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

Ke-Hung Tsui,Horng-Heng Juang,Phei-Lang Chang,Li-Chuan Chung,Tzu-Yi Lee,Tsui-Hsia Feng,Yu-Hsiang Lin,Shu-Yuan Hsu

doi:10.1038/srep12870

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.

Highlights

Urinary bladder carcinoma is the fourth leading malignancy in American males and the eighth most common cause of malignancy-related death[1]
The expression, function, and regulation of Growth differentiation factor-15 (GDF15) in bladder cancer have not been fully explored two recent reports indicated that the epigenetic modulation of GDF15 is an important biomarker in the bladder cancer and the upper tract urothelial carcinoma[17,18]
Studies have shown that the pleiotropic action of GDF15 is involved in cell growth inhibition, apoptosis induction, and invasion enhancement in various cancer cell lines[19]

Summary

Introduction

Urinary bladder carcinoma is the fourth leading malignancy in American males and the eighth most common cause of malignancy-related death[1]. It is practical to explore a new biomarker in detection and develop an understanding in the molecular mechanism of the target gene for bladder cancer. Previous studies have indicated divergent effects of GDF15 in brain, ovarian, intestinal, prostate, and hepatocellular carcinoma[7,8,9,10,11,12,13] suggesting that function of GDF15 has a diverse range of tissue-specific and cell-specific presentations[14,15,16]. The expression, function, and regulation of GDF15 in bladder cancer have not been fully explored two recent reports indicated that the epigenetic modulation of GDF15 is an important biomarker in the bladder cancer and the upper tract urothelial carcinoma[17,18]. The objectives of this study were to determine the expression and regulation of GDF15 in human bladder carcinoma cells, to investigate the tumorigenesis and invasiveness in bladder carcinoma cells engineered to overexpress or knockdown GDF15, and to evaluate the potential mechanisms by which GDF15 suppresses tumorigenesis in human bladder carcinoma cells

Objectives

Methods

Results

Conclusion