Hippo信号通路与早发性卵巢功能不全的相关性研究
Research on the Correlation between the Hippo Signaling Pathway and Premature Ovarian Insufficiency
DOI: 10.12677/md.2025.154062, PDF,   
作者: 王 吉：延安大学医学院，陕西 延安；岳红云*：延安大学附属医院妇产科，陕西 延安
关键词: 早发性卵巢功能不全；Hippo信号通路；治疗；Yes相关蛋白；Premature Ovarian Insufficiency； Hippo Signaling Pathway； Treatment； YAP
摘要: 早发性卵巢功能不全(POI)是育龄期妇女常见的生殖内分泌疾病之一，其发病机制不明、治疗效果差、近远期并发症严重，极大影响女性健康。预防及治疗早发性卵巢功能不全，研究其发生发展机制至关重要。Hippo信号通路通过调节细胞增殖/凋亡来调节器官大小，在POI发病及治疗中发挥重要作用。本文对近年来通过Hippo信号通路治疗POI的研究现状进行综述，以期为进一步研究POI提供新的方向和思考。
Abstract: Premature ovarian insufficiency (POI) is one of the common reproductive endocrine diseases in women of childbearing age. The pathogenesis is unknown, the therapeutic effect is poor, and the short-term and long-term complications are serious, which seriously affects the health of women. It is very important to study the mechanism of the prevention and treatment of premature ovarian insufficiency. Hippo signaling pathway regulates organ size by regulating cell proliferation/apoptosis, and plays an important role in the pathogenesis and treatment of POI. This article reviews the current research status of Hippo signaling pathway in the treatment of POI in recent years, in order to provide a new direction and thinking for further study of POI.
文章引用：王吉, 岳红云. Hippo信号通路与早发性卵巢功能不全的相关性研究[J]. 医学诊断, 2025, 15(4): 459-466. https://doi.org/10.12677/md.2025.154062

参考文献

[1] Coulam, C.B., Adamson, S.C. and Annegers, J.F. (1986) Incidence of Premature Ovarian Failure. Obstetrics & Gynecology, 67, 604-606.
[2] Li, M., Zhu, Y., Wei, J., Chen, L., Chen, S. and Lai, D. (2022) The Global Prevalence of Premature Ovarian Insufficiency: A Systematic Review and Meta-analysis. Climacteric, 26, 95-102. [Google Scholar] [CrossRef] [PubMed]
[3] Webber, L., Davies, M., et al. (2016) ESHRE Guideline: Management of Women with Premature Ovarian Insufficiency. Human Reproduction, 31, 926-937.
[4] 中华医学会妇产科学分会绝经学组. 早发性卵巢功能不全的临床诊疗专家共识(2023版) [J]. 中华妇产科杂志, 2023, 58(10): 721-728.
[5] Yang, Q., Mumusoglu, S., Qin, Y., Sun, Y. and Hsueh, A.J. (2021) A Kaleidoscopic View of Ovarian Genes Associated with Premature Ovarian Insufficiency and Senescence. The FASEB Journal, 35, e21753. [Google Scholar] [CrossRef] [PubMed]
[6] Vujovic, S. (2009) Aetiology of Premature Ovarian Failure. Menopause International, 15, 72-75. [Google Scholar] [CrossRef] [PubMed]
[7] Hsueh, A.J.W., Kawamura, K., Cheng, Y. and Fauser, B.C.J.M. (2015) Intraovarian Control of Early Folliculogenesis. Endocrine Reviews, 36, 1-24. [Google Scholar] [CrossRef] [PubMed]
[8] 胡立桥, 周兆才, 田伟. Hippo信号通路结构生物学研究进展[J]. 遗传, 2017, 39(7): 659-674.
