title: BATF2 Deficiency Promotes Progression in Human Colorectal Cancer via Activation of HGF/MET Signaling: A Potential Rationale for Combining MET Inhibitors with IFNs.
abstract: OBJECTIVE
  BATF2, a novel IFN-stimulated gene, inhibits tumor cell proliferation, invasion, and migration. The objectives of this study were to determine how BATF2 expression is associated with colorectal cancer progression and patient outcome, to investigate how BATF2 overexpression inhibits hepatocyte growth factor (HGF)/MET signaling, and to elucidate the rationale for combining MET inhibitors with IFN.
  
  
  METHODS
  BATF2 expression in colorectal cancer tissues was determined and correlated with colorectal cancer patient prognosis. Cultured colorectal cancer cells were used to investigate the effects of BATF2 overexpression on the malignant phenotype of colorectal cancer cells and HGF/MET signaling. Tumor xenograft models were used to validate the effects of BATF2 on colorectal cancer xenograft growth and assess the efficacy of the combination of MET inhibitors with IFNs in colorectal cancer.
  
  
  RESULTS
  In colorectal cancer tissues, BATF2 was found to be significantly downregulated, and its expression negatively correlated with MET expression. Decreased BATF2 expression was associated with progression and shorter patient survival in colorectal cancer. BATF2 overexpression promoted apoptosis and inhibited proliferation, migration, and invasion in colorectal cancer cells, as well as dramatically blunted tumor xenograft growth. In addition, MET inhibitors in combination with IFNβ produced synergistic cytotoxicity both in vitro and in vivo.
  
  
  CONCLUSIONS
  Together, these novel findings suggest that BATF2, a tumor suppressor gene, is a potent negative regulator of HGF/MET signaling in colorectal cancer and may serve as a prognostic tumor marker. Furthermore, these results provide a rationale for combining MET inhibitors with IFNs in preclinical trials.
authors.affiliation: Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, China. Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China. Department of Pathology, Jinshan Hospital, Fudan University, Shanghai, China. Institute of Pathology, Fudan University, Shanghai, China.
authors.forename: Zebing
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, China. Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China. Institute of Pathology, Fudan University, Shanghai, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Wei
authors.affiliation: Scientific Research Center, Shanghai Public Health Clinical Center, Fudan University, Shanghai, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, China. Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China. Institute of Pathology, Fudan University, Shanghai, China.
authors.forename: Wenli
authors.initials: W
authors.lastname: Cui
authors.affiliation: Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, China. Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China. Institute of Pathology, Fudan University, Shanghai, China.
authors.forename: Bing
authors.initials: B
authors.lastname: Cao
authors.affiliation: Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, China. Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China. Institute of Pathology, Fudan University, Shanghai, China.
authors.forename: Cong
authors.initials: C
authors.lastname: Tan
authors.affiliation: Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, China. Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China. Institute of Pathology, Fudan University, Shanghai, China.
authors.forename: Baohua
authors.initials: B
authors.lastname: Yu
authors.affiliation: Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, China. Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China. Institute of Pathology, Fudan University, Shanghai, China.
authors.forename: Rui
authors.initials: R
authors.lastname: Bi
authors.affiliation: Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, China. Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China. Institute of Pathology, Fudan University, Shanghai, China.
authors.forename: Kaiqin
authors.initials: K
authors.lastname: Xia
authors.affiliation: Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, China. Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China. Department of Pathology, Shanghai Gongli Hospital, Shanghai, China.
authors.forename: Weixiang
authors.initials: W
authors.lastname: Chen
authors.affiliation: Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, China. Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China. Institute of Pathology, Fudan University, Shanghai, China.
authors.forename: Yiqin
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Pathology, Jinshan Hospital, Fudan University, Shanghai, China.
authors.forename: Youyuan
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, China. Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China. Institute of Pathology, Fudan University, Shanghai, China.
authors.forename: Xiang
authors.initials: X
authors.lastname: Du
authors.affiliation: Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, China. Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China. Institute of Pathology, Fudan University, Shanghai, China. xyzhou100@163.com.
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Zhou
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D050976:Basic-Leucine Zipper Transcription Factors / Q000378:metabolism*; D014408:Biomarkers, Tumor / Q000032:analysis; D015153:Blotting, Western; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D018450:Disease Progression; D016147:Genes, Tumor Suppressor; D017228:Hepatocyte Growth Factor / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D053208:Kaplan-Meier Estimate; D051379:Mice; D008807:Mice, Inbred BALB C; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*; D014162:Transfection; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; C099359:BATF protein, human; D050976:Basic-Leucine Zipper Transcription Factors; D014408:Biomarkers, Tumor; C066855:HGF protein, human; D017228:Hepatocyte Growth Factor; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met