环氧化酶-2通过影响髓源抑制性细胞增殖及活化参与肝细胞肿瘤进展

Cyclooxygenase-2 participates in the progression of hepatocellular tumors by affecting the proliferation and activation of myelogenous inhibitory cells

目的:以COX2-PGE2通路为靶标,探讨其调控髓源抑制性细胞(myeloid-derived suppressor cell,MDSC)增殖及活化,进而影响肝细胞肿瘤(hepatocelluar carcinoma,HCC)进展的可能机制。方法:建立小鼠肝细胞肿瘤模型,利用流式细胞术分析外周血及脾脏组织中的MDSC比例,CFSE标记法分析肿瘤浸润MDSCs对T淋巴细胞增殖的影响,ELISA检测肿瘤组织体外培养上清中PGE2水平,Western blot检测肿瘤组织中COX-2表达,最终腹腔注射COX2-PGE2通路的小分子抑制剂吲哚美辛,证实该通路在调控MDSCs增殖活化,进而影响肿瘤进展过程中具有重要作用。结果:随着HCC的进展,小鼠外周血及脾脏中MDSC比例逐渐升高,其对T淋巴细胞增殖的抑制作用,即免疫抑制功能显著增加;肿瘤组织COX-2及PGE2表达水平较正常肝脏显著升高,腹腔注射吲哚美辛能够有效抑制肿瘤生长;过继回输MDSC则在一定程度上降低吲哚美辛的肿瘤抑制作用。结论:HCC发展过程中,肿瘤细胞通过COX2-PGE2通路活化MDSC,促进肿瘤进展。COX2-PGE2通路抑制剂吲哚美辛可通过抑制MDSC介导的免疫抑制作用,减缓肿瘤进程。

Objective:To investigate the possible mechanism of COX2-PGE2 pathway in regulating the proliferation and activation of myeloid-derived suppressor cells(MDSC)and the progression of hepatocellular carcinoma(HCC).Methods:The model of hepatocellular carcinoma in mice was established.The proportion of MDSC in peripheral blood and spleen tissue was analyzed by flow cytometry.The effect of MDSCs infiltration on T lymphocyte proliferation was analyzed by CFSE labeling.The level of PGE2 in the supernatant of tumor tissue was detected by ELISA.The expression of COX-2 in tumor tissue was detected by Western blot.Finally,indomethacin,a small molecule inhibitor of COX2-PGE2 pathway,was used in the abdominal cavity.Injection confirmed that this pathway played an important role in regulating the proliferation and activation of MDSCs,thereby affecting the progress of tumors.Results:With the development of HCC,the proportion of MDSC in peripheral blood and spleen of mice gradually was increased,and the inhibition of T lymphocyte proliferation,i.e.the immunosuppressive function,was significantly increased.The expression of COX-2 and PGE2 in tumor tissue was significantly higher than that in normal liver,and intraperitoneal injection of indomethacin could effectively inhibit the growth of tumors:Adoptive reinfusion of MDSC could reduce the inhibition of indomethacin to some extent.Conclusion:During the development of HCC,tumor cells activate MDSC through COX2-PGE2 pathway,promote the progress of cancer.Indomethacin,a COX2-PGE2 pathway inhibitor,can slow down the progression of cancer by inhibiting MDSC-mediated immunosuppression.