胶质瘤仍然是一个临床挑战,常见的和致命的。胶质母细胞瘤的治疗仍然难以捉摸,研究人员专注于发现新的机制和药物。已经确定,电压门控钠通道(VGSC)的表达在许多恶性肿瘤中异常增加,总的来说,在相应的正常组织中很少表达。这表明离子通道活性似乎与肿瘤的恶性进展有关。VGSC对于它们的活性如何导致癌细胞活性或侵袭性的增加仍然是未知的。某些钠离子通道亚型(例如,Nav1.5和Nav1.7)与包括乳腺癌和结直肠癌在内的癌症的转移和侵袭有关。作者先前的一项研究探索了某些离子通道在神经胶质瘤中的表达,但是很少有与Nav1.6相关的研究。本研究旨在阐明Nav1.6在脑胶质瘤中的表达和作用,并通过虚拟筛选和药物敏感性分析筛选潜在的脑胶质瘤治疗药物。通过逆转录定量PCR和蛋白质印迹分析确定Nav1.6mRNA和蛋白质的相对表达。细胞增殖通过细胞计数试剂盒-8测定法测定。通过细胞伤口愈合测定评估细胞迁移。通过Transwell细胞侵袭实验和流式细胞术检测细胞侵袭和凋亡。最后但并非最不重要的,FDA批准的药物使用虚拟筛选进行筛选,基于Nav1.6的表达和结构的分子对接和NCI‑60药物敏感性分析。在神经胶质瘤细胞中,Nav1.6表达明显上调,多见于细胞质和细胞膜,其表达与病理分级呈正相关。A172和U251细胞增殖减少,当Nav1.6表达被击倒时迁移和入侵,细胞凋亡增加。发现作用于神经胶质瘤细胞的TNF-α(100pg/ml)上调Nav1.6的表达水平,TNF-α参与Nav1.6促进神经胶质瘤恶性进展的过程。最后,某些FDA批准的药物是通过虚拟筛选和药物敏感性分析确定的。总之,本研究证明了Nav1.6在神经胶质瘤中的表达和作用,并确定了几种FDA批准的与Nav1.6高度相关的药物,这些药物可能是神经胶质瘤患者的候选药物.
Gliomas remain a clinical challenge, common and fatal. Treatment of glioblastoma remains elusive, and researchers have focused on discovering new mechanisms and drugs. It has been well established that the expression of voltage‑gated sodium channels (VGSCs) is abnormally increased in numerous malignancies and, in general, is rarely expressed in the corresponding normal tissues. This suggests that ion channel activity appears to be associated with malignant progression of tumors. VGSCs remain largely unknown as to how their activity leads to an increase in cancer cell activity or invasiveness. Certain sodium ion channel subtypes (for instance, Nav1.5 and Nav1.7) are associated with metastasis and invasion in cancers including breast and colorectal cancers. A previous study by the authors explored the expression of certain ion channels in glioma, but there are few studies related to Nav1.6. The current study aimed to elucidate the expression and role of
Nav1.6 in glioma and to screen potential drugs for the treatment of glioma by virtual screening and drug sensitivity analysis.
Nav1.6 relative expression of mRNA and protein was determined by reverse transcription‑quantitative PCR and western blot analysis. Cell proliferation was determined by Cell Counting Kit‑8 assay. Cell migration was assessed by cellular wound healing assay. Cell invasion and apoptosis were detected by Transwell cell invasion assay and flow cytometry. Last but not least, FDA‑approved drugs were screened using virtual screening, molecular docking and NCI‑60 drug sensitivity analyses based on the expression and structure of Nav1.6. In glioma cells,
Nav1.6 was significantly upregulated and expressed mostly in the cytoplasm and cell membrane; its expression was positively correlated with pathological grade. A172 and U251 cells exhibited reduced proliferation, migration and invasion when Nav1.6 expression was knocked down, and apoptosis was increased. TNF‑α (100 pg/ml) acting on glioma cells was found to upregulate the expression level of
Nav1.6, and TNF‑α was involved in the process of
Nav1.6 promoting malignant progression of glioma. Finally, certain FDA‑approved drugs were identified by virtual screening and drug sensitivity analysis. In conclusion, the present study demonstrated the expression and role of Nav1.6 in glioma and identified several FDA‑approved drugs that are highly correlated with Nav1.6 and could be candidate drugs for patients with glioma.