[9] Clark, K.L., George, J.W., Przygrodzka, E., Plewes, M.R., Hua, G., Wang, C., et al. (2022) Hippo Signaling in the Ovary: Emerging Roles in Development, Fertility, and Disease. Endocrine Reviews, 43, 1074-1096. [Google Scholar] [CrossRef] [PubMed]
[10] Yu, F., Zhao, B. and Guan, K. (2015) Hippo Pathway in Organ Size Control, Tissue Homeostasis, and Cancer. Cell, 163, 811-828. [Google Scholar] [CrossRef] [PubMed]
[11] Zhao, B., Wei, X., Li, W., Udan, R.S., Yang, Q., Kim, J., et al. (2007) Inactivation of YAP Oncoprotein by the Hippo Pathway Is Involved in Cell Contact Inhibition and Tissue Growth Control. Genes & Development, 21, 2747-2761. [Google Scholar] [CrossRef] [PubMed]
[12] Lv, X., He, C., Huang, C., Wang, H., Hua, G., Wang, Z., et al. (2019) Timely Expression and Activation of YAP1 in Granulosa Cells Is Essential for Ovarian Follicle Development. The FASEB Journal, 33, 10049-10064. [Google Scholar] [CrossRef] [PubMed]
[13] Lyu, Z., Qin, N., Tyasi, T.L., Zhu, H., Liu, D., Yuan, S., et al. (2016) The Hippo/MST Pathway Member SAV1 Plays a Suppressive Role in Development of the Prehierarchical Follicles in Hen Ovary. PLOS ONE, 11, e0160896. [Google Scholar] [CrossRef] [PubMed]
[14] Li, J., Luo, W., Huang, T. and Gong, Y. (2019) Growth Differentiation Factor 9 Promotes Follicle-Stimulating Hormone-Induced Progesterone Production in Chicken Follicular Granulosa Cells. General and Comparative Endocrinology, 276, 69-76. [Google Scholar] [CrossRef] [PubMed]
[15] Sun, T., Pepling, M.E. and Diaz, F.J. (2015) Lats1 Deletion Causes Increased Germ Cell Apoptosis and Follicular Cysts in Mouse Ovaries. Biology of Reproduction, 93, Article No. 22. [Google Scholar] [CrossRef] [PubMed]
[16] St John, M.A.R., Tao, W., Fei, X., Fukumoto, R., Carcangiu, M.L., Brownstein, D.G., et al. (1999) Mice Deficient of Lats1 Develop Soft-Tissue Sarcomas, Ovarian Tumours and Pituitary Dysfunction. Nature Genetics, 21, 182-186. [Google Scholar] [CrossRef] [PubMed]
[17] Tsoi, M., Morin, M., Rico, C., Johnson, R.L., Paquet, M., Gévry, N., et al. (2019) Lats1 and Lats2 Are Required for Ovarian Granulosa Cell Fate Maintenance. The FASEB Journal, 33, 10819-10832. [Google Scholar] [CrossRef] [PubMed]
[18] Sun, X., Niu, X., Qin, N., Shan, X., Zhao, J., Ma, C., et al. (2021) Novel Insights into the Regulation of LATS2 Kinase in Prehierarchical Follicle Development via the Hippo Pathway in Hen Ovary. Poultry Science, 100, Article ID: 101454. [Google Scholar] [CrossRef] [PubMed]
[19] Yu, H., Yang, Z., Xu, M., Huang, J., Yue, Z. and Guo, B. (2022) Yap Is Essential for Uterine Decidualization through Rrm2/gsh/ros Pathway in Response to Bmp2. International Journal of Biological Sciences, 18, 2261-2276. [Google Scholar] [CrossRef] [PubMed]
[20] Lv, X., He, C., Huang, C., Hua, G., Chen, X., Timm, B.K., et al. (2020) Reprogramming of Ovarian Granulosa Cells by YAP1 Leads to Development of High-Grade Cancer with Mesenchymal Lineage and Serous Features. Science Bulletin, 65, 1281-1296. [Google Scholar] [CrossRef] [PubMed]
