TNFRSF19 within the 13q12.12 Risk Locus Functions as a Lung Cancer Suppressor by Binding Wnt3a to Inhibit Wnt/β-Catenin Signaling

Abstract Cancer risk loci provide special clues for uncovering pathogenesis of cancers. The TNFRSF19 gene located within the 13q12.12 lung cancer risk locus encodes TNF receptor superfamily member 19 (TNFRSF19) protein and has been proved to be a key target gene of a lung tissue–specific tumor suppressive enhancer, but its functional role in lung cancer pathogenesis remains to be elucidated. Here we showed that the TNFRSF19 gene could protect human bronchial epithelial Beas-2B cells from pulmonary carcinogen nicotine-derived nitrosamine ketone (NNK)-induced malignant transformation. Knockout of the TNFRSF19 significantly increased NNK-induced colony formation rate on soft agar. Moreover, TNFRSF19 expression was significantly reduced in lung cancer tissues and cell lines. Restoration of TNFRSF19 expression in A549 lung cancer cell line dramatically suppressed the tumor formation in xenograft mouse model. Interestingly, the TNFRSF19 protein that is an orphan membrane receptor could compete with LRP6 to bind Wnt3a, thereby inhibiting the Wnt/β-catenin signaling pathway that is required for NNK-induced malignant transformation as indicated by protein pulldown, site mutation, and fluorescence energy resonance transfer experiments. Knockout of the TNFRSF19 enhanced LRP6–Wnt3a interaction, promoting β-catenin nucleus translocation and the downstream target gene expression, and thus sensitized the cells to NNK carcinogen. In conclusion, our study demonstrated that the TNFRSF19 inhibited lung cancer carcinogenesis by competing with LRP6 to combine with Wnt3a to inhibit the Wnt/β-catenin signaling pathway. Implications: These findings revealed a novel anti-lung cancer mechanism, highlighting the special significance of TNFRSF19 gene within the 13q12.12 risk locus in lung cancer pathogenesis.