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.
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