title: The microRNA-21/PTEN pathway regulates the sensitivity of HER2-positive gastric cancer cells to trastuzumab.
abstract: BACKGROUND
  The ToGA trial demonstrated the significant efficacy of trastuzumab in addition to chemotherapy in patients with HER2-positive gastric cancer (GC). Although trastuzumab has become a key drug in breast cancer treatment, resistance to trastuzumab is a major problem in clinical practice. The aim of the current study was to identify the micro-RNA (miR)/gene pathway regulating the sensitivity of HER2-positive GC cells to trastuzumab.
  
  
  METHODS
  Correlations between the expression levels of miR-21, PTEN, and p-AKT were analyzed by real-time PCR and Western blot test in HER2-positive GC cell lines. The effects of overexpression or suppression of miR-21 on the sensitivity of GC cells to trastuzumab were also analyzed in vitro.
  
  
  RESULTS
  Overexpression of miR-21 down-regulated PTEN expression, increased AKT phosphorylation, and did not affect HER2 expression. Inversely, suppression of miR-21 increased PTEN expression and down-regulated AKT phosphorylation, but still did not affect HER2 expression. Overexpression of miR-21 decreased the sensitivity of GC cells to trastuzumab, while suppression of miR-21 expression restored the resistance of GC cells to trastuzumab. Overexpression of miR-21 significantly suppressed trastuzumab-induced apoptosis.
  
  
  CONCLUSIONS
  To our knowledge, this study was the first reveal the miR-21/PTEN pathway regulated the sensitivity of HER2-positive GC cell lines to trastuzumab through modulation apoptosis. These findings suggest that this pathway may be crucial to the mechanism of resistance to trastuzumab in GC, which may lead to the development of individualized treatment in clinical practice.
authors.affiliation: Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Kojiro
authors.initials: K
authors.lastname: Eto
authors.forename: Masaaki
authors.initials: M
authors.lastname: Iwatsuki
authors.forename: Masayuki
authors.initials: M
authors.lastname: Watanabe
authors.forename: Satoshi
authors.initials: S
authors.lastname: Ida
authors.forename: Takatsugu
authors.initials: T
authors.lastname: Ishimoto
authors.forename: Shiro
authors.initials: S
authors.lastname: Iwagami
authors.forename: Yoshifumi
authors.initials: Y
authors.lastname: Baba
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Sakamoto
authors.forename: Yuji
authors.initials: Y
authors.lastname: Miyamoto
authors.forename: Naoya
authors.initials: N
authors.lastname: Yoshida
authors.forename: Hideo
authors.initials: H
authors.lastname: Baba
mesh_terms: D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D035683:MicroRNAs / Q000235:genetics*; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D000068878:Trastuzumab; D014407:Tumor Cells, Cultured
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D035683:MicroRNAs; D051059:PTEN Phosphohydrolase; D012333:RNA, Messenger; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; C524940:MIRN21 microRNA, human; C508053:ERBB2 protein, human; C494929:PTEN protein, human