The C228T mutation of TERT promoter frequently occurs in bladder cancer stem cells and contributes to tumorigenesis of bladder cancer.

Chong Li,Xingang Bi,Song Wu,Haifeng Wang,Zhiming Cai,Luyun He,Ying Du,Zhao Yang,Jiansong Wang,Zusen Fan

doi:10.18632/oncotarget.4295

Abstract

Bladder cancer is one of the most common malignant tumors worldwide. Bladder cancer stem cells (BCSCs) have been isolated recently but have not been defined yet. Here we sorted BCSCs from bladder tumor tissues or normal bladder stem cells (NBBCs) from adjacent normal bladder tissues. We found that the C228T mutation (chr5, 1, 295, 228 C > T) of TERT promoter frequently occurs in BCSCs, but not exist in NBBCs. Importantly, introducing the C228T mutation in NBBCs causes TERT overexpression and transformation of bladder cancer. Restoration of the C228T mutation to T228C in BCSCs can recover the TERT expression to a basal level and abolish tumor formation. Additionally, the C228T mutation of TERT promoter triggers TERT expression leading to increased telomerase activity. TERT expression levels are consistent with clinical severity and prognosis of bladder cancer.

Highlights

Bladder cancer is one of the most common malignancies, ranking the fifth most common cancer in Western society [1, 2]
The C228T mutation of telomerase reverse transcriptase (TERT) promoter appears in Bladder cancer stem cells (BCSCs) with high frequency
BCSCs were recently isolated in bladder cancer samples with the surface makers (LineageCD44+CK5+CK20-) [10], similar to normal bladder basal cells (NBBSc)

Summary

Introduction

Bladder cancer is one of the most common malignancies, ranking the fifth most common cancer in Western society [1, 2]. The majority of bladder cancers are histologically classified as urothelial carcinomas [3]. Urothelial carcinomas originate from the bladder urothelium consisting of basal, intermediate, and umbrella cells, representing early, mid, and later differentiation states, respectively [4]. Malignant transformation can occur in any of these cell types that gives rise to tumors with diverse phenotypes [5]. Over 70% is non-muscle-invasive tumors, whereas the remainder is muscle-invasive tumors [6]. The tumorigenesis of bladder cancer remains elusive

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Results

Conclusion