Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
The Key Laboratory for Drug Target Researches and Pharmacodynamic Evaluation of Hubei Province, Hubei, China
Curr Cancer Drug Targets. 2020;20(11):868-874. doi: 10.2174/1568009620999200730184514.
Obesity is a significant risk factor for the development of types of cancer. Programmed death 1 and its ligand programmed death-ligand 1 (PD-L1) play a crucial role in tumor immune escape. Although, the role of PD-L1 in obesity-associated hepatocellular carcinoma (HCC) remains unknown. We previously showed that the natural flavonoid pentamethylquercetin (PMQ) possesses anti-obesity properties.
This study was designed to investigate the effects of PMQ on the development of HCC in obese mice and whether PMQ regulates PD-L1 and expression in HCC.
Monosodium glutamate-induced obese mice were inoculated with H22 tumor cells. Tumor volumes and weights were measured. In vitro, 3T3-L1 preadipocytes were differentiated and lipid accumulation was measured by oil-red staining, and IFN-γ level was detected by Elisa. Hepatoma HepG2 cells were treated with conditional media from 3T3-L1 adipocytes (adi-CM). Western blotting was applied to detect PD-L1 protein levels in tumor tissue and HepG2 cells.
Compared with control mice, H22 tumors grew faster and exhibited higher PD-L1 protein levels in obese mice. PMQ inhibited H22 tumor growth and reduced PD-L1 expression in tumor tissues. PD-L1 protein level was elevated in adi-CM-treated HepG2 cells. IFN-γ was detectable in adi-CM and exogenous IFN-γ induced PD-L1 expression in HepG2 cells. PMQ affected the differentiation of 3T3-L1 preadipocytes, decreased the level of IFN-γ secreted by adipocytes and downregulated adi-CM-induced PD-L1 expression in HepG2 cells.
PMQ could inhibit HCC progression in obese mice at least in part through down-regulating adipocytes-induced PD-L1 expression via IFN-γ signaling.
肥胖是癌症发生的一个重要危险因素。程序性死亡受体 1（PD-1）及其配体程序性死亡配体 1（PD-L1）在肿瘤免疫逃逸中发挥着关键作用。然而，PD-L1 在肥胖相关的肝细胞癌（HCC）中的作用尚不清楚。我们之前的研究表明，天然类黄酮五甲基槲皮素（PMQ）具有抗肥胖作用。
本研究旨在探讨 PMQ 对肥胖小鼠 HCC 发生发展的影响，以及 PMQ 是否调节 HCC 中 PD-L1 的表达。
采用谷氨酸单钠诱导肥胖小鼠接种 H22 肿瘤细胞，测量肿瘤体积和重量。体外，3T3-L1 前脂肪细胞分化，油红染色法测量脂滴积累，ELISA 法检测 IFN-γ 水平。用 3T3-L1 脂肪细胞条件培养基（adi-CM）处理肝癌 HepG2 细胞。Western blot 法检测肿瘤组织和 HepG2 细胞中 PD-L1 蛋白水平。
与对照组小鼠相比，肥胖小鼠的 H22 肿瘤生长更快，肿瘤组织中 PD-L1 蛋白水平更高。PMQ 抑制 H22 肿瘤生长，降低肿瘤组织中 PD-L1 的表达。adi-CM 处理的 HepG2 细胞中 PD-L1 蛋白水平升高。adi-CM 中可检测到 IFN-γ，外源性 IFN-γ 诱导 HepG2 细胞中 PD-L1 的表达。PMQ 影响 3T3-L1 前脂肪细胞的分化，降低脂肪细胞分泌的 IFN-γ 水平，并下调 adi-CM 诱导的 HepG2 细胞中 PD-L1 的表达。
PMQ 至少部分通过 IFN-γ 信号通路下调脂肪细胞诱导的 PD-L1 表达，从而抑制肥胖小鼠 HCC 的进展。
