Expression data from WT and TNFRSF19 KO HNE-1 cells

Genetic susceptibility underlies the pathogenesis of cancer. Through genome-wide association studies, we and others have previously identified a novel susceptibility gene, TNFRSF19, which encodes an orphan member of the TNF receptor superfamily, to be associated with nasopharyngeal carcinoma (NPC) and lung cancer risk. Here, we show that TNFRSF19 is highly expressed in NPC and is required for cell proliferation and NPC development. However, unlike most of TNF receptors, TNFRSF19 is not involved in NF-B activation or associated with TRAF proteins. By affinity purification, we identified TGF receptor type-I (TRI) as a specific binding partner for TNFRSF19. TNFRSF19 binds to the kinase domain of TRI in the cytoplasm and thereby blocks the Smad2/3 association with TRI and subsequent signal transduction. Ectopic expression of TNFRSF19 in normal epithelial cells confers resistance to the cell cycle block induced by TGF, whereas knockout of TNFRSF19 in NPC cells unleashes a potent TGF response characterized by upregulation of Smad2/3 phosphorylation and TGF target gene transcription. Furthermore, elevated TNFRSF19 expression correlates with reduced TGF activity and poor prognosis in NPC patients. Our data reveal that gain-of-function of TNFRSF19 in NPC represents a mechanism by which tumor cells evade the growth-inhibitory action of TGF.

2

Deng C, Lin YX, Qi XK, He GP, Zhang Y, Zhang HJ, Xu M, Feng QS, Bei JX, Zeng YX, Feng L