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ATF3 缺乏可损害 RIF 患者的增殖-分泌期转换和蜕膜化。

ATF3 deficiency impairs the proliferative-secretory phase transition and decidualization in RIF patients.

机构信息

Reproductive Medicine Center, The Affiliated Drum Tower Hospital of Nanjing University Medical School, 210008, Nanjing, People's Republic of China.

Nanjing University Medical School, 210008, Nanjing, People's Republic of China.

出版信息

Cell Death Dis. 2021 Apr 12;12(4):387. doi: 10.1038/s41419-021-03679-8.

DOI:10.1038/s41419-021-03679-8
PMID:33846304
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8041902/
Abstract

Decidualization is a complex process involving cellular proliferation and differentiation of the endometrial stroma and is required to establish and support pregnancy. Dysregulated decidualization has been reported to be a critical cause of recurrent implantation failure (RIF). In this study, we found that Activating transcription factor 3 (ATF3) expression was significantly downregulated in the endometrium of RIF patients. Knockdown of ATF3 in human endometrium stromal cells (hESCs) hampers decidualization, while overexpression could trigger the expression of decidual marker genes, and ameliorate the decidualization of hESCs from RIF patients. Mechanistically, ATF3 promotes decidualization by upregulating FOXO1 via suppressing miR-135b expression. In addition, the endometrium of RIF patients was hyperproliferative, while overexpression of ATF3 inhibited the proliferation of hESCs through CDKN1A. These data demonstrate the critical roles of endometrial ATF3 in regulating decidualization and proliferation, and dysregulation of ATF3 in the endometrium may be a novel cause of RIF and therefore represent a potential therapeutic target for RIF.

摘要

蜕膜化是一个涉及子宫内膜基质细胞增殖和分化的复杂过程，是建立和支持妊娠所必需的。异常的蜕膜化被报道是反复着床失败（RIF）的一个关键原因。在这项研究中，我们发现活化转录因子 3（ATF3）在 RIF 患者的子宫内膜中表达显著下调。在人子宫内膜基质细胞（hESC）中敲低 ATF3 会阻碍蜕膜化，而过表达则可以触发蜕膜标记基因的表达，并改善 RIF 患者来源的 hESC 的蜕膜化。从机制上讲，ATF3 通过抑制 miR-135b 的表达来上调 FOXO1 从而促进蜕膜化。此外，RIF 患者的子宫内膜呈过度增殖状态，而过表达 ATF3 通过 CDKN1A 抑制 hESC 的增殖。这些数据表明，子宫内膜 ATF3 在调节蜕膜化和增殖方面起着关键作用，而子宫内膜中 ATF3 的失调可能是 RIF 的一个新原因，因此代表了 RIF 的一个潜在治疗靶点。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d4cf/8041902/ec0467c40090/41419_2021_3679_Fig7_HTML.jpg
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