TNFR1 and TNFR2, encoded byTNFRSF1AandTNFRSF1B, respectively, are the most well-characterized members among the TNFR superfamily. TNFR1 is expressed in most cell types, while TNFR2 has been reported to be preferentially expressed in leukocytes. Lung cancer remains the leading cause of cancer mortality worldwide but TNFRs’ activities in lung cancer development have not been fully evaluated. Recently, overexpressed TNFR1 was reported in a large proportion of human lung squamous cell carcinomas. Increased TNFR1 coupled with increased UBCH10 caused lung SCC cell dedifferentiation with epithelial–mesenchymal transition features and the metastasis in a combined spontaneous lung SCC and TNFR1 transgenic mouse model. UBCH10, an E2 ubiquitin-conjugating enzyme that is an oncogene, increased Sox2, c-Myc, Twist1, and Bcl2 levels. Increased TNFR1 upregulated UBCH10 expression by activating c-Rel and p65 NF-κB. Lung SCC patients overexpressingTNFRSF1Aand one of these target genes died early compared to lung SCC patients expressing lower levels of these genes. Recently, we also revealed that TNFR2 was required for lung adenocarcinoma progression, delivering a signaling pathway of TNF/TNFR2/NF-κB-c-Rel, in which macrophage-produced ROS and TNF converted CD4 T cells to Foxp3 Treg cells, generating an immunosuppressive tumor microenvironment and promoting lung ADC progression. In human lung ADC cohorts,TNFRSF1Bexpression was highly correlated withTNF,FOXP3, andCD4expression. Of note, TNF stimulated the activities of TNFR1 and TNFR2, two membrane-binding receptors, which accelerate tumorigenesis through diverse mechanisms. This review focuses on these new findings regarding the roles of TNFR1 and TNFR2 in lung SCC and ADC development in humans and mice, and highlights the potential therapeutic targets of human lung cancers.
TNFR1与TNFR2分别由TNFRSF1A和TNFRSF1B基因编码，是肿瘤坏死因子受体超家族中特征最为明确的成员。TNFR1在多数细胞类型中广泛表达，而TNFR2则被报道优先在白细胞中表达。肺癌仍是全球癌症死亡的首要原因，但TNFRs在肺癌发展中的作用尚未得到充分评估。近期研究显示，在大部分人类肺鳞状细胞癌中存在TNFR1过表达现象。在自发性肺鳞癌与TNFR1转基因联合小鼠模型中，TNFR1升高与UBCH10增加共同诱导肺鳞癌细胞出现上皮-间质转化特征的去分化及转移。UBCH10作为一种致癌基因编码的E2泛素结合酶，可提升Sox2、c-Myc、Twist1和Bcl2的表达水平。TNFR1升高通过激活c-Rel和p65 NF-κB上调UBCH10表达。与低表达患者相比，过表达TNFRSF1A及其靶基因的肺鳞癌患者生存期显著缩短。我们近期研究还发现，TNFR2通过介导TNF/TNFR2/NF-κB-c-Rel信号通路推动肺腺癌进展：巨噬细胞产生的活性氧与TNF将CD4 T细胞转化为Foxp3 Treg细胞，形成免疫抑制性肿瘤微环境进而促进肺腺癌发展。在人类肺腺癌队列中，TNFRSF1B表达与TNF、FOXP3及CD4表达高度相关。值得注意的是，TNF可同时激活TNFR1与TNFR2这两种膜结合受体，通过不同机制加速肿瘤发生。本综述聚焦于TNFR1与TNFR2在人类及小鼠肺鳞癌与肺腺癌发展中的最新研究进展，并着重探讨其作为人类肺癌潜在治疗靶点的价值。
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