Abstract
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.
Highlights
Tumor microenvironments (TMEs) are a complex ecology of cells, comprising cancer‐associated fibroblasts and various infiltrating immune cells that provide support to tumor cells during their transition to malignancy, such as tumor‐associated macrophages (TAMs) [1]
The results demonstrated that colony stimulating factor‐1 (CSF1) and its receptor (CSF1R) methylation levels in all 7 successfully analyzed CpG sites were significantly decreased in hepatocellular carcinoma (HCC) compared with their paired adjacent non‐cancerous tissue (ANT) samples (Table II; Fig. 2A) and that the mean methylation difference between HCC and ANTs ranged between 4.9 and 11.0% in the 7 CpG sites (Table II)
The present study investigated whether CSF1R methylation levels in ANTs from patients with HCC had a regulatory effect on HCC progression and whether CSF1R methylation levels in ANTs could be used as clinical biomarkers for HCC
Summary
Tumor microenvironments (TMEs) are a complex ecology of cells, comprising cancer‐associated fibroblasts and various infiltrating immune cells that provide support to tumor cells during their transition to malignancy, such as tumor‐associated macrophages (TAMs) [1]. TAMs are closely associated with tumor proliferation and metastasis and have been demonstrated to promote tumor angiogenesis, cancer cell infiltration into the circulation and suppression of antitumor immune mechanisms [3]. Due to this involvement, TAMs are considered to be potential therapy targets in cancer treatment [4]. During the transition from benign growth to invasive tumor, colony stimulating factor‐1 (CSF1) has been reported to be one of the key cytokines that regulates cancer‐initiated inflammatory responses [6]. CSF1 and its receptor (CSF1R) have been reported to be central to the promotion of migration, survival and proliferation of monocytes [9]
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