The MicroRNA-21/PTEN Pathway Regulates the Sensitivity of HER2-Positive Gastric Cancer Cells to Trastuzumab
The MicroRNA-21/PTEN Pathway Regulates the Sensitivity of HER2-Positive Gastric Cancer Cells to Trastuzumab
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DOI：
10.1245/s10434-013-3325-7
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发表时间：
2014-01-01
影响因子：
3.7
通讯作者：
Baba, Hideo
中科院分区：
文献类型：
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作者：
Eto, Kojiro;Iwatsuki, Masaaki;Baba, Hideo
背景ToGA试验证明了曲妥珠单抗联合化疗在HER 2阳性胃癌（GC）患者中的显著疗效。虽然曲妥珠单抗已成为乳腺癌治疗的关键药物，但对曲妥珠单抗的耐药性是临床实践中的主要问题。本研究的目的是确定micro-RNA（miR）/基因通路调节HER 2阳性胃癌细胞对曲妥珠单抗的敏感性。在HER 2阳性的胃癌细胞系中，通过实时定量PCR和Western印迹试验分析miR-21、PTEN和p-AKT表达水平之间的相关性。体外实验分析miR-21过表达或抑制对胃癌细胞曲妥珠单抗敏感性的影响。miR-21的过表达下调了PTEN的表达，增加了AKT的磷酸化，但不影响HER 2的表达。然而，抑制miR-21增加了PTEN表达并下调了AKT磷酸化，但仍然不影响HER 2表达。过表达miR-21降低了胃癌细胞对曲妥珠单抗的敏感性，而抑制miR-21表达则恢复了胃癌细胞对曲妥珠单抗的耐药性。miR-21的过表达显著抑制曲妥珠单抗诱导的肿瘤坏死。据我们所知，本研究首次揭示了miR-21/PTEN通路通过调节细胞凋亡来调节HER 2阳性胃癌细胞系对曲妥珠单抗的敏感性。这些发现表明，这一途径可能是至关重要的机制，曲妥珠单抗耐药的GC，这可能会导致在临床实践中的个体化治疗的发展。
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.