title: A tumorigenic factor interactome connected through tumor suppressor microRNA-198 in human pancreatic cancer.
abstract: OBJECTIVE
  The majority of pancreatic cancers overexpress mesothelin (MSLN), which contributes to enhanced proliferation, invasion, and migration. However, the MSLN regulatory network is still unclear. Here, we investigated the regulation of a panel of tumorigenic factors and explored the potential of MSLN-regulated miR-198 treatment in vivo.
  
  
  METHODS
  The expression and functional regulation of the tumorigenic factors MSLN, NF-κB, and the homeobox transcription factors (TF) POU2F2 (OCT-2), Pre-B-cell leukemia homeobox factor 1 (PBX-1), valosin-containing protein (VCP), and miR-198 were studied in pancreatic cancer cell lines, patient tumor samples, and xenograft pancreatic cancer mouse models.
  
  
  RESULTS
  We found that miR-198 is downregulated in pancreatic cancer and is involved in an intricate reciprocal regulatory loop with MSLN, which represses miR-198 through NF-κB-mediated OCT-2 induction. Furthermore, miR-198 repression leads to overexpression of PBX-1 and VCP. The dysregulated PBX-1/VCP axis leads to increased tumorigenicity. Reconstitution of miR-198 in pancreatic cancer cells results in reduced tumor growth, metastasis, and increased survival through direct targeting MSLN, PBX-1, and VCP. Most interestingly, reduced levels of miR-198 in human tissue samples are associated with upregulation of these tumorigenic factors (MSLN, OCT-2, PBX-1, VCP) and predict poor survival. Reduced miR-198 expression links this tumor network signature and prognosticates poor patient outcome. High miR-198 disrupts the network and predicts better prognosis and increased survival.
  
  
  CONCLUSIONS
  miR-198 acts as a central tumor suppressor and modulates the molecular makeup of a critical interactome in pancreatic cancer, indicating a potential prognostic marker signature and the therapeutic potential of attacking this tumorigenic network through a central vantage point.
authors.affiliation: Authors' Affiliations: Molecular Surgeon Research Center, Michael E. DeBakey Department of Surgery, Department of Molecular Virology and Microbiology, Duncan Cancer Center, Baylor College of Medicine; and Department of Molecular and Cellular Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas, Graduate Institute of Cancer Biology, China Medical University, Taichung, Taiwan; Center for Translational Research on Inflammatory Diseases, Michael E. DeBakey Veterans Affairs Medical Center, Houston, Texas.
authors.forename: Christian
authors.initials: C
authors.lastname: Marin-Muller
authors.forename: Dali
authors.initials: D
authors.lastname: Li
authors.forename: Uddalak
authors.initials: U
authors.lastname: Bharadwaj
authors.forename: Min
authors.initials: M
authors.lastname: Li
authors.forename: Changyi
authors.initials: C
authors.lastname: Chen
authors.forename: Sally E
authors.initials: SE
authors.lastname: Hodges
authors.forename: William E
authors.initials: WE
authors.lastname: Fisher
authors.forename: Qianxing
authors.initials: Q
authors.lastname: Mo
authors.forename: Mien-Chie
authors.initials: MC
authors.lastname: Hung
authors.forename: Qizhi
authors.initials: Q
authors.lastname: Yao
mesh_terms: D000251:Adenosine Triphosphatases / Q000235:genetics / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D019898:Autocrine Communication / Q000235:genetics; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D004789:Enzyme Activation; D058851:GPI-Linked Proteins / Q000235:genetics / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D053263:Gene Regulatory Networks; D016147:Genes, Tumor Suppressor; D006801:Humans; D000090204:Mesothelin; D051379:Mice; D035683:MicroRNAs / Q000235:genetics*; D016328:NF-kappa B / Q000378:metabolism; D009362:Neoplasm Metastasis; D050813:Octamer Transcription Factor-2 / Q000378:metabolism; D016366:Open Reading Frames / Q000235:genetics; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D000075062:Pre-B-Cell Leukemia Transcription Factor 1; D011379:Prognosis; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D047368:Tumor Burden / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D000074405:Valosin Containing Protein
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D058851:GPI-Linked Proteins; C535221:MIRN198 microRNA, human; C000715527:MSLN protein, human; D035683:MicroRNAs; C000715528:Msln protein, mouse; D016328:NF-kappa B; D050813:Octamer Transcription Factor-2; D000075062:Pre-B-Cell Leukemia Transcription Factor 1; D011518:Proto-Oncogene Proteins; D014409:Tumor Necrosis Factor-alpha; C083400:PBX1 protein, human; D000251:Adenosine Triphosphatases; C000614178:VCP protein, human; D000074405:Valosin Containing Protein; C000614179:Vcp protein, mouse; D000090204:Mesothelin