Endocrine Abstracts (2019) 65 P131 | DOI: 10.1530/endoabs.65.P131

Inflammatory cytokines dysregulate oestrogen metabolism in colorectal cancer

Afnan Banibakhsh, Rowan Hardy & Paul Foster


University of Birmingham, Birmingham, UK


Colorectal cancer (CRC) is the third most common cancer and is one of the highest incidences and mortality tumours worldwide. Our group has previously shown that CRC favours oestradiol synthesis by increasing steroid sulfatase (STS) activity and altering 17β-hydroxysteroid dehydrogenases (HSD17Bs) expression. However, what regulates STS activity and HSD17Bs expression and activity in CRC remains unknown. In breast and prostate cancer inflammatory mediators, such as TNFα, increase STS activity. Therefore, we hypothesised that specific inflammatory cytokines may regulate STS activity and HSD17Bs expression in CRC. To examine this, we tested the effect of TNFα, IL-6, IL-4 and Interferon gamma (IFN-γ) on STS activity, HSD17Bs expression and activity (HSD17B1, HSD17B2, HSD17B4, HSD17B7, HSD17B12), and oestrogen receptor (ERα, ERβ, and GPER) expression in various colon adenoma (R9/C2/51) and CRC cell lines (HCT116, Colo205, LoVo). We also calculated correlation coefficients between these inflammatory cytokines and HSD17Bs and oestrogen receptors expression in the human colon adenocarcinoma (COAD) RNA-Seq dataset (n=440) from The Cancer Genome Atlas (TCGA). TNFα, but not IL-6, IL-4, or IFN-γ, significantly (P<0.001) increased STS activity in CRC cells. TNFα treatment (at 10, 20 and 40 ng/ml for 24 h) also significantly downregulated HSD17B2 expression, whilst increasing the expression of HSD17B7. TNFα had no effect on HSD17B7 or HSD17B12 expression. All other cytokines tested had no effect on HSD17Bs expression or activity. Interrogation of the TCGA COAD dataset also identified positive correlation between TNFα and HSD17Bs supporting our results in cell lines. These novel findings demonstrate that in CRC TNFα increases pathways that favour oestradiol synthesis and thus acts as a potential pro-proliferative mechanism. Coupled with our previous findings that TNFα can increase oestrogen uptake pathways, this data suggests TNFα is the key regulator of oestrogen metabolism in CRC.

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