Journal of assisted reproduction and genetics · 2025
Overexpressed miR-135b in the ovaries of PCOS promotes granulosa cell proliferation by inhibiting Hippo signaling pathway.
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Ren Shimin, Chen Liyang, Xiao Ni, Huang Xueying, Wang Xian, Li Yang, Zhang Bing, Wang Wenjuan, Huang Xin
Аннотация
BACKGROUND: Polycystic ovary syndrome (PCOS) is a multifactorial endocrine disorder, characterized by ovarian structural abnormalities that lead to ovulatory dysfunction. The Hippo signaling pathway is crucial in regulating ovarian enlargement and cortical thickening, which are hallmarks of PCOS, although the regulatory mechanisms remain unclear.
METHODS: We assessed the expression of miR-135b and its target gene LATS2 (large tumor suppressor 2) in granulosa cells from both PCOS and normal ovaries using quantitative PCR. Dual-luciferase assays confirmed their direct interaction. The expression and localization of YAP (yes-associated protein), a key effector of the Hippo pathway, were examined through immunofluorescence in granulosa cells (GCs) from both groups. Additionally, the impact of miR-135b overexpression or inhibition on Hippo pathway genes was investigated in the KGN granulosa cell line, with changes in cell proliferation and apoptosis analyzed by cell proliferation assay and flow cytometry.
RESULTS: MiR-135b was significantly upregulated (9.15-fold) in PCOS granulosa cells and targeted LATS2, a critical Hippo pathway regulator. Dual-luciferase assays confirmed the miR-135b binding site in the 3'-UTR of LATS2. Mechanistically, high miR-135b expression reduced LATS2 levels, impairing YAP phosphorylation, promoting nuclear translocation of unphosphorylated YAP, and driving excessive granulosa cell proliferation.
CONCLUSION: Our findings suggest that miR-135b overexpression in PCOS ovaries contributes to abnormal granulosa cell proliferation by inhibiting the Hippo pathway. This study enhances our understanding of ovarian abnormalities in PCOS and identifies miR-135b as a potential biomarker and therapeutic target for the disorder.
METHODS: We assessed the expression of miR-135b and its target gene LATS2 (large tumor suppressor 2) in granulosa cells from both PCOS and normal ovaries using quantitative PCR. Dual-luciferase assays confirmed their direct interaction. The expression and localization of YAP (yes-associated protein), a key effector of the Hippo pathway, were examined through immunofluorescence in granulosa cells (GCs) from both groups. Additionally, the impact of miR-135b overexpression or inhibition on Hippo pathway genes was investigated in the KGN granulosa cell line, with changes in cell proliferation and apoptosis analyzed by cell proliferation assay and flow cytometry.
RESULTS: MiR-135b was significantly upregulated (9.15-fold) in PCOS granulosa cells and targeted LATS2, a critical Hippo pathway regulator. Dual-luciferase assays confirmed the miR-135b binding site in the 3'-UTR of LATS2. Mechanistically, high miR-135b expression reduced LATS2 levels, impairing YAP phosphorylation, promoting nuclear translocation of unphosphorylated YAP, and driving excessive granulosa cell proliferation.
CONCLUSION: Our findings suggest that miR-135b overexpression in PCOS ovaries contributes to abnormal granulosa cell proliferation by inhibiting the Hippo pathway. This study enhances our understanding of ovarian abnormalities in PCOS and identifies miR-135b as a potential biomarker and therapeutic target for the disorder.