Department of Colorectal Surgery, Sun Yat-sen University Cancer Center, Guangzhou, 510060, PR China; State Key Laboratory of Oncology in South China, Guangzhou, 510060, PR China; Collaborative Innovation Center for Cancer Medicine, Guangzhou, 510060, PR China.
Department of Colorectal Surgery, Sun Yat-sen University Cancer Center, Guangzhou, 510060, PR China; Department of Experimental Research, Sun Yat-sen University Cancer Center, Guangzhou, 510060, PR China; State Key Laboratory of Oncology in South China, Guangzhou, 510060, PR China; Collaborative Innovation Center for Cancer Medicine, Guangzhou, 510060, PR China.
Cancer Lett. 2021 Mar 1;500:119-131. doi: 10.1016/j.canlet.2020.12.017. Epub 2020 Dec 16.
Na1.5, encoded by SCN5A, has been associated with metastasis in colorectal cancer (CRC). Here, we investigated the mechanism by which Na1.5 regulates tumor progression and whether Na1.5 influences chemosensitivity to 5-fluorouracil (5-FU) in CRCs. CRC cases were evaluated for Na1.5 expression. Elevated Na1.5 expression was associated with poor prognosis in CRCs, whereas stage II/III patients with upregulated SCN5A expression could have better survival after receiving 5-FU-based adjuvant chemotherapy. In CRC cells, SCN5A knockdown reduced the proliferation, migration and invasion. According to RNA sequencing, SCN5A knockdown inhibited both the cell cycle and epithelial-mesenchymal transition. In addition, Na1.5 stabilized the KRas-calmodulin complex to modulate Ras signaling, promoting Ca influx through the Na-Ca exchanger and Ca release-activated calcium channel. Meanwhile, SCN5A knockdown increased the 50% inhibitory concentration to 5-FU by upregulating 5-FU-stimulated apoptosis in CRCs. In conclusion, Na1.5 could progress to proliferation and metastasis through Ca/calmodulin-dependent Ras signaling in CRC, and it could also enhance 5-FU-stimulated apoptosis. Clinically, patients with stage II/III CRCs with elevated SCN5A expression demonstrated poor prognosis, yet those patients could benefit more from 5-FU-based chemotherapy than patients with lower SCN5A expression.
钠通道 1.5（Na1.5），由 SCN5A 编码，与结直肠癌（CRC）的转移有关。在这里，我们研究了 Na1.5 调节肿瘤进展的机制，以及 Na1.5 是否影响 CRC 对 5-氟尿嘧啶（5-FU）的化疗敏感性。评估了 CRC 病例中的 Na1.5 表达。Na1.5 表达升高与 CRC 预后不良相关，而 SCN5A 表达上调的 II/III 期患者在接受基于 5-FU 的辅助化疗后可能有更好的生存。在 CRC 细胞中，SCN5A 敲低减少了增殖、迁移和侵袭。根据 RNA 测序，SCN5A 敲低抑制了细胞周期和上皮-间充质转化。此外，Na1.5 稳定 Ras-钙调蛋白复合物以调节 Ras 信号，通过 Na-Ca 交换器促进 Ca 内流和 Ca 释放激活钙通道。同时，SCN5A 敲低通过上调 CRC 中 5-FU 刺激的凋亡，增加了 5-FU 的 50%抑制浓度。总之，Na1.5 可通过 Ca/钙调蛋白依赖性 Ras 信号促进 CRC 中的增殖和转移，还可增强 5-FU 刺激的凋亡。临床上，SCN5A 表达升高的 II/III 期 CRC 患者预后不良，但这些患者比 SCN5A 表达较低的患者从基于 5-FU 的化疗中获益更多。
