Nagamura Yuko, Miyazaki Makoto, Nagano Yoshiko, Yuki Masako, Fukami Kiyoko, Yanagihara Kazuyoshi, Sasaki Kazuki, Sakai Ryuichi, Yamaguchi Hideki
Department of Cancer Cell Research, Sasaki Institute, Sasaki Foundation, Tokyo, Japan.
Laboratory of Genome and Biosignal, School of Life Sciences, Tokyo University of Pharmacy and Life Sciences, Tokyo, Japan.
Oncogenesis. 2021 Mar 6;10(3):25. doi: 10.1038/s41389-021-00314-1.
Met gene amplification has been found in a subset of malignant carcinomas, including diffuse-type gastric carcinoma (DGC), which has a poor prognosis owing to rapid infiltrative invasion and frequent peritoneal dissemination. Met is considered a promising therapeutic target for DGC. However, DGC cells with Met gene amplification eventually acquire resistance to Met inhibitors. Therefore, identification of alternate targets that mediate Met signaling and confer malignant phenotypes is critical. In this study, we conducted a phosphoproteomic analysis of DGC cells possessing Met gene amplification and identified Pleckstrin Homology Domain Containing A5 (PLEKHA5) as a protein that is tyrosine-phosphorylated downstream of Met. Knockdown of PLEKHA5 selectively suppressed the growth of DGC cells with Met gene amplification by inducing apoptosis, even though they had acquired resistance to Met inhibitors. Moreover, PLEKHA5 silencing abrogated the malignant phenotypes of Met-addicted DGC cells, including peritoneal dissemination in vivo. Mechanistically, PLEKHA5 knockdown dysregulates glycolytic metabolism, leading to activation of the JNK pathway that promotes apoptosis. These results indicate that PLEKHA5 is a novel downstream effector of amplified Met and is required for the malignant progression of Met-addicted DGC.
在包括弥漫型胃癌（DGC）在内的一部分恶性肿瘤中发现了Met基因扩增，由于其具有快速浸润性侵袭和频繁腹膜播散的特点，弥漫型胃癌预后较差。Met被认为是弥漫型胃癌一个有前景的治疗靶点。然而，具有Met基因扩增的弥漫型胃癌细胞最终会对Met抑制剂产生耐药性。因此，鉴定介导Met信号传导并赋予恶性表型的替代靶点至关重要。在本研究中，我们对具有Met基因扩增的弥漫型胃癌细胞进行了磷酸化蛋白质组分析，并鉴定出含Pleckstrin同源结构域A5（PLEKHA5）作为在Met下游发生酪氨酸磷酸化的一种蛋白质。敲低PLEKHA5可通过诱导凋亡选择性地抑制具有Met基因扩增的弥漫型胃癌细胞的生长，即使它们已对Met抑制剂产生耐药性。此外，PLEKHA5沉默消除了对Met成瘾的弥漫型胃癌细胞的恶性表型，包括体内腹膜播散。从机制上讲，敲低PLEKHA5会失调糖酵解代谢，导致促进凋亡的JNK途径激活。这些结果表明，PLEKHA5是扩增型Met的一种新型下游效应物，是对Met成瘾的弥漫型胃癌恶性进展所必需的。
