Oestrogen and Testosterone Play Counter-Regulatory Roles in the HIF Pathway

Background: Colorectal cancer (CRC) is the fourth most common type of malignancy after breast, lung and prostate cancer, accounting for 1.93 million new diagnoses and 940,000 deaths in 2020. Even though CRC is not classically considered as a sex-related or hormone-dependent malignancy, surprisingly, sex differences in incidence rates have been observed. Unregulated hypoxia-inducible factor (HIF) signalling plays a key transcriptional factor in the micro-environment of the pathogenesis of cancer, especially solid tumors. In this study, we aimed to determine the roles of estrogen and testosterone in regulating the HIF pathway and how they contribute to the progression of chronic gut inflammation, and therefore colitis-associated cancer. Methods: To investigate the combined effects of hypoxia and sex hormones in regulating the HIF pathway, we performed cell culture studies on Caco-2cells treated with estrogen and testosterone. We also collected rectal biopsies from male and female patients diagnosed with ulcerative colitis and performed immunohistochemistry staining for HIF-1a protein. Samples with positive HIF-1a detection were then selected for immunofluorescence to determine the presence of HIF-inducible GLUT-1 protein. Results: Our data shows statistically significant difference in HIF-1a activation in Caco-2 cells that were treated with estrogen and testosterone in acute hypoxic condition. Immunohistochemistry performed on the samples from male and female patients also suggests opposite results on HIF-1a protein expression in prolonged hypoxia. Our data from immunofluorescence indicate GLUT-1 protein is induced in chronic inflammation a in a HIF-dependent manner. Conclusion: It is scientifically plausible that estrogen and testosterone have counter-regulatory roles in autoregulating the HIF signalling pathway, therefore affecting acute and chronic inflammation on a sex-specific manner, explaining the disparity of epidemiology and survival rates of ulcerative colitis and CRC in males and females. Further experimental and clinical investigations should be aimed to explore the therapeutic potential of hormone antagonists as an early intervention in ulcerative colitis patient to prevent the occurrence of colorectal cancer.