期刊
CANCER LETTERS
卷 500, 期 -, 页码 119-131出版社
ELSEVIER IRELAND LTD
DOI: 10.1016/j.canlet.2020.12.017
关键词
Na(v)1.5; Colorectal cancer; Calcium influx; Calmodulin; 5-fluorouracil-stimulated apoptosis
类别
资金
- National Natural Science Foundation of China [82073159, 81871971, 81772595]
- National Key R&D Program of China [2017YFC0908200]
- Sun Yat-sen University Clinical Research 5010 Program [2014013]
- Science and Technology Program of Guangzhou [201803010117]
- Young Teacher Foundation of Sun Yat-sen University [13ykpy46]
Na(v)1.5, encoded by SCN5A, plays a significant role in metastasis of colorectal cancer (CRC). Upregulation of Na(v)1.5 is associated with poor prognosis in CRCs, while it stabilizes the KRas-calmodulin complex to modulate Ras signaling and promote Ca2+ influx, leading to enhanced 5-FU-stimulated apoptosis in CRCs. CRC patients with elevated SCN5A expression may benefit more from 5-FU-based chemotherapy.
Na(v)1.5, encoded by SCN5A, has been associated with metastasis in colorectal cancer (CRC). Here, we investigated the mechanism by which Na(v)1.5 regulates tumor progression and whether Na(v)1.5 influences chemosensitivity to 5-fluorouracil (5-FU) in CRCs. CRC cases were evaluated for Na(v)1.5 expression. Elevated Na(v)1.5 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, Na(v)1.5 stabilized the KRas-calmodulin complex to modulate Ras signaling, promoting Ca2+ influx through the Na+-Ca2+ exchanger and Ca2+ release-activated calcium channel. Meanwhile, SCN5A knockdown increased the 50% inhibitory concentration to 5-FU by upregulating 5-FU-stimulated apoptosis in CRCs. In conclusion, Na(v)1.5 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 elevated SCN5A expression demonstrated poor prognosis, yet those patients could benefit more from 5-FU-based chemotherapy than patients with lower SCN5A expression.
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