title: STAT3 activation in monocytes accelerates liver cancer progression.
abstract: BACKGROUND
  Signal transducer and activator of transcription 3 (STAT3) is an important transcription factor ubiquitously expressed in different cell types. STAT3 plays an essential role in cell survival, proliferation, and differentiation. Aberrantly hyper-activated STAT3 signaling in cancer cells and in the tumor microenvironment has been detected in a wide variety of human cancers and is considered an important factor for cancer initiation, development, and progression. However, the role of STAT3 activation in monocytes in the development of HCC has not been well understood.
  
  
  METHODS
  Immunohistochemical analysis of phosphorylated STAT3 was performed on tissue microarray from HCC patients. Using a co-culture system in vivo, HCC cell growth was determined by the MTT assay. In vivo experiments were conducted with mice given diethylinitrosamine (DEN), which induces HCC was used to investigate the role of STAT3 expression in monocytes on tumor growth. Real-time PCR was used to determine the expression of cell proliferation and cell arrest associated genes in the tumor and nontumor tissue from liver.
  
  
  RESULTS
  Phosphorylated STAT3 was found in human hepatocellular carcinoma tissue samples and was expressed in tumor cells and also in monocytes. Phosphorylated STAT3 expression in monocyte was significantly correlated to advanced clinical stage of HCC and a poor prognosis. Using a co-culture system in vivo, monocytes promoted HCC cell growth via the IL-6/STAT3 signaling pathway. The STAT3 inhibitor, NSC 74859, significantly suppressed tumor growth in vivo in mice with diethylinitrosamine (DEN)-induced HCC. In this animal model, blockade of STAT3 with NSC 74859 induced tumor cell apoptosis, while inhibiting both tumor cells and monocytes proliferation. Furthermore, NSC 74859 treatment suppressed cancer associated inflammation in DEN-induce HCC.
  
  
  CONCLUSIONS
  Our data suggest constitutively activated STAT3 monocytes promote liver tumorigenesis in clinical patients and animal experiments. Thus, STAT3 in tumor infiltrating inflammatory cells may an attractive target for liver cancer therapy.
authors.affiliation: Department of General Surgery, First Affiliated Hospital of Anhui MedicalUniversity, Anhui, Hefei, People’s Republic of China.
authors.forename: Wen-Yong
authors.initials: WY
authors.lastname: Wu
authors.forename: Jun
authors.initials: J
authors.lastname: Li
authors.forename: Zheng-Sheng
authors.initials: ZS
authors.lastname: Wu
authors.forename: Chang-Le
authors.initials: CL
authors.lastname: Zhang
authors.forename: Xiang-Ling
authors.initials: XL
authors.lastname: Meng
mesh_terms: D000636:Aminosalicylic Acids / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001557:Benzenesulfonates / Q000494:pharmacology; D002273:Carcinogens; D006528:Carcinoma, Hepatocellular / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004052:Diethylnitrosamine; D004195:Disease Models, Animal; D018450:Disease Progression; D006801:Humans; D015850:Interleukin-6 / Q000494:pharmacology; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism*; D012337:RNA, Ribosomal, 18S / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D000636:Aminosalicylic Acids; D001557:Benzenesulfonates; D002273:Carcinogens; D015850:Interleukin-6; C520337:NSC 74859; D012337:RNA, Ribosomal, 18S; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D004052:Diethylnitrosamine