TNFSF9 exerts an inhibitory effect on hepatocellular carcinoma
TNFSF9 exerts an inhibitory effect on hepatocellular carcinoma
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TNFSF9对肝细胞癌发挥抑制作用
DOI：
10.1111/1751-2980.12489
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发表时间：
2017
影响因子：
3.5
通讯作者：
Tu Hong
中科院分区：
文献类型：
--
作者：
Shen Yu Ling;Gan Yu;Gao Hai Feng;Fan Ying Chao;Wang Qing;Yuan Hui;Song Yan Fang;Wang Jia Dong;Tu Hong
肿瘤坏死因子超家族成员9（TNFSF 9），也称为4 - 1BBL和CD 137 L，由于其作为T细胞共刺激因子的功能，已参与癌症免疫治疗。方法采用免疫组化法检测106例肝细胞癌（HCC）组织及癌旁正常肝组织中TNF-9的表达，同时采用定量PCR和Western blot检测HCC细胞系中TNF-9的表达。采用3-（4，5-二乙基噻唑-2-基）-5-（3-羧基甲氧基苯基）-2-（4-磺基苯基）-2H-四唑内盐（MTS）法和transwell法检测TNF SF 9对肝癌细胞增殖、迁移和侵袭的影响。我们还评估了TNFSF 9对人肝癌原位小鼠模型中肝癌肿瘤生长和转移的影响。大约70%的肝癌组织中TNFSF 9表达下调。在所有四种HCC细胞系中也一致地观察到TNFSF 9表达降低。无论是TNFSF 9的过表达还是重组TNFSF 9蛋白的处理，都可以显着抑制Huh 7和SMMC-7721肝癌细胞的体外增殖、迁移和侵袭。体内实验进一步证实了TNFSF 9对肝癌的抑制作用。与对照组相比，原位移植TNFSF 9过表达的Huh 7细胞的小鼠肿瘤明显变小，肝内转移和远处转移减少。基于其免疫刺激方面和肿瘤抑制特性，TNFSF 9可能是一个有希望的肝癌治疗靶点。
OBJECTIVETumor necrosis factor superfamily member 9 (TNFSF9), also known as 4‐1BBL and CD137L, has been implicated in cancer immunotherapy due to its function as a T‐cell co‐stimulator. We aimed to investigate the role of TNFSF9 in the cancer pathogenesis in hepatocellular carcinoma (HCC).METHODSTNFSF9 expression was examined by immunohistochemistry in 106 pairs of HCC and adjacent non‐tumorous tissues, and by quantitative polymerase chain reaction and Western blot in HCC cell lines. The impact of TNFSF9 on the proliferation, migration and invasion of HCC cells was determined using the 3‐(4,5‐diethylthiazol‐2‐yl)‐5‐(3‐carboxymethoxyphenyl)‐2‐(4‐sulfophenyl)‐2H‐tetrazolium, inner salt (MTS) and transwell assaysin vitro. We also assessed the influence of TNFSF9 on the growth and metastasis of HCC tumors in an orthotopic mouse model of human HCC.RESULTSTNFSF9 expression was downregulated in approximately 70% of HCC tissues. A decreased expression of TNFSF9 was also consistently observed in all the four HCC cell lines. Either the overexpression of TNFSF9 or treatment with recombinant TNFSF9 protein could significantly inhibit the proliferation, migration and invasion of Huh7 and SMMC‐7721 HCC cellsin vitro. The inhibitory effect of TNFSF9 on HCC was further confirmedin vivo. Mice orthotopically transplanted with TNFSF9‐overexpressing Huh7 cells developed significantly smaller tumors with less intrahepatic metastasis and distant metastasis compared with the control group.CONCLUSIONSTNFSF9 may be a tumor suppressor in HCC. Based on its immune stimulatory aspect and the tumor inhibition property, TNFSF9 may be a promising therapeutic target for HCC.