[21] Hu, L., Su, T., Luo, R., Zheng, Y., Huang, J., Zhong, Z., et al. (2018) Hippo Pathway Functions as a Downstream Effector of AKT Signaling to Regulate the Activation of Primordial Follicles in Mice. Journal of Cellular Physiology, 234, 1578-1587. [Google Scholar] [CrossRef] [PubMed]
[22] Ye, H., Li, X., Zheng, T., Hu, C., Pan, Z., Huang, J., et al. (2017) The Hippo Signaling Pathway Regulates Ovarian Function via the Proliferation of Ovarian Germline Stem Cells. Cellular Physiology and Biochemistry, 41, 1051-1062. [Google Scholar] [CrossRef] [PubMed]
[23] Dupont, J. and Scaramuzzi, R.J. (2016) Insulin Signalling and Glucose Transport in the Ovary and Ovarian Function during the Ovarian Cycle. Biochemical Journal, 473, 1483-1501. [Google Scholar] [CrossRef] [PubMed]
[24] Enzo, E., Santinon, G., Pocaterra, A., Aragona, M., Bresolin, S., Forcato, M., et al. (2015) Aerobic Glycolysis Tunes YAP/TAZ Transcriptional Activity. The EMBO Journal, 34, 1349-1370. [Google Scholar] [CrossRef] [PubMed]
[25] Leroy, J.L.M.R., Vanholder, T., Mateusen, B., Christophe, A., Opsomer, G., de Kruif, A., et al. (2005) Non-Esterified Fatty Acids in Follicular Fluid of Dairy Cows and Their Effect on Developmental Capacity of Bovine Oocytes in Vitro. Reproduction, 130, 485-495. [Google Scholar] [CrossRef] [PubMed]
[26] Sorrentino, G., Ruggeri, N., Specchia, V., Cordenonsi, M., Mano, M., Dupont, S., et al. (2014) Metabolic Control of YAP and TAZ by the Mevalonate Pathway. Nature Cell Biology, 16, 357-366. [Google Scholar] [CrossRef] [PubMed]
[27] Cox, A.G., Hwang, K.L., Brown, K.K., Evason, K.J., Beltz, S., Tsomides, A., et al. (2016) Yap Reprograms Glutamine Metabolism to Increase Nucleotide Biosynthesis and Enable Liver Growth. Nature Cell Biology, 18, 886-896. [Google Scholar] [CrossRef] [PubMed]
[28] Yang, C., Stampouloglou, E., Kingston, N.M., Zhang, L., Monti, S. and Varelas, X. (2018) Glutamine‐Utilizing Transaminases Are a Metabolic Vulnerability of TAZ/YAP‐Activated Cancer Cells. EMBO reports, 19, e43577. [Google Scholar] [CrossRef] [PubMed]
[29] Zhang, X., Zhao, H., Li, Y., Xia, D., Yang, L., Ma, Y., et al. (2018) The Role of YAP/TAZ Activity in Cancer Metabolic Reprogramming. Molecular Cancer, 17, Article No. 134. [Google Scholar] [CrossRef] [PubMed]
[30] Cheng, F., Wang, J., Wang, R., Pan, R., Cui, Z., Wang, L., et al. (2024) FGF2 Promotes the Proliferation of Injured Granulosa Cells in Premature Ovarian Failure via Hippo-Yap Signaling Pathway. Molecular and Cellular Endocrinology, 589, Article ID: 112248. [Google Scholar] [CrossRef] [PubMed]
[31] Luo, J. and Sun, Z. (2023) MicroRNAs in POI, DOR and Por. Archives of Gynecology and Obstetrics, 308, 1419-1430. [Google Scholar] [CrossRef] [PubMed]
[32] Maher, J.Y., Islam, M.S., Yin, O., Brennan, J., Gough, E., Driggers, P., et al. (2022) The Role of Hippo Pathway Signaling and A-Kinase Anchoring Protein 13 in Primordial Follicle Activation and Inhibition. F&S Science, 3, 118-129. [Google Scholar] [CrossRef] [PubMed]
