title: Aspirin minimized the pro-metastasis effect of sorafenib and improved survival by up-regulating HTATIP2 in hepatocellular carcinoma.
abstract: OBJECTIVE
  We previously demonstrated the pro-metastasis effect of sorafenib in hepatocellular carcinoma (HCC), which is mediated by down-regulation of tumor suppressor HTATIP2. The aim of the present study was to determine whether aspirin minimizes this effect and improves survival.
  
  
  METHODS
  The effects of sorafenib, aspirin, and combined sorafenib and aspirin were observed in HCCLM3 and HepG2 xenograft nude mice. Tumor growth, intrahepatic metastasis (IHM), lung metastasis, and survival were assessed. Polymerase chain reaction (PCR) array, real-time (RT)-PCR, and Western blotting were used to examine gene expression. The anti-invasion and anti-metastasis effects of aspirin were studied in HTATIP2-knockdown and HTATIP2-overexpressing HCC cell lines. The molecular mechanism of HTATIP2 regulation by aspirin was explored.
  
  
  RESULTS
  Aspirin suppressed the pro-invasion and pro-metastasis effects of sorafenib in HCC and up-regulated HTATIP2 expression. Aspirin did not inhibit the proliferation of HCC cells, but it decreased the invasiveness of HCC with lower expression of HTATIP2 and increased expression of a set of markers, indicating a mesenchymal-to-epithelial transition in tumor cells. The up-regulation of HTATPI2 expression by aspirin is most likely mediated through inhibition of cyclooxygenase (COX) 2 expression.
  
  
  CONCLUSIONS
  Aspirin minimized the pro-metastasis effect of sorafenib by up-regulating the tumor suppressor HTATIP2; this mechanism is mediated through inhibition of COX2.
authors.affiliation: Liver Cancer Institute and Zhongshan Hospital, Fudan University; Key Laboratory for Carcinogenesis and Cancer Invasion, The Chinese Ministry of Education, Shanghai, P.R. China.
authors.forename: Lu
authors.initials: L
authors.lastname: Lu
authors.forename: Hui-Chuan
authors.initials: HC
authors.lastname: Sun
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.forename: Zong-Tao
authors.initials: ZT
authors.lastname: Chai
authors.forename: Xiao-Dong
authors.initials: XD
authors.lastname: Zhu
authors.forename: Ling-Qun
authors.initials: LQ
authors.lastname: Kong
authors.forename: Wen-Quan
authors.initials: WQ
authors.lastname: Wang
authors.forename: Ke-Zhi
authors.initials: KZ
authors.lastname: Zhang
authors.forename: Yuan-Yuan
authors.initials: YY
authors.lastname: Zhang
authors.forename: Qiang-Bo
authors.initials: QB
authors.lastname: Zhang
authors.forename: Jian-Yang
authors.initials: JY
authors.lastname: Ao
authors.forename: Jia-Qi
authors.initials: JQ
authors.lastname: Li
authors.forename: Lu
authors.initials: L
authors.lastname: Wang
authors.forename: Wei-Zhong
authors.initials: WZ
authors.lastname: Wu
authors.forename: Zhao-You
authors.initials: ZY
authors.lastname: Tang
mesh_terms: D000123:Acetyltransferases / Q000235:genetics*; D000818:Animals; D001241:Aspirin / Q000008:administration & dosage / Q000494:pharmacology*; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000401:mortality / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D051546:Cyclooxygenase 2 / Q000235:genetics; D004195:Disease Models, Animal; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D053263:Gene Regulatory Networks / Q000187:drug effects; D056945:Hep G2 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology*; D008297:Male; D051379:Mice; D009362:Neoplasm Metastasis; D009536:Niacinamide / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D010671:Phenylurea Compounds / Q000008:administration & dosage / Q000494:pharmacology*; D000077157:Sorafenib; D014157:Transcription Factors / Q000235:genetics*; D047368:Tumor Burden / Q000187:drug effects / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
chemical_list: D010671:Phenylurea Compounds; D014157:Transcription Factors; D009536:Niacinamide; D000077157:Sorafenib; D051546:Cyclooxygenase 2; D000123:Acetyltransferases; C111246:HTATIP2 protein, human; D001241:Aspirin