
authors.initials: Q
authors.lastname: Xiao
authors.forename: Kai
authors.initials: K
authors.lastname: Qu
authors.forename: Chenji
authors.initials: C
authors.lastname: Wang
authors.forename: Yahui
authors.initials: Y
authors.lastname: Kong
authors.forename: Chao
authors.initials: C
authors.lastname: Liu
authors.forename: Deke
authors.initials: D
authors.lastname: Jiang
authors.forename: Hexige
authors.initials: H
authors.lastname: Saiyin
authors.forename: Fan
authors.initials: F
authors.lastname: Jia
authors.forename: Canrong
authors.initials: C
authors.lastname: Ni
authors.forename: Taoyang
authors.initials: T
authors.lastname: Chen
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Zhang
authors.forename: Pingzhao
authors.initials: P
authors.lastname: Zhang
authors.forename: Wenxin
authors.initials: W
authors.lastname: Qin
authors.forename: Qingwen
authors.initials: Q
authors.lastname: Sun
authors.forename: Hongyang
authors.initials: H
authors.lastname: Wang
authors.forename: Qing
authors.initials: Q
authors.lastname: Yi
authors.forename: Jun
authors.initials: J
authors.lastname: Liu
authors.forename: Haojie
authors.initials: H
authors.lastname: Huang
authors.forename: Long
authors.initials: L
authors.lastname: Yu
mesh_terms: D000818:Animals; D023102:Anoikis; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D003598:Cytoskeletal Proteins; D019008:Drug Resistance, Neoplasm; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005786:Gene Expression Regulation / Q000502:physiology*; D055785:Gene Knockdown Techniques; D006801:Humans; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D047908:Intracellular Signaling Peptides and Proteins; D008113:Liver Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D009687:Nuclear Proteins / Q000502:physiology*; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015854:Up-Regulation
chemical_list: D003598:Cytoskeletal Proteins; C498539:HDGFL3 protein, human; D047908:Intracellular Signaling Peptides and Proteins; D009687:Nuclear Proteins; D012333:RNA, Messenger; D048049:Extracellular Signal-Regulated MAP Kinases