Department of Pharmacology, School of Pharmacy, Qingdao University Medical College, #1 Ningde Road, Qingdao, 266073, China.
Department of Gastroenterology, Xinqiao Hospital, Army Medical University, Chongqing, 400037, China.
Oncogene. 2022 Aug;41(35):4169-4182. doi: 10.1038/s41388-022-02412-9. Epub 2022 Jul 26.
Plasma membrane Na/Ca exchanger 1 (NCX1) is a bidirectional ion transporter to operate in Ca entry or exit modes, and TRPC1 is Ca-permeable channel. Both NCX1 and TRPC1 play critical roles in maintaining cytosolic free Ca ([Ca]) homeostasis in mammalian cells. Although either TRPC1 channel or Ca 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 Ca entry mode, raising [Ca] in GC cells. Moreover, CaCl, H. pylori and their virulence factors all enhanced expressions and activities of NCX1 and TRPC1, and evoked aberrant Ca 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 Ca/AKT/β-catenin pathway. Since the Ca exit mode and the Ca 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 Ca entry mode to potentially treat digestive cancer with less side effect.
质膜钠离子/钙交换蛋白 1（NCX1）是一种双向离子转运体，可在钙内流或外流模式下发挥作用，而 TRPC1 是钙通透通道。NCX1 和 TRPC1 在维持哺乳动物细胞胞质游离钙([Ca])稳态中都起着至关重要的作用。尽管 TRPC1 通道或 NCX1 的钙内流模式都与某些肿瘤发生有关，但尚未探讨 NCX1 和 TRPC1 的协调是否涉及幽门螺杆菌相关人类胃癌（GC）的发病机制。在这里，我们发现 NCX1 的蛋白表达在人类 GC 标本中显著增强，与 GC 患者的肿瘤进展和不良生存相关。TRPC1 和 NCX1 平行增强，在人类 GC 细胞中共定位和结合。通过功能偶联，TRPC1 驱动 NCX1 进入钙内流模式，使 GC 细胞内的[Ca]升高。此外，CaCl2、幽门螺杆菌及其毒力因子均增强了 NCX1 和 TRPC1 的表达和活性，并通过 AKT/β-catenin 通路引发异常钙内流，促进 GC 细胞的增殖、迁移和侵袭。肿瘤生长和转移也依赖于皮下异种移植 GC 小鼠模型中 NCX1 的增强表达。总的来说，我们的研究结果表明，TRPC1/NCX1 偶联可能通过 Ca/AKT/β-catenin 通路促进幽门螺杆菌相关 GC 的发生。由于 NCX1 的钙外排模式和钙内流模式在大多数生理和病理条件下分别发挥不同的作用，靶向 TRPC1/NCX1 偶联可能是一种选择性阻断钙内流模式的新策略，以潜在地治疗消化癌，副作用更小。
