title: Anti-apoptotic effects of osteopontin through the up-regulation of Mcl-1 in gastrointestinal stromal tumors.
abstract: BACKGROUND
  Osteopontin (OPN) is a secreted phosphoprotein expressed by neoplastic cells involved in the malignant potential and aggressive phenotypes of human malignancies, including gastrointestinal stromal tumors (GISTs). Our previous study showed that OPN can promote tumor cell proliferation in GISTs. In this series, we further aim to investigate the effect of OPN on apoptosis in GISTs.
  
  
  METHODS
  The expression of apoptotic and anti-apoptotic proteins in response to OPN was evaluated. In vitro effects of OPN against apoptosis in GIST were also assessed. GIST specimens were also used for analyzing protein expression of specific apoptosis-related molecules and their clinicopathologic significance.
  
  
  RESULTS
  Up-regulation of β-catenin and anti-apoptotic proteins Mcl-1 with concomitant suppression of apoptotic proteins in response to OPN was noted. A significant anti-apoptotic effect of OPN on imatinib-induced apoptosis was identified. Furthermore, Mcl-1 overexpression was significantly associated with OPN and β-catenin expression in tumor tissues, as well as worse survival clinically.
  
  
  CONCLUSIONS
  Our study identifies anti-apoptotic effects of OPN that, through β-catenin-mediated Mcl-1 up-regulation, significantly antagonized imatinib-induced apoptosis in GISTs. These results provide a potential rationale for therapeutic strategies targeting both OPN and Mcl-1 of the same anti-apoptotic signaling pathway, which may account for resistance to imatinib in GISTs.
authors.forename: Kai-Hsi
authors.initials: KH
authors.lastname: Hsu
authors.forename: Hung-Wen
authors.initials: HW
authors.lastname: Tsai
authors.forename: Pin-Wen
authors.initials: PW
authors.lastname: Lin
authors.forename: Yun-Shang
authors.initials: YS
authors.lastname: Hsu
authors.forename: Pei-Jung
authors.initials: PJ
authors.lastname: Lu
authors.affiliation: Department of Surgery, National Cheng Kung University, College of Medicine, Tainan 70428, Taiwan. ysshan@mail.ncku.edu.tw.
authors.forename: Yan-Shen
authors.initials: YS
authors.lastname: Shan
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D001549:Benzamides / Q000494:pharmacology; D015153:Blotting, Western; D049109:Cell Proliferation; D019008:Drug Resistance, Neoplasm; D005260:Female; D046152:Gastrointestinal Stromal Tumors / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D000068877:Imatinib Mesylate; D007124:Immunoenzyme Techniques; D008297:Male; D008875:Middle Aged; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000235:genetics / Q000378:metabolism*; D009367:Neoplasm Staging; D053495:Osteopontin / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D010879:Piperazines / Q000494:pharmacology; D011379:Prognosis; D011743:Pyrimidines / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D015854:Up-Regulation; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; C579095:MCL1 protein, human; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D010879:Piperazines; D011743:Pyrimidines; D051176:beta Catenin; D053495:Osteopontin; D000068877:Imatinib Mesylate