Molecular mechanism of XB130 adaptor protein mediates trastuzumab resistance in gastric cancer
Molecular mechanism of XB130 adaptor protein mediates trastuzumab resistance in gastric cancer
复制标题
XB130接头蛋白介导胃癌曲妥珠单抗耐药的分子机制
DOI：
10.1007/s12094-022-02974-w
复制
发表时间：
2022-10-25
影响因子：
3.4
通讯作者：
Zuo，Qiang
中科院分区：
文献类型：
--
作者：
Yang，Shengnan;Wang，Binbin;Zuo，Qiang
研究背景近年来的研究表明，PI 3 K/AKT信号通路的激活是参与HER 2+胃癌曲妥珠单抗耐药的重要分子机制。然而，如何在曲妥珠单抗治疗过程中有效抑制与耐药相关的AKT活性？方法本研究采用western blot、qRT-PCR、CCK 8、Co-IP等技术，探讨曲妥珠单抗体外耐药的可能机制。结果曲妥珠单抗耐药的胃癌细胞株中，XB 130衔接蛋白的表达显著增加，而XB 130的敲低可通过下调p-AKT逆转曲妥珠单抗的耐药。此外，耐药细胞中p-SRC（Tyr 416）增加，这可能有助于XB 130与PI 3 K p85α的结合。结论在HER 2+胃癌中，XB 130通过与SRC激酶介导的PI 3 K p85α结合，激活PI 3 K/AKT信号通路，调节PTEN基因的转录，从而导致曲妥珠单抗耐药。并进而在SRC-XB 130-PTEN之间形成正反馈回路。
BackgroundRecent studies have shown that the activation of PI3K/AKT signaling pathway is an essential molecular mechanism participating in trastuzumab resistance in HER2 + GC (gastric cancer). However, how can we effectively inhibit AKT activity associated with drug resistance during trastuzumab treatment? Screening inhibitors against the upstream receptors of PI3K/AKT signaling pathway or interacting proteins of members has become an important way.MethodsIn this study, western blot, qRT-PCR, CCK8, Co-IP and other techniques were used to explore possible mechanisms participating in trastuzumab resistance in vitro. Besides, the xenograft mouse model and GC tissue samples from patients were used to further validate the in-vitro results.ResultsThe expression of XB130 adaptor protein was remarkably increased in GC cell lines resistant to trastuzumab, and knockdown of XB130 could reverse the resistance via downregulating p-AKT. In addition, p-SRC (Tyr416) was increased in resistant cells, which could facilitate the binding of XB130 to PI3K p85α. It was also discovered that XB130 could negatively regulate PTEN gene transcription, and thus a positive feedback loop was formed between SRC-XB130-PTEN.ConclusionsIn HER2 + GC, XB130 contributes to trastuzumab resistance by stimulating the PI3K/AKT signaling pathway through binding to PI3K p85α under the mediation of SRC kinase and regulating PTEN gene transcription, and in turn forming a positive feedback loop between SRC-XB130-PTEN.