title: Sorafenib down-regulates expression of HTATIP2 to promote invasiveness and metastasis of orthotopic hepatocellular carcinoma tumors in mice.
abstract: OBJECTIVE
  Antiangiogenic agents can sometimes promote tumor invasiveness and metastasis, but little is known about the effects of the antiangiogenic drug sorafenib on progression of hepatocellular carcinoma (HCC).
  
  
  METHODS
  Sorafenib was administered orally (30 mg · kg(-1) · day(-1)) to mice with orthotopic tumors grown from HCC-LM3, SMMC7721, or HepG2 cells. We analyzed survival times of mice, along with tumor growth, metastasis within liver and to lung, and induction of the epithelial-mesenchymal transition. Polymerase chain reaction arrays were used to determine the effects of sorafenib on gene expression patterns in HCC cells. We analyzed regulation of HIV-1 Tat interactive protein 2 (HTATIP2) by sorafenib and compared levels of this protein in tumor samples from 75 patients with HCC (21 who received sorafenib after resection and 54 who did not).
  
  
  RESULTS
  Sorafenib promoted invasiveness and the metastatic potential of orthotopic tumors grown from SMMC7721 and HCC-LM3 cells but not from HepG2 cells. In gene expression analysis, HTATIP2 was down-regulated by sorafenib. HCC-LM3 cells that expressed small hairpin RNAs against HTATIP2 (knockdown) formed less invasive tumors in mice following administration of sorafenib than HCC-LM3 without HTATIP2 knockdown. Alternatively, HepG2 cells that expressed transgenic HTATIP2 formed more invasive tumors in mice following administration of sorafenib. Sorafenib induced the epithelial-mesenchymal transition in HCC cell lines, which was associated with expression of HTATIP2. Sorafenib regulated expression of HTATIP2 via Jun-activated kinase (JAK) and signal transducer and activator of transcription (STAT)3 signaling. Sorafenib therapy prolonged recurrence-free survival in patients who expressed lower levels of HTATIP2 compared with higher levels.
  
  
  CONCLUSIONS
  Sorafenib promotes invasiveness and the metastatic potential of orthotopic tumors from HCC cells in mice, down-regulating expression of HTATIP2 via JAK-STAT3 signaling.
authors.affiliation: Liver Cancer Institute and Zhongshan Hospital, Fudan University, Key Laboratory for Carcinogenesis and Cancer Invasion, The Chinese Ministry of Education, Shanghai 200032, P.R. China.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.forename: Hui-Chuan
authors.initials: HC
authors.lastname: Sun
authors.forename: Wen-Quan
authors.initials: WQ
authors.lastname: Wang
authors.forename: Qiang-Bo
authors.initials: QB
authors.lastname: Zhang
authors.forename: Peng-Yuan
authors.initials: PY
authors.lastname: Zhuang
authors.forename: Yu-Quan
authors.initials: YQ
authors.lastname: Xiong
authors.forename: Xiao-Dong
authors.initials: XD
authors.lastname: Zhu
authors.forename: Hua-Xiang
authors.initials: HX
authors.lastname: Xu
authors.forename: Ling-Qun
authors.initials: LQ
authors.lastname: Kong
authors.forename: Wei-Zhong
authors.initials: WZ
authors.lastname: Wu
authors.forename: Lu
authors.initials: L
authors.lastname: Wang
authors.forename: Tian-Qiang
authors.initials: TQ
authors.lastname: Song
authors.forename: Qiang
authors.initials: Q
authors.lastname: Li
authors.forename: Zhao-You
authors.initials: ZY
authors.lastname: Tang
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000473:pathology* / Q000503:physiopathology*; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects*; D056945:Hep G2 Cells; D006801:Humans; D053612:Janus Kinases / Q000502:physiology; D008113:Liver Neoplasms / Q000473:pathology* / Q000503:physiopathology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009361:Neoplasm Invasiveness / Q000503:physiopathology; D009362:Neoplasm Metastasis / Q000503:physiopathology; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D010671:Phenylurea Compounds / Q000494:pharmacology*; D012097:Repressor Proteins / Q000502:physiology*; D050796:STAT3 Transcription Factor / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology; D000077157:Sorafenib; D014183:Transplantation, Heterologous; D025521:Tumor Suppressor Proteins / Q000502:physiology*
chemical_list: D020533:Angiogenesis Inhibitors; D010671:Phenylurea Compounds; D012097:Repressor Proteins; D050796:STAT3 Transcription Factor; C525546:Tip30 protein, mouse; D025521:Tumor Suppressor Proteins; D009536:Niacinamide; D000077157:Sorafenib; D053612:Janus Kinases