RECK/GPR124-driven WNT signaling in pancreatic and gastric cancer cells

IF 4.5 2区医学 Q1 ONCOLOGY

Cancer Science Pub Date : 2024-06-26 DOI:10.1111/cas.16258

Hai Yu, Susumu Kohno, Dominic Chih-Cheng Voon, Nada Hamdy Hussein, Yuanyuan Zhang, Joji Nakayama, Yujiro Takegami, Chiaki Takahashi

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引用次数: 0

Abstract

RECK has been described to modulate extracellular matrix components through negative regulation of MMP activities. Recently, RECK was demonstrated to bind to an orphan G protein-coupled receptor GPR124 to mediate WNT7 signaling in nontumor contexts. Here, we attempted to clarify the role of RECK in driving WNT signaling in cancer cells. RECK and GPR124 formed a complex in 293T cells, and when both were expressed, WNT signaling was significantly enhanced in a WNT7-dependent manner. This cooperation was abolished when RECK mutants unable to bind to GPR124 were transduced. RECK stimulated the growth of KRAS-mutated pancreatic ductal adenocarcinoma (PDAC) cells with increased sensitivity to WNT inhibitor in a GPR124-dependent manner. A gastric cancer cell line SH10TC endogenously expresses both RECK and GPR124 under regular culture conditions. In this cell line, inhibited cell growth and WNT signaling as well as increased apoptosis in the GPR124 depletion was dominantly found over those in the RECK deletion. These findings suggest that RECK promotes tumor cell growth by positively modulating WNT signaling through GPR124. This study proposes that the RECK/GPR124 complex might be a good therapeutic target in PDAC and gastric cancer.

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胰腺癌和胃癌细胞中由 RECK/GPR124 驱动的 WNT 信号转导。

据描述，RECK 可通过负向调节 MMP 活性来调节细胞外基质成分。最近，研究证明 RECK 与孤儿 G 蛋白偶联受体 GPR124 结合，在非肿瘤环境中介导 WNT7 信号转导。在此，我们试图阐明 RECK 在癌细胞中驱动 WNT 信号转导的作用。RECK 和 GPR124 在 293T 细胞中形成复合物，当两者都表达时，WNT 信号以依赖 WNT7 的方式显著增强。当转导不能与 GPR124 结合的 RECK 突变体时，这种合作被取消。RECK 以 GPR124 依赖性的方式刺激 KRAS 突变的胰腺导管腺癌（PDAC）细胞生长，并增加其对 WNT 抑制剂的敏感性。胃癌细胞株 SH10TC 在常规培养条件下内源表达 RECK 和 GPR124。在该细胞系中，细胞生长和 WNT 信号转导受抑制以及细胞凋亡增加的情况在 GPR124 缺失比 RECK 缺失明显。这些发现表明，RECK 通过 GPR124 积极调节 WNT 信号，从而促进肿瘤细胞的生长。本研究认为，RECK/GPR124复合物可能是PDAC和胃癌的一个很好的治疗靶点。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Cancer Science 医学-肿瘤学

自引率

3.50%

发文量

406

审稿时长

2 months

期刊介绍： Cancer Science (formerly Japanese Journal of Cancer Research) is a monthly publication of the Japanese Cancer Association. First published in 1907, the Journal continues to publish original articles, editorials, and letters to the editor, describing original research in the fields of basic, translational and clinical cancer research. The Journal also accepts reports and case reports. Cancer Science aims to present highly significant and timely findings that have a significant clinical impact on oncologists or that may alter the disease concept of a tumor. The Journal will not publish case reports that describe a rare tumor or condition without new findings to be added to previous reports; combination of different tumors without new suggestive findings for oncological research; remarkable effect of already known treatments without suggestive data to explain the exceptional result. Review articles may also be published.