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RUNX1 通过调节胃癌细胞中 SOS1 的表达来正向调控 ErbB2/HER2 信号通路。

RUNX1 positively regulates the ErbB2/HER2 signaling pathway through modulating SOS1 expression in gastric cancer cells.

机构信息

Department of Human Health Sciences, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto, 606-8507, Japan.

Department of Chemistry, Graduate School of Science, Kyoto University, Sakyo-ku, Kyoto, 606-8502, Japan.

出版信息

Sci Rep. 2018 Apr 23;8(1):6423. doi: 10.1038/s41598-018-24969-w.

DOI:10.1038/s41598-018-24969-w
PMID:29686309
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5913281/
Abstract

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.

摘要

RUNX1 作为癌基因或抑癌基因的双重功能在各种恶性肿瘤中得到了广泛研究，但它在胃癌中的作用仍不清楚。在胃癌中经常会发现 ErbB2/HER2 信号通路的上调，这有助于维持这些癌细胞。该信号级联反应部分由 son of sevenless 同源物 (SOS) 家族介导，该家族作为 RTK 级联中的衔接蛋白发挥作用。在此，我们报告 RUNX1 通过反式激活 SOS1 表达来调节胃癌细胞中的 ErbB2/HER2 信号通路，使其成为针对这种癌症的抗肿瘤策略中的理想靶标。从机制上讲，RUNX1 与位于 SOS1 启动子中的 RUNX1 结合 DNA 序列相互作用，并正向调节它。RUNX1 的敲低导致 SOS1 的表达减少以及 ErbB2/HER2 的去磷酸化，随后抑制了胃癌细胞的增殖。我们还发现我们的新型 RUNX 抑制剂 (Chb-M') 一致导致 ErbB2/HER2 信号通路失活，并对几种胃癌细胞系有效。总之，我们的工作确定了 RUNX1 与胃癌中 ErbB2/HER2 信号通路的新相互作用，这可能可用于该恶性肿瘤的治疗。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3c91/5913281/2bc4b81a05d0/41598_2018_24969_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3c91/5913281/42eb02dc4ea3/41598_2018_24969_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3c91/5913281/bb0ee6f43ed4/41598_2018_24969_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3c91/5913281/aae2bf7aa350/41598_2018_24969_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3c91/5913281/59f8716ab754/41598_2018_24969_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3c91/5913281/545e541b8c0f/41598_2018_24969_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3c91/5913281/e7dbba41feb2/41598_2018_24969_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3c91/5913281/5c3066d09fe3/41598_2018_24969_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3c91/5913281/2bc4b81a05d0/41598_2018_24969_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3c91/5913281/42eb02dc4ea3/41598_2018_24969_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3c91/5913281/bb0ee6f43ed4/41598_2018_24969_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3c91/5913281/aae2bf7aa350/41598_2018_24969_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3c91/5913281/59f8716ab754/41598_2018_24969_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3c91/5913281/545e541b8c0f/41598_2018_24969_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3c91/5913281/e7dbba41feb2/41598_2018_24969_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3c91/5913281/5c3066d09fe3/41598_2018_24969_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3c91/5913281/2bc4b81a05d0/41598_2018_24969_Fig8_HTML.jpg

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