MicroRNA-144-3p protects against chemotherapy-induced apoptosis of ovarian granulosa cells and activation of primordial follicles by targeting MAP3K9.
MicroRNA-144-3p protects against chemotherapy-induced apoptosis of ovarian granulosa cells and activation of primordial follicles by targeting MAP3K9.
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DOI：
10.1186/s40001-023-01231-2
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发表时间：
2023-08-03
影响因子：
4.2
通讯作者：
Wang, Fang
中科院分区：
文献类型：
--
作者：
Liu, Meng;Xiao, Bang;Zhu, Yiqing;Chen, Meiting;Huang, Jinfeng;Guo, Haiyan;Wang, Fang
卵巢早衰（POF）的定义是闭经，卵巢萎缩，低雌激素，促性腺激素水平升高，40岁以下不孕。POF常由化疗药物诱发。然而，关于化疗介导的卵巢功能损害的潜在机制尚不清楚。在这项研究中，在顺铂诱导的POF小鼠模型中观察到颗粒细胞（GC）凋亡增加和原始卵泡异常激活。我们随后观察到POF小鼠原发性卵巢GC中miR-144- 3 p的显著下调和丝裂原活化蛋白激酶9（MAP 3 K9）的上调，如微阵列所示。此外，MAP 3 K9在用顺铂处理的人卵巢颗粒细胞（COV 434）中表达更高，并且被鉴定为miR-144- 3 p的新靶点。功能分析显示，miR-144- 3 p通过沉默MAP 3 K9表达，抑制下游p38丝裂原活化蛋白激酶（MAPK）通路的活性，从而减弱顺铂诱导的GC凋亡。同时，miR-144- 3 p通过靶向Map 3 k9抑制顺铂诱导的POF小鼠原始卵泡的过早耗竭，从而降低磷脂酰肌醇-4，5-二磷酸3-激酶（PI 3 K）/蛋白激酶B（AKT）通路的磷酸化和激活。综上所述，本研究揭示了miR-144- 3 p对卵巢功能的保护作用，揭示了POF发生发展的表观遗传调控机制，为卵巢储备功能的研究提供了新的生物标志物。在线版本包含补充材料，可通过10.1186/s40001-023-01231-2获得。
Premature ovarian failure (POF) is defined by amenorrhea, ovarian atrophy, hypoestrogenism, elevated gonadotropin level, and infertility under the age of 40. POF is frequently induced by chemotherapeutic agents. However, the underlying mechanisms regarding chemotherapy-mediated damage to ovarian function are unclear. In this study, enhanced apoptosis of granulosa cells (GCs) and aberrant activation of primordial follicles were observed in a POF mouse model induced by cisplatin. We subsequently observed significant downregulation of miR-144-3p and upregulation of mitogen-activated protein kinase kinase kinase 9 (MAP3K9) in primary ovarian GCs from POF mice, as revealed by microarrays. Furthermore, MAP3K9 expression was higher in human ovarian granulosa cells (COV434) treated with cisplatin and was identified as a novel target of miR-144-3p. Functional analysis revealed that miR-144-3p attenuated cisplatin induced apoptosis of GCs via silencing MAP3K9 expression, which suppressed the activity of the downstream p38 mitogen activated protein kinase (MAPK) pathway. Meanwhile, miR-144-3p prevented premature primordial follicle depletion in cisplatin-induced POF mice through targeting Map3k9, which led to a decline in the phosphorylation and activation of the phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)/protein kinase b (AKT) pathway. Taken together, this study revealed the protective effects of miR-144-3p on ovarian function and shed light on the epigenetic regulatory mechanism in the development of POF, which might provide new biomarkers for the ovarian reserve. The online version contains supplementary material available at 10.1186/s40001-023-01231-2.
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影响因子：
8.5
作者：
Liu T;Lin J;Chen C;Nie X;Dou F;Chen J;Wang Z;Gong Z
通讯作者：
Gong Z
影响因子：
9.1
作者：
Ding, Lijun;Yan, Guijun;Sun, Haixiang
通讯作者：
Sun, Haixiang
影响因子：
6.7
作者：
Imbar, Tal;Eisenberg, Iris
通讯作者：
Eisenberg, Iris
microRNA 在卵巢早衰中的作用
DOI：
10.1186/s12958-017-0256-3
发表时间：
2017-05-12
期刊：
Reproductive biology and endocrinology : RB&E
影响因子：
--
作者：
Guo Y;Sun J;Lai D
通讯作者：
Lai D
DOI：
10.1186/1477-7827-11-16
发表时间：
2013-03-01
期刊：
Reproductive biology and endocrinology : RB&E
影响因子：
--
作者：
Li X;Kang X;Deng Q;Cai J;Wang Z
通讯作者：
Wang Z