Blockade of CHRNB2 signaling with a therapeutic monoclonal antibody attenuates the aggressiveness of gastric cancer cells
Blockade of CHRNB2 signaling with a therapeutic monoclonal antibody attenuates the aggressiveness of gastric cancer cells
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DOI：
10.1038/s41388-021-01945-9
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发表时间：
2021-07-30
期刊：
影响因子：
8
通讯作者：
Kodera, Yasuhiro
中科院分区：
文献类型：
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作者：
Kanda, Mitsuro;Shimizu, Dai;Kodera, Yasuhiro
在这里，我们评估了针对胆碱能受体烟碱受体β2亚单位(CHRNB2)的抗体在胃癌中的治疗潜力。为了研究这些抗体在体外和小鼠异种移植模型中对恶性表型的影响，我们通过基因组编辑产生基因敲除，进行RNA干扰介导的基因表达下调，并在胃癌细胞中异位表达CHRNB2。体外和体内实验观察抗CHRNB2抗体对癌细胞增殖的影响。我们确定了chrnb2缺乏对小鼠的影响以及chrnb2在胃癌临床标本中表达的临床意义。CHRNB2基因敲除抑制了胃癌细胞的增殖，而强制过表达CHRNB2则促进了细胞的增殖。CHRNB2基因敲除显著影响细胞存活和与转移相关的功能。针对CHRNB2 C端和N端的多克隆抗体的作用引导了抗CHRNB2单抗的发展，从而在体内外抑制了胃癌细胞的生长。通路分析表明，CHRNB2通过PI3K-AKT和JAK-STAT通路干扰信号传导。基因缺失的小鼠表现出正常的生殖、器官功能和运动功能。CHRNB2调节与转移相关的多种肿瘤表型，用特异性抗体阻断CHRNB2的表达显示出控制胃癌转移的前景。
Here, we evaluated the therapeutic potential of antibodies (Abs) targeting cholinergic receptor nicotinic beta 2 subunit (CHRNB2) in gastric cancer. To investigate the effects of these Abs on malignant phenotypes in vitro and in mouse xenograft models, we generated gene knockouts through genome editing, performed RNA interference-mediated knockdown of gene expression, and ectopically expressed CHRNB2 in gastric cancer cells. The effects of anti-CHRNB2 Abs on the proliferation of cancer cells were evaluated both in vitro and in vivo. We determined the effects of Chrnb2 deficiency on mice and the clinical significance of CHRNB2 expression in gastric cancer clinical specimens. Knockdown of CHRNB2 attenuated gastric cancer cell proliferation, whereas forced overexpression of CHRNB2 increased cell proliferation. Knockout of CHRNB2 significantly influenced cell survival and functions associated with metastasis. The effects of polyclonal Abs targeting the C- and N-termini of CHRNB2 guided the development of anti-CHRNB2 monoclonal Abs that inhibited the growth of gastric cancer cells in vitro and in vivo. Pathway analysis revealed that CHRNB2 interfered with signaling through the PI3K-AKT and JAK-STAT pathways. Chrnb2-deficient mice exhibited normal reproduction, organ functions, and motor functions. CHRNB2 regulates multiple oncological phenotypes associated with metastasis, and blockade of CHRNB2 expression using specific Abs shows promise for controlling metastasis in gastric cancer.