Growth differentiation factor-15: A p53- and demethylation-upregulating gene represses cell proliferation, invasion, and tumorigenesis in bladder carcinoma cells

Growth differentiation factor-15 (GDF15), a member of the TGF-β superfamily, affects tumor biology of certain cancers, but remains poorly understood in bladder cancer cells. This study determined the expression, regulation, function, and potential downstream target genes of GDF15 in bladder carcinoma cells. The transitional papilloma carcionoma cells (RT4) expressed higher levels of GDF15 as compared with the bladder carcinoma cells (HT1376 and T24). Treatments of recombinant human GDF15 (rhGDF15) reduced the proliferations of HT1376 and T24 cells. Expression of GDF15 was upregulated via DNA demethylation and p53. The cell proliferation, invasion, and tumorigenesis were reduced in ectopic overexpression of GDF15, while enhanced in GDF15 knockdown. The expressions of mammary serine protease inhibitor (MASPIN) and N-myc downstream-regulated family genes (NDRG1, NDRG2, and NDRG3) were upregulated by GDF15 overexpressions and rhGDF15 treatments in bladder carcinoma cells. GDF15 knockdown induced epithelial-mesenchymal transition (EMT) and F-actin polarization in HT1376 cells. Our results suggest that enhanced expressions of MASPIN and N-myc downstream-regulated family genes and the modulation of EMT may account for the inhibitory functions of GDF15 in the cell proliferation, invasion, and tumorigenesis of bladder carcinoma cells. The GDF15 should be considered as a tumor suppressor in human bladder carcinoma cells.