Further characterization of tryptophan metabolism and its dysregulation in fibroids.
Further characterization of tryptophan metabolism and its dysregulation in fibroids.
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DOI：
10.1016/j.xfss.2022.04.005
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发表时间：
2022-11
期刊：
影响因子：
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通讯作者：
Khorram, Omid
中科院分区：
文献类型：
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作者：
Chuang, Tsai-Der;Quintanilla, Derek;Boos, Drake;Khorram, Omid
确定色氨酸（Trp）催化酶在肌瘤和匹配的子宫肌层中的表达，并确定种族和MED 12突变对其表达的影响。实验室研究。学术研究实验室育龄妇女接受子宫切除术前没有激素药物。从不同种族/民族的子宫切除病例中获得肌瘤和匹配的子宫肌层。通过qRT-PCR测定来自不同人种/种族组的女性的肌瘤和匹配的子宫肌层中以及MED 12突变阳性和突变阴性肿瘤中Trp分解代谢途径、色氨酸转运蛋白、CYP 1B 1中的酶的表达。ELISA法测定血清素、犬尿氨酸（KYNA）和NAD水平。与子宫肌层相比，子宫肌瘤过度表达TPH 1、KAT 2、SLC 7A 8和SLC 7A 5 mRNA，并降低KYNU、WARS 1 mRNA的表达，而WARS 2、AFMID、KMO、KAT 1、KAT 3和KAT 4的表达无变化（n=81）。CYP 1B 1的mRNA表达，AhR激活的标志物在肌瘤中更高。与MED 12突变阴性肿瘤相比，携带MED 12突变的肿瘤表达更多CYP 1B 1，WARS 1，KAT 1，KAT 3和KAT 4 mRNA水平较低。人种/种族影响KYNU的表达，与白人相比，非洲裔美国人和西班牙裔患者的肿瘤表达较低水平的KYNU mRNA。我们还定量了作为Trp催化剂的终产物的血清素、KYNA和NAD的水平。5-羟色胺和KYNA的水平没有显著差异，而与配对的子宫肌层相比，肌瘤中的NAD水平较低。NAD水平的降低与人种/种族无关。除了TDO 2/IDO 1之外，在肌瘤中的Trp代谢途径和Trp转运蛋白中的其他酶的表达存在显著的失调。MED 12突变状态和种族/民族对该途径组分的表达具有选择性影响。另外的功能研究将是必要的，以建立色氨酸降解途径在纤维瘤发病机制中的生理意义及其作为新疗法靶点的潜力。
To determine the expression of enzymes in tryptophan (Trp) catabolism in fibroids and matched myometrium and determine the influence of race and MED12 mutation on their expression. Experimental laboratory study. Academic research laboratory Reproductive age women undergoing hysterectomy on no hormonal medications prior to surgery. Fibroids and matched myometrium were obtained from hysterectomy cases from different race/ethnic groups. The expression of enzymes in Trp catabolic pathway, tryptophan transporters, CYP1B1 in fibroids and matched myometrium of women from different race/ethnic groups and in tumors with MED12-mutation-positive and mutation-negative tumors was determined by qRT-PCR. The levels of serotonin, kynurenine acid (KYNA) and NAD were determined by ELISA. Fibroids overexpressed TPH1, KAT2, SLC7A8 and SLC7A5 mRNA and reduced expression of KYNU, WARS1 mRNA with no changes in the expression of WARS2, AFMID, KMO, KAT1, KAT3 and KAT4 as compared with matched myometrium (n=81). The mRNA expression of CYP1B1, a marker of AhR activation was higher in fibroids. Tumors bearing the MED12 mutation expressed more CYP1B1, and lower WARS1, KAT1, KAT3 and KAT4 mRNA levels as compared to MED12-mutation-negative tumors. Race/ethnicity affected the expression of KYNU with tumors from African Americans and Hispanic patients expressing lower levels of KYNU mRNA as compared with Caucasians. We also quantified the levels of serotonin, KYNA and NAD which are the end products of Trp catabolism. There were no significant differences in levels of serotonin and KYNA, while NAD levels were lower in fibroids as compared to paired myometrium. This reduction in NAD level was independent of race/ethnicity. In addition to TDO2/IDO1 there is marked dysregulation in the expression of other enzymes in Trp metabolic pathway and Trp transporters in fibroids. Both MED12 mutation status and race/ethnicity had selective effects on the expression of components of this pathway. Additional functional studies will be necessary to establish the physiological significance of tryptophan degradation pathway in fibroid pathogenesis and its potential as a target for novel therapies.