Abstract
Uterine leiomyomas (fibroids) are common benign tumors in women. The tryptophan metabolism through the kynurenine pathway plays important roles in tumorigenesis in general. Leiomyomas expressing mutated mediator complex subunit 12 (mut-MED12) were reported to contain significantly decreased tryptophan levels; the underlying mechanism and the role of the tryptophan metabolism-kynurenine pathway in leiomyoma tumorigenesis, however, remain unknown. We here assessed the expression and regulation of the key enzymes that metabolize tryptophan. Among these, the tissue mRNA levels of tryptophan 2,3-dioxygenase (TDO2), the rate limiting enzyme of tryptophan metabolism through the kynurenine pathway, was 36-fold higher in mut-MED12 compared to adjacent myometrium (P < 0.0001), and 14-fold higher compared to wild type (wt)-MED12 leiomyoma (P < 0.05). The mRNA levels of other tryptophan metabolizing enzymes, IDO1 and IDO2, were low and not significantly different, suggesting that TDO2 is the key enzyme responsible for reduced tryptophan levels in mut-MED12 leiomyoma. R5020 and medroxyprogesterone acetate (MPA), two progesterone agonists, regulated TDO2 gene expression in primary myometrial and leiomyoma cells expressing wt-MED12; however, this effect was absent or blunted in leiomyoma cells expressing G44D mut-MED12. These data suggest that MED12 mutation may alter progesterone-mediated TDO2 expression in leiomyoma, leading to lower levels of tryptophan in mut-MED12 leiomyoma. This highlights that fibroids can vary widely in their response to progesterone as a result of mutation status and provides some insight for understanding the effect of tryptophan-kynurenine pathway on leiomyoma tumorigenesis and identifying targeted interventions for fibroids based on their distinct molecular signatures.
Highlights
Uterine leiomyomas are benign neoplasms that arise from uterine smooth muscle and represent the most common benign tumor in reproductive-age women
TDO2 Gene Expression Is Upregulated in Leiomyoma Expressing mut‐MED12
We showed that TDO2 gene expression is upregulated in LM expressing mutated MED12, and that the regulatory effect of progestins (R5020 and medroxyprogesterone acetate (MPA)) on TDO2 expression in MM and wt-MED12 LM cells is lost or decreased in LM cells expressing G44D mut-MED12
Summary
Uterine leiomyomas (fibroids, LM) are benign neoplasms that arise from uterine smooth muscle and represent the most common benign tumor in reproductive-age women. While a majority of LM are asymptomatic, they commonly cause menorrhagia, dysmenorrhea, and infertility and approximately 30% of identified fibroids require intervention [1]. While some medical therapies have shown promise in symptomatic management, hysterectomy or myomectomy remains the most common approach to treatment. Advances in minimally invasive surgery have improved recovery and minimized hospital stays overall for these patients, but the socioeconomic burden remains significant, costing an estimated $34.4 billion for the 200,000 hysterectomies and 30,000 myomectomies performed each year to treat fibroids [2]. New approaches to medical management for fibroids are desperately needed. A variety of mutations have been identified that seem to give rise to unique growth patterns [3]. One distinct subtype carries a mutation in mediator complex subunit 12 (mutMED12) and comprises 70% of all LM.
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