ZNF460激活ZDHHC7转录和STAT3磷酸化促进肝细胞癌进展

ZNF460 Mediates STAT3 Phosphorylation to Promote Progression of Hepatocellular Carcinoma by Activating ZDHHC7 Transcription

背景:ZNF460为锌指蛋白家族成员,具有转录因子活性,参与调节多种细胞功能。研究显示其与多种消化系统恶性肿瘤密切相关。目的:分析ZNF460在肝细胞癌(HCC)中的表达,探讨其对HCC增殖能力的影响和可能的作用机制。方法:对含76例HCC组织和相应癌旁组织的组织芯片进行免疫组化染色,分析ZNF460表达水平及其与TNM分期的相关性。以CCK-8实验和克隆形成实验评估ZNF460对HCC细胞增殖的影响。通过LinkedOmics数据库筛选HCC中与ZNF460表达呈正相关的基因并进行KEGG和GSEA通路富集分析,结合过表达或敲低ZNF460以及双荧光素酶报告基因实验等对HCC中ZNF460可能的下游分子进行探究和验证。结果:ZNF460在HCC中高表达且与不良TNM分期相关。ZNF460可促进HCC细胞增殖,可能的机制为ZNF460激活棕榈酰转移酶DHHC7编码基因ZDHHC7转录,促进STAT3棕榈酰化,从而上调其磷酸化水平。结论:ZNF460在HCC中高表达,可通过激活STAT3促进癌细胞增殖和肿瘤进展,有望成为HCC新的分子标志物和治疗靶点。

Background:ZNF460 is a member of the zinc finger protein family transcription factors,and is involved in the regulation of a variety of cellular functions.It has been demonstrated to be closely related to digestive system cancers.Aims:To analyze the expression level of ZNF460 in hepatocellular carcinoma(HCC),and explore the effect and potential mechanisms of ZNF460 on tumor cell proliferation.Methods:Immunohistochemical staining was used to determine the expression level of ZNF460 in tissue microarray of 76 HCC and paired adjacent tissues,and the correlation between ZNF460 expression and TNM staging was analyzed.The effect of ZNF460 on HCC cell proliferation was evaluated by CCK⁃8 and colony formation assays.Genes positively related to ZNF460 expression in HCC were screened through LinkedOmics database,and the KEGG and GSEA pathway enrichment analyses were performed;the possible downstream molecules of ZNF460 were explored and verified by overexpression or knockdown of ZNF460 in HCC cells combined with luciferase reporter assay and other experiments.Results:ZNF460 was highly expressed in HCC and was positively correlated with TNM staging.ZNF460 promoted the proliferation of HCC cells,and the underlying mechanism might be associated with the transcriptional activation of ZDHHC7,the coding gene of palmitoyl transferase DHHC7 and the subsequent STAT3 palmitoylation and phosphorylation.Conclusions:ZNF460 is highly expressed in HCC and promotes cell proliferation and tumor progression via STAT3 activation.It might be a promising molecular marker and therapeutic target for HCC.