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Co-expression and functional interactions of Death Receptor 3 and E-selectin in clear cell renal cell carcinoma.

R. Al‐Lamki,Jun Wang,J. Pober,J. Bradley

Published 2022 in American Journal of Pathology

ABSTRACT

Similar to the behavior of inflamed tubular epithelial cells (TECs), clear cell renal carcinoma (ccRCC) cells express death receptor 3 (DR3 or TNFSFR25) in situ, and expression increases with tumor grade. Surprisingly, E-selectin, which can be induced in endothelial cells by DR3 signaling, is also expressed by ccRCC cells and also increases with tumor grade. In ccRCC organ cultures, addition of tumor necrosis factor-like 1A (TL1A or TNFSF15), the ligand for DR3, activates NF-κB and MAP kinases, induces both DR3 and E-selectin expression in an NF-κB-dependent manner and promotes cell cycle entry. DR3 immunoprecipitated from ccRCC tissue contains Sialyl Lewis X moieties, the ligand recognized by E-selectin, and proximity ligation assays reveal DR3, and E-selectin interact on ccRCC cells. Like addition of TL1A, addition of soluble E-selectin to ccRCC organ cultures activates NF-κB and MAP kinases in ccRCC cells and increases both DR3 and E-selectin expression and cell-cycle entry. In contrast, normal renal tubular epithelium, which poorly expresses DR3, is minimally responsive to either of these ligands. These data suggest a functional role for autocrine/paracrine DR3/E-selectin interactions in ccRCC and its progression, revealing a potential new target for therapeutic intervention.

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