[33] Ernst, E.H., Grøndahl, M.L., Grund, S., Hardy, K., Heuck, A., Sunde, L., et al. (2017) Dormancy and Activation of Human Oocytes from Primordial and Primary Follicles: Molecular Clues to Oocyte Regulation. Human Reproduction, 32, 1684-1700. [Google Scholar] [CrossRef] [PubMed]
[34] Kawamura, K., Cheng, Y., Suzuki, N., Deguchi, M., Sato, Y., Takae, S., et al. (2013) Hippo Signaling Disruption and AKT Stimulation of Ovarian Follicles for Infertility Treatment. Proceedings of the National Academy of Sciences of the United States of America, 110, 17474-17479. [Google Scholar] [CrossRef] [PubMed]
[35] Pankhurst, M.W. (2017) A Putative Role for Anti-Müllerian Hormone (AMH) in Optimising Ovarian Reserve Expenditure. Journal of Endocrinology, 233, R1-R13. [Google Scholar] [CrossRef] [PubMed]
[36] Liu, W., Zhang, J., Wang, L., Liang, S., Xu, B., Ying, X., et al. (2021) The Protective Effects of Rapamycin Pretreatment on Ovarian Damage during Ovarian Tissue Cryopreservation and Transplantation. Biochemical and Biophysical Research Communications, 534, 780-786. [Google Scholar] [CrossRef] [PubMed]
[37] Goldman, K.N., Chenette, D., Arju, R., Duncan, F.E., Keefe, D.L., Grifo, J.A., et al. (2017) mTORC1/2 Inhibition Preserves Ovarian Function and Fertility during Genotoxic Chemotherapy. Proceedings of the National Academy of Sciences of the United States of America, 114, 3186-3191. [Google Scholar] [CrossRef] [PubMed]
[38] Zhang, J.M., Lu, X.L. and Wang, H.X. (2020) Inhibition of mTORC1 Signaling Pathway Is a Valid Therapeutic Strategy in Transplantation of Cryopreserved Mouse Ovarian Tissue. CryoLetters, 41, 38-43.
[39] Castrillon, D.H., Miao, L., Kollipara, R., Horner, J.W. and DePinho, R.A. (2003) Suppression of Ovarian Follicle Activation in Mice by the Transcription Factor Foxo3a. Science, 301, 215-218. [Google Scholar] [CrossRef] [PubMed]
[40] Lee, H.N. and Chang, E.M. (2019) Primordial Follicle Activation as New Treatment for Primary Ovarian Insufficiency. Clinical and Experimental Reproductive Medicine, 46, 43-49. [Google Scholar] [CrossRef] [PubMed]
[41] Halder, G., Dupont, S. and Piccolo, S. (2012) Transduction of Mechanical and Cytoskeletal Cues by YAP and Taz. Nature Reviews Molecular Cell Biology, 13, 591-600. [Google Scholar] [CrossRef] [PubMed]
[42] Gumbiner, B.M. and Kim, N. (2014) The Hippo-Yap Signaling Pathway and Contact Inhibition of Growth. Journal of Cell Science, 127, 709-717. [Google Scholar] [CrossRef] [PubMed]
[43] Díaz-García, C., Herraiz, S., Pamplona, L., Subirá, J., Soriano, M.J., Simon, C., et al. (2022) Follicular Activation in Women Previously Diagnosed with Poor Ovarian Response: A Randomized, Controlled Trial. Fertility and Sterility, 117, 747-755. [Google Scholar] [CrossRef] [PubMed]
[44] Dupont, S., Morsut, L., Aragona, M., Enzo, E., Giulitti, S., Cordenonsi, M., et al. (2011) Role of YAP/TAZ in Mechanotransduction. Nature, 474, 179-183. [Google Scholar] [CrossRef] [PubMed]
