The MicroRNA-21/PTEN Pathway Regulates the Sensitivity of HER2-Positive Gastric Cancer Cells to Trastuzumab

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• 作者：Kojiro Eto MD (1)
  Masaaki Iwatsuki MD ; PhD (1)
  Masayuki Watanabe MD ; PhD (1)
  Satoshi Ida MD ; PhD (1)
  Takatsugu Ishimoto MD ; PhD (1)
  Shiro Iwagami MD ; PhD (1)
  Yoshifumi Baba MD ; PhD (1)
  Yasuo Sakamoto MD ; PhD (1)
  Yuji Miyamoto MD ; PhD (1)
  Naoya Yoshida MD ; PhD (1)
  Hideo Baba MD ; PhD ; FACS (1)
  
• 刊名：Annals of Surgical Oncology
• 出版年：2014
• 出版时间：January 2014
• 年：2014
• 卷：21
• 期：1
• 页码：343-350
• 全文大小：516 KB
• 作者单位：Kojiro Eto MD (1)
  Masaaki Iwatsuki MD, PhD (1)
  Masayuki Watanabe MD, PhD (1)
  Satoshi Ida MD, PhD (1)
  Takatsugu Ishimoto MD, PhD (1)
  Shiro Iwagami MD, PhD (1)
  Yoshifumi Baba MD, PhD (1)
  Yasuo Sakamoto MD, PhD (1)
  Yuji Miyamoto MD, PhD (1)
  Naoya Yoshida MD, PhD (1)
  Hideo Baba MD, PhD, FACS (1)
  
  1. Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
  
• ISSN：1534-4681

文摘

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.