TNFR1 and TNFR2, Which Link NF-κB Activation, Drive Lung Cancer Progression, Cell Dedifferentiation, and Metastasis

Abstract

TNFR1 and TNFR2, encoded by TNFRSF1A and TNFRSF1B, 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 overexpressing TNFRSF1A and 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, TNFRSF1B expression was highly correlated with TNF, FOXP3, and CD4 expression. 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.

Cancer marker TNFRSF1A: From single‑cell heterogeneity of renal cell carcinoma to functional validation

“…TNFRSF1A and TNFRSF1B are the most well-characterized members of the TNFR superfamily ( 47 ). TNFRSF1B is preferentially expressed in leukocytes, while TNFRSF1A is reported to be expressed in most cell types ( 48 , 49 ). Nevertheless, the present study indicated that the interactions of TNF-TNFRSF1A exhibited greater specificity than those of TNF-TNFRSF1B within renal cancer tissues.…”

Relationship of Tumor Necrosis Factor Alpha, Monocyte-Lymphocyte Ratio, and Neutrophil-Lymphocyte Ratio of Bronchial Washing Fluid with Histopathology, Stage, and Bronchoscopic Lesions of Non-Small Cell Carcinoma Lung Cancer

“…Overexpression of TNFR1 is also found in lung adenocarcinoma, but TNFR2 has a different role. Stimulation of TNFR2 by TNF- produced by macrophages converts CD4 T lymphocytes into Treg cells that play a role in the progression of lung adenocarcinoma [16].…”

HspBP1 in Complex with the Peptide of the Innate Immunity Protein Tag7 is Able to Lyse Tumor Cells Carrying TNFR1 Receptor

“…TNF receptors are well characterized and intensively studied [ 3 ]. The most well-known specific TNF receptor is TNFR1 [ 4 ]. TNFR1 is present in many tissues on various cells, including tumor cells [ 5 ].…”