[45] Shah, J.S., Sabouni, R., Cayton Vaught, K.C., Owen, C.M., Albertini, D.F. and Segars, J.H. (2018) Biomechanics and Mechanical Signaling in the Ovary: A Systematic Review. Journal of Assisted Reproduction and Genetics, 35, 1135-1148. [Google Scholar] [CrossRef] [PubMed]
[46] De Roo, C., Lierman, S., Tilleman, K. and De Sutter, P. (2020) In-Vitro Fragmentation of Ovarian Tissue Activates Primordial Follicles through the Hippo Pathway. Human Reproduction Open, 2020, hoaa048. [Google Scholar] [CrossRef] [PubMed]
[47] Calvo, F., Ege, N., Grande-Garcia, A., Hooper, S., Jenkins, R.P., Chaudhry, S.I., et al. (2013) Mechanotransduction and Yap-Dependent Matrix Remodelling Is Required for the Generation and Maintenance of Cancer-Associated Fibroblasts. Nature Cell Biology, 15, 637-646. [Google Scholar] [CrossRef] [PubMed]
[48] Huang, Q., Liu, B., Jiang, R., Liao, S., Wei, Z., Bi, Y., et al. (2019) G-CSF-Mobilized Peripheral Blood Mononuclear Cells Combined with Platelet-Rich Plasma Accelerate Restoration of Ovarian Function in Cyclophosphamide-Induced POI Rats. Biology of Reproduction, 101, 91-101. [Google Scholar] [CrossRef] [PubMed]
[49] Vural, B., Duruksu, G., Vural, F., Gorguc, M. and Karaoz, E. (2019) Effects of VEGF + Mesenchymal Stem Cells and Platelet-Rich Plasma on Inbred Rat Ovarian Functions in Cyclophosphamide-Induced Premature Ovarian Insufficiency Model. Stem Cell Reviews and Reports, 15, 558-573. [Google Scholar] [CrossRef] [PubMed]
[50] Song, D., Zhong, Y., Qian, C., Zou, Q., Ou, J., Shi, Y., et al. (2016) Human Umbilical Cord Mesenchymal Stem Cells Therapy in Cyclophosphamide-Induced Premature Ovarian Failure Rat Model. BioMed Research International, 2016, Article ID: 2517514. [Google Scholar] [CrossRef] [PubMed]
[51] Mohamed, S.A., Shalaby, S., Brakta, S., Elam, L., Elsharoud, A. and Al-Hendy, A. (2019) Umbilical Cord Blood Mesenchymal Stem Cells as an Infertility Treatment for Chemotherapy Induced Premature Ovarian Insufficiency. Biomedicines, 7, Article 7. [Google Scholar] [CrossRef] [PubMed]
[52] Ling, L., Feng, X., Wei, T., Wang, Y., Wang, Y., Wang, Z., et al. (2019) Human Amnion-Derived Mesenchymal Stem Cell (hAD-MSC) Transplantation Improves Ovarian Function in Rats with Premature Ovarian Insufficiency (POI) at Least Partly through a Paracrine Mechanism. Stem Cell Research & Therapy, 10, Article No. 46. [Google Scholar] [CrossRef] [PubMed]
[53] Elfayomy, A.K., Almasry, S.M., El-Tarhouny, S.A. and Eldomiaty, M.A. (2016) Human Umbilical Cord Blood-Mesenchymal Stem Cells Transplantation Renovates the Ovarian Surface Epithelium in a Rat Model of Premature Ovarian Failure: Possible Direct and Indirect Effects. Tissue and Cell, 48, 370-382. [Google Scholar] [CrossRef] [PubMed]
[54] Fu, X., He, Y., Xie, C. and Liu, W. (2008) Bone Marrow Mesenchymal Stem Cell Transplantation Improves Ovarian Function and Structure in Rats with Chemotherapy-Induced Ovarian Damage. Cytotherapy, 10, 353-363. [Google Scholar] [CrossRef] [PubMed]