The role of TRPV1 ion channels in the suppression of gastric cancer development.
The role of TRPV1 ion channels in the suppression of gastric cancer development.
复制标题
TRPV1离子通道在抑制胃癌发展中的作用。
DOI：
10.1186/s13046-020-01707-7
复制
发表时间：
2020-10-02
期刊：
影响因子：
--
通讯作者：
Dong H
中科院分区：
文献类型：
--
作者：
Gao N;Yang F;Chen S;Wan H;Zhao X;Dong H
虽然大多数钙离子通道的异常表达和功能已知促进胃肠道肿瘤，瞬时受体电位香草酸受体1（TRPV 1）通道和胃癌（GC）之间的关联尚未被探讨。在此，我们试图确定TRPV 1通道在GC发展中的作用，并阐明其中涉及的潜在分子机制。采用免疫组化、qPCR、Western印迹、免疫荧光等方法检测TRPV 1在GC细胞和组织中的mRNA和蛋白表达，并通过临床病理分析探讨TRPV 1在GC中的临床意义。CCK 8法、集落形成法、流式细胞术检测胃癌细胞的增殖和存活情况，transwell法检测胃癌细胞的迁移和侵袭能力。采用裸鼠肿瘤异种移植和腹膜播散试验研究TRPV 1在体内胃癌发生中的作用。TRPV 1在人原发性胃癌组织中的表达与癌旁组织相比显著下调。胃癌组织中TRPV 1蛋白表达降低与肿瘤大小、组织学分级、淋巴结转移、临床分期呈正相关，与胃癌患者预后不良密切相关。此外，TRPV 1的表达与Ki 67、VEGFR和E-cadherin密切相关，所有这些都是众所周知的增殖和转移的癌症标志物。TRPV 1蛋白主要表达在几个GC细胞系的质膜上。TRPV 1过表达可使胃癌细胞周期阻滞于G1期，抑制胃癌细胞增殖，并减弱胃癌细胞的迁移和侵袭能力，而TRPV 1敲低则可使胃癌细胞的上述指标增加。TRPV 1在体内显著减少胃肿瘤的大小、数量和腹膜播散。在机制上，TRPV 1在GC细胞中过表达增加[Ca 2 +]i，激活CaMKKβ和AMPK磷酸化，并降低cyclin D1和MMP 2的表达，而TRPV 1敲低则诱导相反的效应。TRPV 1通过一种新的Ca 2 +/CaMKKβ/AMPK途径独特地抑制GC的发展，其下调与人类GC患者的生存率低相关。因此，TRPV 1上调及其下游信号传导可能代表GC预防和治疗的有希望的靶点。
Although the aberrant expression and function of most Ca2+-permeable channels are known to promote gastrointestinal tumors, the association between transient receptor potential vanilloid receptor 1 (TRPV1) channels and gastric cancer (GC) has not yet been explored. Herein, we sought to determine the role of TRPV1 channels in the development of GC and to elucidate the underlying molecular mechanisms involved therein. Immunohistochemistry, qPCR, Western blot, immunofluorescence assays were used to detect the mRNA and protein expression of TRPV1 in GC cells and tissues, and the clinical significance of TRPV1 in GC was also studied by clinicopathologic analysis. CCK8, colony formation, flow cytometry assays were used to detect the proliferation and survival of GC cells, while transwell assay was used to detect migration and invasion of GC cells in vitro. Tumor xenograft and peritoneal dissemination assays in nude mice were used to examine the role of TRPV1 in GC development in vivo. TRPV1 expression was significantly downregulated in human primary GC tissues compared to their adjacent tissues. The decreased expression of TRPV1 proteins in GC tissues was positively correlated with tumor size, histological grade, lymphatic metastasis, clinical stage, and was strongly correlated with poor prognosis of GC patients. Moreover, the expression of TRPV1 was closely correlated with Ki67, VEGFR, and E-cadherin, all of which are the well-known cancer markers for proliferation and metastasis. TRPV1 proteins were predominately expressed on the plasma membrane in several GC cell lines. TRPV1 overexpression blocked cell cycle at G1 phase to inhibit GC cell proliferation and attenuated migration and invasion of GC cells in vitro, but TRPV1 knockdown increased these parameters. TRPV1 significantly reduced gastric tumor size, number and peritoneal dissemination in vivo. Mechanistically, TRPV1 overexpression in GC cells increased [Ca2+]i, activated CaMKKβ and AMPK phosphorylation, and decreased expression of cyclin D1 and MMP2, while TRPV1 knockdown induced the opposite effects. TRPV1 uniquely suppresses GC development through a novel Ca2+/CaMKKβ/AMPK pathway and its downregulation is correlated with poor survival of human GC patients. Thus, TRPV1 upregulation and its downstream signaling may represent a promising target for GC prevention and therapy.
登录
查看更多内容
影响因子：
30.5
作者：
Bertin S;Aoki-Nonaka Y;de Jong PR;Nohara LL;Xu H;Stanwood SR;Srikanth S;Lee J;To K;Abramson L;Yu T;Han T;Touma R;Li X;González-Navajas JM;Herdman S;Corr M;Fu G;Dong H;Gwack Y;Franco A;Jefferies WA;Raz E
通讯作者：
Raz E
影响因子：
15.9
作者：
de Jong, Petrus R.;Takahashi, Naoki;Raz, Eyal
通讯作者：
Raz, Eyal
影响因子：
4.7
作者：
Kania E;Roest G;Vervliet T;Parys JB;Bultynck G
通讯作者：
Bultynck G
影响因子：
24.5
作者：
Chang HR;Nam S;Kook MC;Kim KT;Liu X;Yao H;Jung HR;Lemos R Jr;Seo HH;Park HS;Gim Y;Hong D;Huh I;Kim YW;Tan D;Liu CG;Powis G;Park T;Liang H;Kim YH
通讯作者：
Kim YH
影响因子：
7.2
作者：
Bruner, Heather C.;Derksen, Patrick W. B.
通讯作者：
Derksen, Patrick W. B.