Lou Lei, Deng Tingyun, Yuan Qing, Wang Lianghou, Wang Zhi, Li Xiang
Department of Preclinical Medicine, Hunan Normal University School of Medicine, Changsha, 410013, China.
Cancer Cell Int. 2024 Jun 12;24(1):206. doi: 10.1186/s12935-024-03322-4.
Human liver cancer stem-like cells (HLCSLCs) are widely acknowledged as significant factors in the recurrence and eradication of hepatocellular carcinoma (HCC). The sustenance of HLCSLCs' stemness is hypothesized to be intricately linked to the epigenetic process of DNA methylation modification of genes associated with anticancer properties. The present study aimed to elucidate the stemness-maintaining mechanism of HLCSLCs and provide a novel idea for the clearance of HLCSLCs.
The clinical relevance of DNMT1 and SOCS1 in hepatocellular carcinoma (HCC) patients was evaluated through the GEO and TCGA databases. Cellular immunofluorescence assay, methylation-specific PCR, chromatin immunoprecipitation were conducted to explore the expression of DNMT1 and SOCS1 and the regulatory relationship between them in HLCSLCs. Spheroid formation, soft agar colony formation, expression of stemness-associated molecules, and tumorigenicity of xenograft in nude mice were used to evaluate the stemness of HLCSLCs.
The current analysis revealed a significant upregulation of DNMT1 and downregulation of SOCS1 in HCC tumor tissues compared to adjacent normal liver tissues. Furthermore, patients exhibiting an elevated DNMT1 expression or a reduced SOCS1 expression had low survival. This study illustrated the pronounced expression and activity of DNMT1 in HLCSLCs, which effectively targeted the promoter region of SOCS1 and induced hypermethylation, consequently suppressing the expression of SOCS1. Notably, the stemness of HLCSLCs was reduced upon treatment with DNMT1 inhibitors in a concentration-dependent manner. Additionally, the overexpression of SOCS1 in HLCSLCs significantly mitigated their stemness. The knockdown of SOCS1 expression reversed the effect of DNMT1 inhibitor on the stemness of HLCSLCs. DNMT1 directly binds to the SOCS1 promoter. In vivo, DNMT1 inhibitors suppressed SOCS1 expression and inhibited the growth of xenograft.
DNMT1 targets the promoter region of SOCS1, induces hypermethylation of its CpG islands, and silences its expression, thereby promoting the stemness of HLCSLCs.
人肝癌干细胞样细胞（HLCSLCs）被广泛认为是肝细胞癌（HCC）复发和根治的重要因素。据推测，HLCSLCs干性的维持与具有抗癌特性相关基因的DNA甲基化修饰的表观遗传过程密切相关。本研究旨在阐明HLCSLCs的干性维持机制，并为清除HLCSLCs提供新思路。
通过GEO和TCGA数据库评估DNMT1和SOCS1在肝细胞癌（HCC）患者中的临床相关性。进行细胞免疫荧光分析、甲基化特异性PCR、染色质免疫沉淀，以探讨DNMT1和SOCS1在HLCSLCs中的表达及其调控关系。采用球体形成、软琼脂集落形成、干性相关分子表达及裸鼠异种移植瘤致瘤性评估HLCSLCs的干性。
当前分析显示，与相邻正常肝组织相比，HCC肿瘤组织中DNMT1显著上调，SOCS1下调。此外，DNMT1表达升高或SOCS1表达降低的患者生存率较低。本研究表明DNMT1在HLCSLCs中表达明显且活性较高，其有效靶向SOCS1的启动子区域并诱导高甲基化，从而抑制SOCS1的表达。值得注意的是，用DNMT1抑制剂处理后，HLCSLCs的干性以浓度依赖方式降低。此外，HLCSLCs中SOCS1的过表达显著减轻了它们的干性。敲低SOCS1表达可逆转DNMT1抑制剂对HLCSLCs干性的影响。DNMT1直接与SOCS1启动子结合。在体内，DNMT1抑制剂抑制SOCS1表达并抑制异种移植瘤的生长。
DNMT1靶向SOCS1的启动子区域，诱导其CpG岛高甲基化并使其表达沉默，从而促进HLCSLCs的干性。
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