title: Growth differentiation factor-15: a p53- and demethylation-upregulating gene represses cell proliferation, invasion, and tumorigenesis in bladder carcinoma cells.
abstract: 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.
authors.affiliation: 1] Department of Urology, Chang Gung Memorial Hospital, Kwei-Shan, Tao-Yuan, Taiwan, ROC [2] Department of Traditional Chinese Medicine, College of Medicine, Chang Gung University, Kwei-Shan, Tao-Yuan, Taiwan, ROC.
authors.forename: Ke-Hung
authors.initials: KH
authors.lastname: Tsui
authors.affiliation: Department of Anatomy, College of Medicine, Chang Gung University, Kwei-Shan, Tao-Yuan, Taiwan, ROC.
authors.forename: Shu-Yuan
authors.initials: SY
authors.lastname: Hsu
authors.affiliation: Department of Anatomy, College of Medicine, Chang Gung University, Kwei-Shan, Tao-Yuan, Taiwan, ROC.
authors.forename: Li-Chuan
authors.initials: LC
authors.lastname: Chung
authors.affiliation: Department of Urology, Chang Gung Memorial Hospital, Kwei-Shan, Tao-Yuan, Taiwan, ROC.
authors.forename: Yu-Hsiang
authors.initials: YH
authors.lastname: Lin
authors.affiliation: School of Nursing, College of Medicine, Chang Gung University, Kwei-Shan, Tao-Yuan, Taiwan, ROC.
authors.forename: Tsui-Hsia
authors.initials: TH
authors.lastname: Feng
authors.affiliation: Department of Anatomy, College of Medicine, Chang Gung University, Kwei-Shan, Tao-Yuan, Taiwan, ROC.
authors.forename: Tzu-Yi
authors.initials: TY
authors.lastname: Lee
authors.affiliation: 1] Department of Urology, Chang Gung Memorial Hospital, Kwei-Shan, Tao-Yuan, Taiwan, ROC [2] Department of Traditional Chinese Medicine, College of Medicine, Chang Gung University, Kwei-Shan, Tao-Yuan, Taiwan, ROC.
authors.forename: Phei-Lang
authors.initials: PL
authors.lastname: Chang
authors.affiliation: Department of Anatomy, College of Medicine, Chang Gung University, Kwei-Shan, Tao-Yuan, Taiwan, ROC.
authors.forename: Horng-Heng
authors.initials: HH
authors.lastname: Juang
mesh_terms: D000199:Actins / Q000235:genetics; D063646:Carcinogenesis / Q000235:genetics*; D002277:Carcinoma / Q000235:genetics / Q000473:pathology; D018797:Cell Cycle Proteins / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics*; D019175:DNA Methylation / Q000235:genetics; D015536:Down-Regulation / Q000235:genetics; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D055436:Growth Differentiation Factor 15 / Q000235:genetics*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics; D009361:Neoplasm Invasiveness / Q000235:genetics*; D015533:Transcriptional Activation / Q000235:genetics; D016212:Transforming Growth Factor beta / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*; D015854:Up-Regulation / Q000235:genetics*; D001743:Urinary Bladder / Q000473:pathology; D001749:Urinary Bladder Neoplasms / Q000235:genetics* / Q000473:pathology; D000099259:N-myc Downstream-Regulated Gene 1 Protein
chemical_list: D000199:Actins; D018797:Cell Cycle Proteins; D055436:Growth Differentiation Factor 15; D047908:Intracellular Signaling Peptides and Proteins; D016212:Transforming Growth Factor beta; D016159:Tumor Suppressor Protein p53; D000099259:N-myc Downstream-Regulated Gene 1 Protein; C526140:GDF15 protein, human; C495901:TP53 protein, human