title: HAb18G/CD147 promotes pSTAT3-mediated pancreatic cancer development via CD44s.
abstract: OBJECTIVE
  Signal transducer and activator of transcription 3 (STAT3) plays a critical role in initiation and progression of pancreatic cancer. However, therapeutically targeting STAT3 has failed clinically. We previously identified HAb18G/CD147 as an effective target for cancer treatment. In this study, we aimed to investigate the potential role of HAb18G/CD147 in STAT3-involved pancreatic tumorigenesis in vitro and in vivo.
  
  
  METHODS
  The expression of HAb18G/CD147, pSTAT3, and CD44s was determined in tissue microarrays. The tumorigenic function and molecular signaling mechanism of HAb18G/CD147 were assessed by in vitro cellular and clonogenic growth, reporter assay, immunoblot assay, immunofluorescence staining, immunoprecipitation, and in vivo tumor formation using loss or gain-of-function strategies.
  
  
  RESULTS
  Highly expressed HAb18G/CD147 promoted cellular and clonogenic growth in vitro and tumorigenicity in vivo. Cyclophilin A (CyPA), a ligand of CD147, stimulated STAT3 phosphorylation and its downstream genes cyclin D1/survivin through HAb18G/CD147-dependent mechanisms. HAb18G/CD147 was associated and colocalized with cancer stem cell marker CD44s in lipid rafts. The inhibitors of STAT3 and survivin, as well as CD44s neutralizing antibodies suppressed the HAb18G/CD147-induced cell growth. High HAb18G/CD147 expression in pancreatic cancer was significantly correlated with the poor tumor differentiation, and the high coexpression of HAb18G/CD147-CD44s-STAT3 associated with poor survival of patients with pancreatic cancer.
  
  
  CONCLUSIONS
  We identified HAb18G/CD147 as a novel upstream activator of STAT3, which interacts with CD44s and plays a critical role in the development of pancreatic cancer. The data suggest that HAb18G/CD147 could be a promising therapeutic target for highly aggressive pancreatic cancer and a surrogate marker in the STAT3-targeted molecular therapies.
authors.affiliation: Authors' Affiliations: Departments of Radiation Oncology and Surgery, University of Michigan Medical Center; Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, Michigan; Cell Engineering Research Centre and Department of Cell Biology, State Key Laboratory of Cancer Biology, Fourth Military Medical University, Xi'an; Department of Hematology/Oncology, Hainan University Medical School, Haikou, Hainan, China; Departments of Molecular Biosciences and Radiation Oncology, University of Kansas, Lawrence, Kansas; Department of Pediatrics, College of Medicine; and Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, Ohio State University, Columbus, Ohio.
authors.forename: Ling
authors.initials: L
authors.lastname: Li
authors.forename: Wenhua
authors.initials: W
authors.lastname: Tang
authors.forename: Xiaoqing
authors.initials: X
authors.lastname: Wu
authors.forename: David
authors.initials: D
authors.lastname: Karnak
authors.forename: Xiaojie
authors.initials: X
authors.lastname: Meng
authors.forename: Rachel
authors.initials: R
authors.lastname: Thompson
authors.forename: Xinbao
authors.initials: X
authors.lastname: Hao
authors.forename: Yongmin
authors.initials: Y
authors.lastname: Li
authors.forename: Xiaotan T
authors.initials: XT
authors.lastname: Qiao
authors.forename: Jiayuh
authors.initials: J
authors.lastname: Lin
authors.forename: James
authors.initials: J
authors.lastname: Fuchs
authors.forename: Diane M
authors.initials: DM
authors.lastname: Simeone
authors.forename: Zhi-Nan
authors.initials: ZN
authors.lastname: Chen
authors.forename: Theodore S
authors.initials: TS
authors.lastname: Lawrence
authors.forename: Liang
authors.initials: L
authors.lastname: Xu
mesh_terms: D000368:Aged; D000818:Animals; D051926:Basigin / Q000096:biosynthesis*; D063646:Carcinogenesis; D045744:Cell Line, Tumor; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D018960:Hyaluronan Receptors / Q000096:biosynthesis*; D053208:Kaplan-Meier Estimate; D008297:Male; D051379:Mice; D008875:Middle Aged; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000473:pathology; D050796:STAT3 Transcription Factor / Q000096:biosynthesis*; D015398:Signal Transduction / Q000235:genetics; D046888:Tissue Array Analysis; D023041:Xenograft Model Antitumor Assays
chemical_list: C497886:BSG protein, human; C473647:CD44S antigen; D018960:Hyaluronan Receptors; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D051926:Basigin