Cui Bin, Fan Xiaoxiao, Zhou Daizhan, He Lifeng, Li Yirun, Li Dandan, Lin Hui
China-UK-NYNU-RRes Joint Laboratory of Insect Biology, Henan Key Laboratory of Insect Biology in Funiu Mountain, Nanyang Normal University, Nanyang, Henan 473061, P.R. China.
Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310016, P.R. China.
Oncol Lett. 2020 Aug;20(2):1835-1845. doi: 10.3892/ol.2020.11726. Epub 2020 Jun 11.
Tumor-associated macrophages (TAMs) are important in tumor microenvironments and are closely associated with cancer occurrence, metastasis and progression. Colony stimulating factor 1 receptor (CSF1R) serves a crucial role in TAM formation. Whether CSF1R expression is regulated by DNA methylation in hepatocellular carcinoma (HCC) has not been fully elucidated. In the current study, HCC and adjacent non-cancerous tissue (ANT) samples were collected from 160 patients with HCC. CSF1R methylation levels were analyzed using a Mass ARRAY Analyzer to establish the potential impact of CSF1R methylation alternations on HCC clinicopathological characteristics. The mean methylation level of the CSF1R promoter (chr 5:149492491-149492958) was demonstrated to be significantly higher in ANTs compared with HCC tissues (65.3±7.5% vs. 57.3±14.4%, respectively; P<0.0001). CSF1R also exhibited decreased expression in HCC tissues compared with ANTs (P=0.0026). However, CSF1R expression was negatively correlated with CSF1R methylation levels in ANTs (r>0.4; P<0.0001). Further analysis indicated that patients with diabetes exhibited lower methylation levels in ANTs compared with HCC tissues (P=0.0062). Furthermore, CSF1R hypomethylation in ANTs was associated with a larger number of tumors (P=0.0332), larger tumor size (P=0.0494) and higher tumor grade (P=0.0244). Therefore, methylation alternation of the CSF1R promoter region analyzed in the present study was a key regulatory mechanism on CSF1R expression and ANT hypomethylation indicated poor clinicopathological characteristics of HCC. CSF1R may be a potential immunological therapeutic target for HCC.
肿瘤相关巨噬细胞（TAM）在肿瘤微环境中起重要作用，且与癌症的发生、转移和进展密切相关。集落刺激因子1受体（CSF1R）在TAM形成中起关键作用。肝细胞癌（HCC）中CSF1R表达是否受DNA甲基化调控尚未完全阐明。在本研究中，收集了160例HCC患者的HCC及癌旁非癌组织（ANT）样本。使用Mass ARRAY分析仪分析CSF1R甲基化水平，以确定CSF1R甲基化改变对HCC临床病理特征的潜在影响。结果表明，ANT中CSF1R启动子（chr 5:149492491 - 149492958）的平均甲基化水平显著高于HCC组织（分别为65.3±7.5%和57.3±14.4%；P<0.0001）。与ANT相比，CSF1R在HCC组织中的表达也降低（P = 0.0026）。然而，ANT中CSF1R表达与CSF1R甲基化水平呈负相关（r>0.4；P<0.0001）。进一步分析表明，与HCC组织相比，糖尿病患者的ANT甲基化水平较低（P = 0.0062）。此外，ANT中CSF1R低甲基化与更多的肿瘤数量（P = 0.0332）、更大的肿瘤大小（P = 0.0494）和更高的肿瘤分级（P = 0.0244）相关。因此，本研究中分析的CSF1R启动子区域的甲基化改变是CSF1R表达的关键调节机制，ANT低甲基化提示HCC临床病理特征较差。CSF1R可能是HCC潜在的免疫治疗靶点。
