NCX1 coupled with TRPC1 to promote gastric cancer via Ca(2+)/AKT/β-catenin pathway.
NCX1 coupled with TRPC1 to promote gastric cancer via Ca(2+)/AKT/β-catenin pathway.
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NCX1 与 TRPC1 结合通过 Ca2 /AKT/β-catenin 通路促进胃癌发生
DOI：
10.1038/s41388-022-02412-9
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发表时间：
2022-08
期刊：
影响因子：
8
通讯作者：
Dong, Hui
中科院分区：
文献类型：
--
作者：
Wan, Hanxing;Gao, Nannan;Lu, Wei;Lu, Cheng;Chen, Jun;Wang, Yimin;Dong, Hui
质膜Na+/Ca 2+交换器1（NCX 1）是一种双向的离子转运蛋白，以Ca 2+进入或排出的方式工作，TRPC 1是一种Ca 2+渗透通道。NCX 1和TRPC 1在维持哺乳动物细胞胞浆游离Ca 2+（[Ca 2 +]cyt）稳态中起关键作用。虽然TRPC 1通道或NCX 1的Ca 2+进入模式与某些肿瘤发生有关，但NCX 1和TRPC 1的协同作用是否参与H.幽门相关的人胃癌（GC）。我们发现NCX 1蛋白在胃癌组织中的表达显著增强，这与胃癌患者的肿瘤进展和生存率相关。TRPC 1和NCX 1在人GC细胞中被双增强、共定位和结合。通过功能偶联，TRPC 1驱动NCX 1进入Ca 2+进入模式，提高GC细胞中的[Ca 2 +]cyt。CaCl_2、H. pylori及其毒力因子均能增强NCX 1和TRPC 1的表达和活性，并通过AKT/β-catenin途径诱导胃癌细胞异常Ca 2+内流，促进胃癌细胞的增殖、迁移和侵袭。在皮下移植的GC小鼠模型中，肿瘤的生长和转移也依赖于NCX 1表达的增强。总之，我们的研究结果表明TRPC 1/NCX 1偶联可能促进H.幽门螺杆菌相关性GC通过Ca 2 +/AKT/β-catenin途径。由于NCX 1的Ca 2+退出模式和Ca 2+进入模式分别在大多数生理和病理条件下发挥不同的作用，靶向TRPC 1/NCX 1偶联可能是选择性阻断Ca 2+进入模式以潜在地治疗消化道肿瘤的新策略，副作用较小。
Plasma membrane Na+/Ca2+ exchanger 1 (NCX1) is a bidirectional ion transporter to operate in Ca2+ entry or exit modes, and TRPC1 is Ca2+-permeable channel. Both NCX1 and TRPC1 play critical roles in maintaining cytosolic free Ca2+ ([Ca2+]cyt) homeostasis in mammalian cells. Although either TRPC1 channel or Ca2+ entry mode of NCX1 is implicated in some tumorigenesis, it has not been explored if a coordination of NCX1 and TRPC1 involves in the pathogenesis of H. pylori-associated human gastric cancer (GC). Here we found the protein expression of NCX1 was significantly enhanced in human GC specimens, which correlated with tumor progression and poor survival in GC patients. TRPC1 and NCX1 were parallelly enhanced, co-localized and bound in human GC cells. By a functional coupling, TRPC1 drives NCX1 to the Ca2+ entry mode, raising [Ca2+]cyt in GC cells. Moreover, CaCl2, H. pylori and their virulence factors all enhanced expressions and activities of NCX1 and TRPC1, and evoked aberrant Ca2+ entry to promote proliferation, migration, and invasion of GC cells through AKT/β-catenin pathway. Tumor growth and metastasis also depended on the enhanced expression of NCX1 in subcutaneously xenografted GC mouse model. Overall, our findings indicate that TRPC1/NCX1 coupling may promote H. pylori-associated GC through the Ca2+/AKT/β-catenin pathway. Since the Ca2+ exit mode and the Ca2+ entry mode of NCX1 play different roles under mostly physiological and pathological conditions respectively, targeting TRPC1/NCX1 coupling could be a novel strategy for selectively blocking Ca2+ entry mode to potentially treat digestive cancer with less side effect.
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影响因子：
3.2
作者：
Timmons, Jennifer A.;Rao, Jaladanki N.;Turner, Douglas J.;Zou, Tongtong;Liu, Lan;Xiao, Lan;Wang, Peng-Yuan;Wang, Jian-Ying
通讯作者：
Wang, Jian-Ying
影响因子：
5.5
作者：
Chovancova B;Liskova V;Babula P;Krizanova O
通讯作者：
Krizanova O
DOI：
10.1186/s13046-020-01707-7
发表时间：
2020-10-02
期刊：
Journal of experimental & clinical cancer research : CR
影响因子：
--
作者：
Gao N;Yang F;Chen S;Wan H;Zhao X;Dong H
通讯作者：
Dong H
影响因子：
254.7
作者：
Joshi, Smita S.;Badgwell, Brian D.
通讯作者：
Badgwell, Brian D.
影响因子：
--
作者：
Percie du Sert N;Hurst V;Ahluwalia A;Alam S;Avey MT;Baker M;Browne WJ;Clark A;Cuthill IC;Dirnagl U;Emerson M;Garner P;Holgate ST;Howells DW;Karp NA;Lazic SE;Lidster K;MacCallum CJ;Macleod M;Pearl EJ;Petersen OH;Rawle F;Reynolds P;Rooney K;Sena ES;Silberberg SD;Steckler T;Würbel H
通讯作者：
Würbel H