Resolvin D1 prevents epithelial-mesenchymal transition and reduces the stemness features of hepatocellular carcinoma by inhibiting paracrine of cancer-associated fibroblast-derived COMP
Resolvin D1 prevents epithelial-mesenchymal transition and reduces the stemness features of hepatocellular carcinoma by inhibiting paracrine of cancer-associated fibroblast-derived COMP
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Resolvin D1 通过抑制癌症相关成纤维细胞衍生的 COMP 的旁分泌来防止上皮间质转化并减少肝细胞癌的干性特征。
DOI：
10.1186/s13046-019-1163-6
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发表时间：
2019-04-18
影响因子：
11.3
通讯作者：
Tu, Kangsheng
中科院分区：
文献类型：
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作者：
Sun, Liankang;Wang, Yufeng;Tu, Kangsheng
癌症干细胞（CSCs）需要基质信号来维持多能性和自我更新能力，从而导致肿瘤转移。Resolvin D1 （RvD1）是一种内源性抗炎脂质介质，最近被发现通过作用于基质细胞发挥抗癌作用。我们之前的研究表明，肝星状细胞（hsc）来源的软骨寡聚基质蛋白（COMP）有助于肝细胞癌（HCC）的进展。然而，RvD1是否抑制癌相关成纤维细胞（CAFs）衍生的COMP旁分泌以阻止HCC的上皮-间充质转化（EMT）和癌变仍有待阐明。方法从HCC组织中分离scafs。建立直接和间接共培养模型，分析体外RvD1存在下HCC细胞与CAFs的相互作用。采用transwell法和肿瘤球形成法测定HCC细胞的侵袭性和干性。通过联合植入CAFs和HCC细胞建立皮下肿瘤形成和原位肝肿瘤模型，在体内评价RvD1的作用。为研究RvD1抑制CAFs COMP旁分泌的机制，采用ELISA、western blotting、活性氧（reactive oxygen species， ROS）检测、免疫荧光染色、双荧光素酶报告基因法和染色质免疫沉淀法分析了RvD1抑制CAFs COMP旁分泌的各种信号分子。结果在共培养条件下，RvD1治疗可以抑制cafs诱导的癌干细胞样特性和肝癌细胞的EMT。体内研究表明，RvD1干预抑制了CAFs对HCC肿瘤生长和转移的促进作用。此外，RvD1通过抑制COMP的分泌来抑制ca诱导的肝癌细胞EMT和干细胞特征。机制上，甲氧基肽受体2 （FPR2）受体介导了RvD1对ca中COMP和叉头盒M1 （FOXM1）表达的抑制作用。值得注意的是，RvD1通过靶向FPR2/ROS/FOXM1信号通路，以旁分泌方式损害cf -来源的COMP，最终消除FOXM1对COMP启动子的募集。结论RvD1通过靶向FPR2/ROS/FOXM1信号通路抑制肝癌细胞的EMT和癌变，从而抑制cafs来源的COMP旁分泌。因此，RvD1可能是促进HCC治疗结果的潜在药物。
BackgroundCancer stem cells (CSCs) require stromal signals for maintaining pluripotency and self-renewal capacities to confer tumor metastasis. Resolvin D1 (RvD1), an endogenous anti-inflammatory lipid mediator, has recently been identified to display anti-cancer effects by acting on stroma cells. Our previous study reveals that hepatic stellate cells (HSCs)-derived cartilage oligomeric matrix protein (COMP) contributes to hepatocellular carcinoma (HCC) progression. However, whether RvD1 inhibits paracrine of cancer-associated fibroblasts (CAFs)-derived COMP to prevent epithelial-mesenchymal transition (EMT) and cancer stemness in HCC remains to be elucidated.MethodsCAFs were isolated from HCC tissues. Direct and indirect co-culture models were established to analyze the interactions between HCC cells and CAFs in the presence of RvD1 in vitro. The transwell and tumor sphere formation assays were used to determine invasion and stemness of HCC cells. The subcutaneous tumor formation and orthotopic liver tumor models were established by co-implantation of CAFs and HCC cells to evaluate the role of RvD1 in vivo. To characterize the mechanism of RvD1 inhibited paracrine of COMP in CAFs, various signaling molecules were analyzed by ELISA, western blotting, reactive oxygen species (ROS) detection, immunofluorescence staining, dual luciferase reporter assay and chromatin immunoprecipitation assay.ResultsOur data revealed that RvD1 treatment can impede the CAFs-induced cancer stem-like properties and the EMT of HCC cells under co-culture conditions. In vivo studies indicated that RvD1 intervention repressed the promoting effects of CAFs on tumor growth and metastasis of HCC. Furthermore, RvD1 inhibited CAF-induced EMT and stemness features of HCC cells by suppressing the secretion of COMP. Mechanistically, formyl peptide receptor 2 (FPR2) receptor mediated the suppressive effects of RvD1 on COMP and forkhead box M1 (FOXM1) expression in CAFs. Notably, RvD1 impaired CAF-derived COMP in a paracrine manner by targeting FPR2/ROS/FOXM1 signaling to ultimately abrogate FOXM1 recruitment to the COMP promoter.ConclusionOur results indicated that RvD1 impaired paracrine of CAFs-derived COMP by targeting FPR2/ROS/FOXM1 signaling to repress EMT and cancer stemness in HCC. Thus, RvD1 may be a potential agent to promote treatment outcomes in HCC.