Transferrin receptor 1 promotes the fibroblast growth factor receptor-mediated oncogenic potential of diffused-type gastric cancer
Transferrin receptor 1 promotes the fibroblast growth factor receptor-mediated oncogenic potential of diffused-type gastric cancer
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DOI：
10.1038/s41388-022-02270-5
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发表时间：
2022-03-25
期刊：
影响因子：
8
通讯作者：
Sakai, Ryuichi
中科院分区：
文献类型：
--
作者：
Shirakihara, Takuya;Yamaguchi, Hideki;Sakai, Ryuichi
弥漫型胃癌（DGC）是一种高度侵袭性的胃腺癌亚型，经常表现出分散的腹膜转移。以往的研究表明，受体酪氨酸激酶（RTK）的基因，如成纤维细胞生长因子受体2（FGFR2）或Met，在一些DGC细胞系中扩增，导致相应的RTK的组成性激活。在这些细胞系中，癌细胞的存活似乎依赖于RTK的激活。为了获得对DGC特异性RTK的下游信号传导途径的新见解，通过连续两轮免疫沉淀从两种DGC细胞系的裂解物中纯化与活化的FGFR 2相关的含磷酸酪氨酸的蛋白。结果，转铁蛋白受体1（TfR1）被鉴定为FGFR 2的结合配偶体。生化分析证实，TfR1蛋白结合FGFR2，并在酪氨酸20（Tyr20）磷酸化的FGFR2激酶活性依赖性的方式。TfR1的敲除和FGFR2抑制剂的治疗在体外引起铁摄取的显著损害和细胞增殖的抑制。此外，TfR1在DGC细胞中的表达水平的抑制显着降低了它们的致瘤性和腹膜播散的能力。研究表明，当TfR1在DGC细胞中被结合伴侣FGFR 2磷酸化时，会促进这些癌细胞的增殖和致瘤性。这些结果表明，TfR1功能的控制可以作为DGC与激活FGFR 2的治疗靶点。
Diffuse-type gastric cancer (DGC) is a highly invasive subtype of gastric adenocarcinoma that frequently exhibits scattered peritoneal metastasis. Previous studies have shown that the genes of receptor tyrosine kinases (RTKs), such as fibroblast growth factor receptor 2 (FGFR2) or Met, are amplified in some DGC cell lines, leading to the constitutive activation of corresponding RTKs. In these cell lines, the survival of cancer cells appears to be dependent on the activation of RTKs. To gain novel insights into the downstream signaling pathways of RTKs specific to DGC, phosphotyrosine-containing proteins associated with activated FGFR2 were purified through two sequential rounds of immunoprecipitation from the lysates of two DGC cell lines. As a result, transferrin receptor 1 (TfR1) was identified as the binding partner of FGFR2. Biochemical analysis confirmed that TfR1 protein binds to FGFR2 and is phosphorylated at tyrosine 20 (Tyr20) in an FGFR2 kinase activity-dependent manner. The knockdown of TfR1 and treatment with an inhibitor of FGFR2 caused significant impairment in iron uptake and suppression of cellular proliferation in vitro. Moreover, the suppression of expression levels of TfR1 in the DGC cells significantly reduced their tumorigenicity and potency of peritoneal dissemination. It was indicated that TfR1, when phosphorylated by the binding partner FGFR2 in DGC cells, promotes proliferation and tumorigenicity of these cancer cells. These results suggest that the control of TfR1 function may serve as a therapeutic target in DGC with activated FGFR2.