背景:与白人女性相比,黑人女性受到子宫肌瘤的影响不成比例,包括早期诊断,更高的频率,更严重的症状。这种种族差异背后的病因仍然难以捉摸。
目的:本研究的目的是评估黑人和白人女性正常子宫肌层(无纤维瘤子宫)和高危子宫肌层(含纤维瘤子宫)的分子差异。
方法:我们对从自我鉴定的黑人和白人女性(非西班牙裔或拉丁裔)获得的正常和高危子宫肌层组织进行了全基因组RNA-seq,以确定整体基因表达谱并进行富集途径分析(每组n=3)。我们最初评估了种族之间相同类型组织(正常或高危子宫肌层)内的差异。随后,我们分析了每个种族中正常子宫肌层和高危子宫肌层的转录组,并确定了它们之间的差异.我们通过实时PCR(样本量范围=5-12)验证了我们的发现,蛋白质印迹(样本量范围=5-6),和免疫组织化学技术(样本量范围=9-16)。
结果:转录组学分析揭示了正常和高危子宫肌层组织中黑人和白人女性的不同特征。有趣的是,与白人妇女相比,黑人妇女的正常子宫肌层中与细胞外基质和机械传感相关的基因和途径更丰富。转录因子富集分析检测到,与白人女性相比,黑人正常子宫肌层中血清反应转录因子位置基序的活性更高。此外,在相同的比较中,我们观察到心肌素相关转录因子-血清反应因子和血清反应因子的表达水平升高。此外,我们注意到增加的mRNA和蛋白质水平的vinculin,血清反应因子的靶基因,与白人女性相比,黑人女性的正常子宫肌层组织。重要的是,正常子宫肌层向高危子宫肌层转换的转录组特征在黑人和白人女性中不同.具体来说,我们观察到,细胞外基质相关通路参与了从正常子宫肌层向高危子宫肌层的转变,并且这些过程在黑人女性中加剧.我们发现生腱蛋白C水平升高,I型胶原α1链,纤连蛋白和,来自黑人妇女的正常子宫肌层组织中的磷酸化-p38MAPK(Thr180/Tyr182,活性)蛋白水平,而在白人女性的样本中没有观察到这种差异。
结论:这些发现表明,子宫肌瘤的种族差异可能归因于黑人妇女子宫肌层细胞外基质的产生增加,甚至在肿瘤出现之前。需要进一步的研究来了解观察到的种族差异的早期生命决定因素。
BACKGROUND: Black women experience a disproportionate impact of uterine fibroids compared to White women, including earlier diagnosis, higher frequency, and more severe symptoms. The etiology underlying this racial disparity remains elusive.
OBJECTIVE: The aim of this study was to evaluate the molecular differences in normal myometrium (fibroid-free uteri) and at-risk myometrium (fibroid-containing uteri) tissues in Black and White women.
METHODS: We conducted whole-genome RNA-seq on normal and at-risk myometrium tissues obtained from both self-identified Black and White women (not Hispanic or Latino) to determine global gene expression profiles and to conduct enriched pathway analyses (n=3 per group). We initially assessed the differences within the same type of tissue (normal or at-risk myometrium) between races. Subsequently, we analyzed the transcriptome of normal myometrium compared to at-risk myometrium in each race and determined the differences between them. We validated our findings through real-time PCR (sample size range=5-12), western blot (sample size range=5-6), and immunohistochemistry techniques (sample size range=9-16).
RESULTS: The transcriptomic analysis revealed distinct profiles between Black and White women in normal and at-risk myometrium tissues. Interestingly, genes and pathways related to extracellular matrix and mechanosensing were more enriched in normal myometrium from Black than White women. Transcription factor enrichment analysis detected greater activity of the serum response transcription factor positional motif in normal myometrium from Black compared to White women. Furthermore, we observed increased expression levels of myocardin-related transcription factor-serum response factor and the serum response factor in the same comparison. In addition, we noted increased expression of both mRNA and protein levels of vinculin, a target gene of the serum response factor, in normal myometrium tissues from Black women as compared to White women. Importantly, the transcriptomic profile of normal to at-risk myometrium conversion differs between Black and White women. Specifically, we observed that extracellular matrix-related pathways are involved in the transition from normal to at-risk myometrium and that these processes are exacerbated in Black women. We found increased levels of
Tenascin C, type I collagen alpha 1 chain, fibronectin, and phospho-p38 MAPK (Thr180/Tyr182, active) protein levels in at-risk over normal myometrium tissues from Black women, whereas such differences were not observed in samples from White women.
CONCLUSIONS: These findings indicate that the racial disparities in uterine fibroids may be attributed to heightened production of extracellular matrix in the myometrium in Black women, even before the tumors appear. Future research is needed to understand early life determinants of the observed racial differences.