title: Transforming growth factor β and Ras/MEK/ERK signaling regulate the expression level of a novel tumor suppressor Lefty.
abstract: OBJECTIVE
  The objectives of the present study were (i) to identify a novel tumor suppressor gene whose expression level was regulated by transforming growth factor (TGF-β) and (ii) to evaluate the effect of Ras/MEK/ERK signaling on TGF-β-dependent Lefty up-regulation.
  
  
  METHODS
  Human pancreatic cancer cell lines were used. The effect of Ras/MEK/ERK pathway on TGF-β-mediated Lefty up-regulation was tested by adding K-ras small interfering RNA, MEK inhibitor U0126, or extracellular signal-regulated kinase (ERK) inhibitor LY294002.
  
  
  RESULTS
  Transforming growth factor β upregulated Lefty messenger RNA levels within 6 of the 7 cell lines. Lefty exerts an antagonistic effect against the tumor-promoting molecule, Nodal, as recombinant Lefty suppressed Nodal-mediated proliferation. Interestingly, inhibition of the Ras/MEK/ERK pathway dramatically enhanced TGF-mediated Lefty up-regulation, suggesting that Ras/MEK/ERK signaling suppresses TGF-β-Lefty pathway.
  
  
  CONCLUSIONS
  Our data suggest that Lefty is a novel TGF-β target molecule that mediates growth inhibition of pancreatic cancer cells. In addition, activation of the Ras/MEK/ERK pathway serves as a mechanism by which pancreatic cancer escapes from growth inhibition by the TGF-β-Lefty axis. The results imply a novel therapeutic strategy for pancreatic cancer, that is, combination treatment with Ras/MEK/ERK inhibitors and TGF-β.
authors.affiliation: Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan. bluebirdmiyata@hotmail.com
authors.forename: Naoteru
authors.initials: N
authors.lastname: Miyata
authors.forename: Toshifumi
authors.initials: T
authors.lastname: Azuma
authors.forename: Shigenari
authors.initials: S
authors.lastname: Hozawa
authors.forename: Hajime
authors.initials: H
authors.lastname: Higuchi
authors.forename: Akiko
authors.initials: A
authors.lastname: Yokoyama
authors.forename: Ayano
authors.initials: A
authors.lastname: Kabashima
authors.forename: Toru
authors.initials: T
authors.lastname: Igarashi
authors.forename: Keita
authors.initials: K
authors.lastname: Saeki
authors.forename: Toshifumi
authors.initials: T
authors.lastname: Hibi
mesh_terms: D002070:Butadienes / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002867:Chromones / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D055458:Left-Right Determination Factors / Q000235:genetics*; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors; D009025:Morpholines / Q000494:pharmacology; D009570:Nitriles / Q000494:pharmacology; D020411:Oligonucleotide Array Sequence Analysis; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011720:Pyrazoles / Q000494:pharmacology; D011724:Pyridazines / Q000494:pharmacology; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D025521:Tumor Suppressor Proteins / Q000235:genetics; D015854:Up-Regulation / Q000187:drug effects; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D002070:Butadienes; D002867:Chromones; C505241:FR 180204; C526161:LEFTY1 protein, human; D055458:Left-Right Determination Factors; D009025:Morpholines; D009570:Nitriles; D011720:Pyrazoles; D011724:Pyridazines; D016212:Transforming Growth Factor beta; D025521:Tumor Suppressor Proteins; C113580:U 0126; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D048049:Extracellular Signal-Regulated MAP Kinases; D020928:Mitogen-Activated Protein Kinases; D018631:ras Proteins