Miao Li1,2,3, Han Zhao1,2,3, Shi-Gang Zhao1,2,3, Dai-Min Wei1,2,3, Yue-Ran Zhao1,2,3, Tao Huang1,2,3, Tahir Muhammad1,2,3, Lei Yan1,2,3, Fei Gao4, Lei Li1,2,3,5, Gang Lu1,2,3,6, Wai-Yee Chan6, Peter C K Leung7, Andrea Dunaif8, Hong-Bin Liu1,2,3,6, Zi-Jiang Chen1,2,3. 1. Center for Reproductive Medicine, Shandong University, Jinan, China. 2. National Research Center for Assisted Reproductive Technology and Reproductive Genetics, Jinan China. 3. The Key Laboratory of Reproductive Endocrinology (Shandong University), Ministry of Education, Jinan, China. 4. State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China. 5. Department of Biological Sciences, University of Notre Dame, Notre Dame, Indiana. 6. CUHK-SDU Joint Laboratory on Reproductive Genetics, School of Biomedical Sciences, the Chinese University of Hong Kong, Hong Kong, China. 7. Department of Obstetrics and Gynaecology, Child and Family Research Institute, University of British Columbia, Vancouver, Canada. 8. Icahn School of Medicine at Sinai, New York.
Abstract
CONTEXT: The high mobility group AT hook 2 (HMGA2) gene was previously identified in a genome-wide association study as a candidate risk gene that might be related to polycystic ovary syndrome (PCOS). Whether HMGA2 contributes to promoting granulosa cell (GC) proliferation in PCOS remains unknown. OBJECTIVE: We sought to determine whether HMGA2 is involved in the ovarian dysfunction of PCOS and in the mechanism of increased GC proliferation. PATIENTS AND CELLS: mRNA expression was analyzed in ovarian GCs from 96 women with PCOS and 58 healthy controls. Immortalized human GCs (KGN and SVOG cells) were used for the mechanism study. MAIN OUTCOME MEASURES: mRNA expression in ovarian GCs was measured using quantitative RT-PCR, and KGN cells were cultured for proliferation assays after overexpression or knockdown of target genes. Protein expression analysis, luciferase assays, and RNA binding protein immunoprecipitation assays were used to confirm the mechanism study. RESULTS: HMGA2 and IGF2 mRNA binding protein 2 (IMP2) were highly expressed in the GCs of women with PCOS, and the HMGA2/IMP2 pathway promoted GC proliferation. Cyclin D2 and SERPINE1 mRNA binding protein 1 were regulated by IMP2 and were highly expressed in women with PCOS. CONCLUSIONS: The HMGA2/IMP2 pathway was activated in women with PCOS and promoted the proliferation of GCs. This might provide new insights into the dysfunction of GCs in PCOS.
CONTEXT: The high mobility group AT hook 2 (HMGA2) gene was previously identified in a genome-wide association study as a candidate risk gene that might be related to polycystic ovary syndrome (PCOS). Whether HMGA2 contributes to promoting granulosa cell (GC) proliferation in PCOS remains unknown. OBJECTIVE: We sought to determine whether HMGA2 is involved in the ovarian dysfunction of PCOS and in the mechanism of increased GC proliferation. PATIENTS AND CELLS: mRNA expression was analyzed in ovarian GCs from 96 women with PCOS and 58 healthy controls. Immortalized human GCs (KGN and SVOG cells) were used for the mechanism study. MAIN OUTCOME MEASURES: mRNA expression in ovarian GCs was measured using quantitative RT-PCR, and KGN cells were cultured for proliferation assays after overexpression or knockdown of target genes. Protein expression analysis, luciferase assays, and RNA binding protein immunoprecipitation assays were used to confirm the mechanism study. RESULTS:HMGA2 and IGF2 mRNA binding protein 2 (IMP2) were highly expressed in the GCs of women with PCOS, and the HMGA2/IMP2 pathway promoted GC proliferation. Cyclin D2 and SERPINE1 mRNA binding protein 1 were regulated by IMP2 and were highly expressed in women with PCOS. CONCLUSIONS: The HMGA2/IMP2 pathway was activated in women with PCOS and promoted the proliferation of GCs. This might provide new insights into the dysfunction of GCs in PCOS.
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