Hypoxia-inducible proteins HIF1α and lactate dehydrogenase LDH5, key markers of anaerobic metabolism, relate with stem cell markers and poor post-radiotherapy outcome in bladder cancer

Abstract

Purpose: To assess whether anaerobic metabolism, proliferation activity and stem cell content are linked with radioresistance in bladder cancer. Materials and methods: Tissue sections from 66 patients with invasive transitional cell bladder cancer treated with hypofractionated accelerated radiotherapy, was immunohistochemically analyzed for the Hypoxia-Inducible Factor 1α (HIF1α) and the anaerobic glycolysis enzyme lactate dehydrogenase 5 (LDH5). Proliferation index (Ki-67) and stem-cell marker (cluster of differentiation CD44, aldehyde dehydrogenase ALDH1) expression was also examined. Results: Both HIF1α and LDH5 expression were linked with high CD44 stem cell population (p = 0.001 and 0.05, respectively), while high Ki-67 proliferation index was linked with nuclear LDH5 expression (p = 0.03) and high histological grade (p = 0.02). A strong significant association of HIF1α (p = 0.0009) and of LDH5 (p < 0.0001) with poor local relapse free survival (LRFS) was noted, which was also confirmed in multivariate analysis. A significant association with overall survival was also noted. Silencing of lactate dehydrogenase LDHA gene in the human RT112 bladder cancer cell line, or exposure to oxamate (LDH activity inhibitor), resulted in strong radio-sensitization. Conclusions: HIF1α and LDH5 are markers of poor outcome in patients with bladder cancer treated with radiotherapy. Blockage of anaerobic metabolism may prove of importance in clinical radiotherapy.

Keywords:

• HIF1α
• LDH
• CD44
• proliferation index
• bladder cancer
• radiotherapy

Acknowledgements

The study was financially supported by the Democritus University of Thrace, Special Account Project code 81006

Disclosure statement

The authors report no conflict of interest. The authors alone are responsible for the content and writing of the paper.