Functional role of the long noncoding RNA X-inactive specific transcript in leiomyoma pathogenesis.
Functional role of the long noncoding RNA X-inactive specific transcript in leiomyoma pathogenesis.
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DOI：
10.1016/j.fertnstert.2020.07.024
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发表时间：
2021-01
影响因子：
6.7
通讯作者：
Khorram O
中科院分区：
文献类型：
--
作者：
Chuang TD;Rehan A;Khorram O
目的探讨长链非编码RNA（IncRNA）X失活特异性转录本（XIST）在子宫肌瘤中的表达及其功能。实验研究学术研究实验室女性子宫切除平滑肌瘤。XIST的过度表达和表达不足; SP1的阻断。XIST在平滑肌瘤中的表达及其对miR-29 c、miR-200 c及其靶点的影响与匹配的子宫肌层相比，平滑肌瘤表达的XIST显着更多，这与种族/民族和月经周期阶段无关。采用三维球体培养系统，观察17β-雌二醇、孕酮及其联合作用对子宫肌瘤平滑肌细胞（LSMC）XIST表达的影响。用SP1抑制剂光神霉素A和SP1 siRNA处理可下调XIST的表达。XIST的敲低导致细胞增殖的抑制、miR-29 c和miR-200 c的上调以及这些miRNA的靶基因即I型胶原（COL 1A 1）、III型胶原（COL 3A 1）和纤连蛋白（FN 1）的伴随抑制。相反，在子宫肌层平滑肌细胞（MSMC）中XIST的过表达抑制了miR-29 c和miR-200 c，并诱导了COL 1A 1、COL 3A 1和FN 1水平。使用RNA免疫沉淀分析，我们证实XIST具有超过miR-29 c和miR-200 c的海绵活性，与子宫肌层相比，这在平滑肌瘤中更明显。我们的数据表明，XIST在平滑肌瘤中的表达增加导致miR-29 c和miR-200 c的表达减少，从而上调这些microRNA靶向的基因，包括COL 1A 1、COL 3A 1和FN 1，这些基因在与肌瘤相关的细胞外基质积累中起关键作用。XIST通过调控miR-29 c和miR-200 c的表达在平滑肌瘤发病中发挥作用
To determine the expression and functional roles of a long non-coding RNA (IncRNA) X-inactive specific transcript (XIST) in leiomyoma. Experimental study Academic research laboratory Women undergoing hysterectomy for leiomyoma. Over and under expression of XIST; blockade of SP1. Expression of XIST in leiomyoma and its effects on miR-29c, miR-200c and their targets. Leiomyoma expressed significantly more XIST as compared with matched myometrium which was independent of race/ethnicity and menstrual cycle phase. Using three-dimensional spheroid culture system, XIST levels were induced in leiomyoma smooth muscle cells (LSMC) following treatment with 17β-Estradiol, progesterone and their combination. The expression of XIST was down-regulated by treatment with the SP1 inhibitor mithramycin A and SP1 siRNA. Knockdown of XIST resulted in inhibition of cell proliferation, up-regulation of miR-29c and miR-200c and a concomitant inhibition of target genes of these miRNAs namely, collagen type I (COL1A1), collagen type III (COL3A1) and fibronectin (FN1). In contrast, overexpression of XIST in myometrium smooth muscle cells (MSMC) repressed miR-29c and miR-200c, and induced COL1A1, COL3A1 and FN1 levels. Using RNA immunoprecipitation analysis we confirmed XIST has sponge activity over miR-29c and miR-200c which is more pronounced in leiomyoma as compared with myometrium. Our data demonstrate that increased expression of XIST in leiomyoma results in reduced expression of miR-29c and miR-200c with a consequent up-regulation of genes targeted by these microRNAs including COL1A1, COL3A1 and FN1 which play key roles in extracellular matrix accumulation associated with fibroids. XIST plays a role in leiomyoma pathogenesis through its regulation of expression of miR-29c and miR-200c
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