RUNX1 positively regulates the ErbB2/HER2 signaling pathway through modulating SOS1 expression in gastric cancer cells.
RUNX1 positively regulates the ErbB2/HER2 signaling pathway through modulating SOS1 expression in gastric cancer cells.
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DOI：
10.1038/s41598-018-24969-w
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发表时间：
2018-04-23
影响因子：
4.6
通讯作者：
Kamikubo Y
中科院分区：
文献类型：
--
作者：
Mitsuda Y;Morita K;Kashiwazaki G;Taniguchi J;Bando T;Obara M;Hirata M;Kataoka TR;Muto M;Kaneda Y;Nakahata T;Liu PP;Adachi S;Sugiyama H;Kamikubo Y
矮小相关转录因子1(RUNX1)作为癌基因或抑癌基因的双重功能已经在多种恶性肿瘤中得到了广泛的研究，但其在胃癌中的作用仍不清楚。ErbB2/HER2信号通路的上调在胃癌中是常见的，并有助于这些癌细胞的维持。这一信号级联部分是由七个同源基因(SOS)家族的SON介导的，SON在RTK级联中作为适配蛋白发挥作用。在此，我们报道RUNX1通过反式激活SOS1的表达来调节胃癌细胞中的ErbB2/HER2信号通路，使其成为抗肿瘤治疗的理想靶点。在机制上，RUNX1与位于SOS1启动子的RUNX1结合DNA序列相互作用并正向调节它。RUNX1基因敲除导致SOS1表达下降，ErbB2/HER2去磷酸化，从而抑制胃癌细胞的增殖。我们还发现，我们的新型RUNX抑制剂(ChB-M‘)持续导致ErbB2/HER2信号通路的失活，并对几种胃癌细胞株有效。综上所述，我们的工作确定了RUNX1和ErbB2/HER2信号通路在胃癌中的一种新的相互作用，这可能被用于治疗这种恶性肿瘤。
The dual function of runt-related transcriptional factor 1 (RUNX1) as an oncogene or oncosuppressor has been extensively studied in various malignancies, yet its role in gastric cancer remains elusive. Up-regulation of the ErbB2/HER2 signaling pathway is frequently-encountered in gastric cancer and contributes to the maintenance of these cancer cells. This signaling cascade is partly mediated by son of sevenless homolog (SOS) family, which function as adaptor proteins in the RTK cascades. Herein we report that RUNX1 regulates the ErbB2/HER2 signaling pathway in gastric cancer cells through transactivating SOS1 expression, rendering itself an ideal target in anti-tumor strategy toward this cancer. Mechanistically, RUNX1 interacts with the RUNX1 binding DNA sequence located in SOS1 promoter and positively regulates it. Knockdown of RUNX1 led to the decreased expression of SOS1 as well as dephosphorylation of ErbB2/HER2, subsequently suppressed the proliferation of gastric cancer cells. We also found that our novel RUNX inhibitor (Chb-M’) consistently led to the deactivation of the ErbB2/HER2 signaling pathway and was effective against several gastric cancer cell lines. Taken together, our work identified a novel interaction of RUNX1 and the ErbB2/HER2 signaling pathway in gastric cancer, which can potentially be exploited in the management of this malignancy.
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