ID2 mediates the transforming growth factor-β1-induced Warburg-like effect seen in the peritoneum of women with endometriosis

STUDY QUESTION: Is inhibitor of DNA binding protein 2 (ID2) a mediator of the transforming growth factor (TGF)-β1-induced Warburg-like effect seen in the peritoneum of women with endometriosis?

STUDY FINDING: The TGF-β1-induced changes in the metabolic phenotype of peritoneal mesothelial cells from women with endometriosis are mediated through the ID2 pathway.

WHAT IS KNOWN ALREADY: TGF-β1 induces the metabolic conversion of glucose to lactate via aerobic glycolysis (the 'Warburg effect') in the peritoneum of women with endometriosis, through increased expression of the transcription factor hypoxia inducible factor α (HIF-1α). ID proteins are transcriptional targets of TGF-β1.

STUDY DESIGN, SAMPLES/MATERIALS, AND METHODS: Expression of ID2 was investigated in luteal phase peritoneal biopsies from women with regular menstrual cycles, with and without endometriosis (n = 8-10 each group) by quantitative RT-PCR (qRT-PCR) and immunohistochemistry. ID2 mRNA expression in primary human peritoneal mesothelial cells (HPMC) and immortalized mesothelial cells (MeT-5A) was assessed by qRT-PCR (n = 6). The effects of TGF-β1 and ID2 siRNA on HIF-1α mRNA expression and lactate secretion was assessed using qRT-PCR and a colorimetric lactate assay.

MAIN RESULTS AND THE ROLE OF CHANCE: ID2 is localised to peritoneal mesothelial and stromal cells of women with and without endometriosis. ID2 mRNA expression is lower in peritoneum adjacent to the endometriosis lesions compared to distal sites (p < 0.01). Exposure of HPMC and MeT-5A cells to physiological concentrations of TGF-β1 decreases ID2 mRNA expression (P < 0.01, P < 0.001, respectively, versus control). ID2 knockdown increases HIF-1α mRNA expression (p < 0.01) and lactate secretion (p < 0.05 versus scrambled control) to the same degree as with exposure to TGF-β1.

LIMITATIONS, REASONS FOR CAUTION: Primary human cell cultures and a cell line were used in this study, and thus the results may not fully represent the situation in vivo. The results should also be replicated using a larger number of samples.

WIDER IMPLICATIONS OF THE FINDINGS: Novel therapeutics that target the TGFβ/ID pathway offer a potential role in the treatment of endometriosis.

LARGE SCALE DATA: N/A STUDY FUNDING AND COMPETING INTERESTS: This work was funded by a Wellbeing of Women research grant (R42533) awarded to AWH, JKB and WCD; and an MRC Centre Grant G1002033. VJY received grant support from Federation of Women Graduates (134225) and a PhD studentship from the College of Medicine and Veterinary Medicine at the University of Edinburgh. There are no competing interests to declare.