Voltage-gated sodium channel Nav1.5 promotes tumor progression and enhances chemosensitivity to 5-fluorouracil in colorectal cancer.
Voltage-gated sodium channel Nav1.5 promotes tumor progression and enhances chemosensitivity to 5-fluorouracil in colorectal cancer.
复制标题
DOI：
10.1016/j.canlet.2020.12.017
复制
发表时间：
2020-12
期刊：
影响因子：
9.7
通讯作者：
Qiao-qi Sui;J. Peng;K. Han;Junzhong Lin;Rong-xin Zhang;Q. Ou;Jiayi Qin;Yuxiang Deng;Wenhao Zhou-Wen
中科院分区：
文献类型：
--
作者：
Qiao-qi Sui;J. Peng;K. Han;Junzhong Lin;Rong-xin Zhang;Q. Ou;Jiayi Qin;Yuxiang Deng;Wenhao Zhou-Wen
由SCN 5A编码的Nav1.5与结直肠癌（CRC）的转移有关。在这里，我们研究了Nav1.5调节肿瘤进展的机制，以及Nav1.5是否影响CRC对5-氟尿嘧啶（5-FU）的化疗敏感性。对CRC病例进行Nav1.5表达评估。Nav1.5表达升高与CRCs预后不良相关，而SCN 5A表达上调的II/III期患者在接受5-FU辅助化疗后生存率更高。在CRC细胞中，SCN 5A敲低降低增殖、迁移和侵袭。根据RNA测序，SCN 5A敲低抑制细胞周期和上皮-间充质转化。此外，Nav1.5稳定KRas-钙调蛋白复合物以调节Ras信号传导，通过Na+-Ca 2+交换器和Ca 2+释放激活的钙通道促进Ca 2+内流。同时，通过上调5-FU刺激的CRCs凋亡，SCN 5A敲低增加了对5-FU的50%抑制浓度。结论：Nav1.5可通过Ca 2 +/钙调素依赖性Ras信号通路促进结直肠癌细胞的增殖和转移，并可增强5-FU诱导的细胞凋亡。临床上，SCN 5A表达升高的II/III期CRC患者预后较差，但这些患者比SCN 5A表达较低的患者更能从5-FU化疗中获益。
Nav1.5, encoded bySCN5A, has been associated with metastasis in colorectal cancer (CRC). Here, we investigated the mechanism by which Nav1.5 regulates tumor progression and whether Nav1.5 influences chemosensitivity to 5-fluorouracil (5-FU) in CRCs. CRC cases were evaluated for Nav1.5 expression. Elevated Nav1.5 expression was associated with poor prognosis in CRCs, whereas stage II/III patients with upregulatedSCN5Aexpression could have better survival after receiving 5-FU-based adjuvant chemotherapy. In CRC cells,SCN5Aknockdown reduced the proliferation, migration and invasion. According to RNA sequencing,SCN5Aknockdown inhibited both the cell cycle and epithelial-mesenchymal transition. In addition, Nav1.5 stabilized the KRas-calmodulin complex to modulate Ras signaling, promoting Ca2+influx through the Na+-Ca2+exchanger and Ca2+release-activated calcium channel. Meanwhile,SCN5Aknockdown increased the 50% inhibitory concentration to 5-FU by upregulating 5-FU-stimulated apoptosis in CRCs. In conclusion, Nav1.5 could progress to proliferation and metastasis through Ca2+/calmodulin-dependent Ras signaling in CRC, and it could also enhance 5-FU-stimulated apoptosis. Clinically, patients with stage II/III CRCs with elevatedSCN5Aexpression demonstrated poor prognosis, yet those patients could benefit more from 5-FU-based chemotherapy than patients with lowerSCN5Aexpression.