Hepatocellular carcinoma (HCC) is a major malignancy that stands second in terms of global cancer-related mortality. STAT3 has been described as a latent transcription factor that promotes tumorigenesis. This study was designed to examine the effect of vitexin on STAT3 signaling and important hallmarks of cancer. HCC cells were employed to decipher the impact of vitexin on activation of STAT3 signaling using Western blotting, EMSA, immunocytochemistry, and reporter assay. The combinational apoptotic effects of vitexin with approved anti-cancer drugs was examined by live-dead assay, and its anti-invasive potential was studied using matrigel assay. The results obtained in cell-based assays were verified using in silico analysis. Vitexin effectively inhibited sustained activation of JAK1, JAK2, Src, and STAT3 in HCC cells. Vitexin downregulated DNA binding ability, reduced the nuclear pool of STAT3, and diminished epidermal growth factor (EGF)-driven STAT3 gene expression. Interestingly, treatment with tyrosine phosphatase inhibitor altered the vitexin-induced STAT3 phosphorylation, and the attenuation of STAT3 by vitexin was found to be driven through the upregulation of PTPεC. The combinational studies indicated that vitexin can exhibit substantial apoptotic effects with doxorubicin and sorafenib. It also suppressed the CXCL12-induced cell invasion. The results of cell-based assays are supported by in silico analysis as the vitexin displayed favorable interaction with kinase domain of JAK2 protein. Overall, this study demonstrated that vitexin can act as a potential blocker of the STAT3 signaling cascade and mitigate the survival as well as invasion of HCC cells.

中文翻译：

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Vitexin通过靶向STAT3信号通路消除肝癌细胞的侵袭和存活。

肝细胞癌（HCC）是一种主要的恶性肿瘤，在全球癌症相关死亡率方面名列第二。STAT3被描述为促进肿瘤发生的潜在转录因子。这项研究旨在检查vitexin对STAT3信号传导和癌症重要标志的作用。使用Western印迹，EMSA，免疫细胞化学和报告基因分析法，将HCC细胞用于研究vitexin对STAT3信号激活的影响。通过活死分析检查了vitexin与批准的抗癌药物的组合凋亡作用，并使用matrigel分析研究了其抗侵袭潜力。使用计算机分析验证了在基于细胞的分析中获得的结果。Vitexin有效抑制HCC细胞中JAK1，JAK2，Src和STAT3的持续活化。胎蛋白下调DNA结合能力，减少STAT3的核库，并减少表皮生长因子（EGF）驱动的STAT3基因表达。有趣的是，酪氨酸磷酸酶抑制剂的治疗改变了胎蛋白诱导的STAT3磷酸化，并且发现由胎蛋白引起的STAT3的衰减是由PTPεC的上调驱动的。联合研究表明，vitexin对阿霉素和索拉非尼具有明显的凋亡作用。它还抑制了CXCL12诱导的细胞侵袭。基于计算机的分析结果得到了计算机分析的支持，因为葡萄膜蛋白显示出与JAK2蛋白激酶结构域的良好相互作用。总体而言，这项研究表明，vitexin可以作为STAT3信号级联反应的潜在阻断剂，减轻HCC细胞的存活和侵袭。