{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T04:14:08Z","timestamp":1791519248252,"version":"4.3.4"},"reference-count":57,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2022,6,2]],"date-time":"2022-06-02T00:00:00Z","timestamp":1654128000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Central Public-interest Scientific Institution Basal Research Fund, CAFS","award":["2020JBFM04"],"award-info":[{"award-number":["2020JBFM04"]}]},{"name":"Central Public-interest Scientific Institution Basal Research Fund, CAFS","award":["2021XT08"],"award-info":[{"award-number":["2021XT08"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>High temperature affects egg quality and increases follicular atresia in teleosts. The present study aimed to explore the regulated mechanism of ovary syndrome of Nile tilapia (Oreochromis niloticus) exposed to heat stress. To this end, we conducted histological and biochemical analyses and integrated miRNA-target gene analyses. The histochemical analyses confirmed that heat stress promoted the apoptosis of granulosa cell and therefore resulted in increased follicular atresia in the ovary. Heat stress led to the differential expression of multiple miRNAs (miR-27e, -27b-3p, -33, -34a -133a-5p, and -301b-5p). In a luciferase activity assay, miR-33 bound to the 3\u2032-untranslated region (UTR) of the TGF\u03b21I1 (transforming growth factor-\u03b21-induced transcript 1) gene and inhibited its expression. A TGF\u03b21I1 gene signal was detected in the granulosa cells of Nile tilapia by immunohistochemical analysis. Up-regulation of the miR-33 of tilapia at 6 d and 12 d exposed to heat (34.5 \u00b0C \u00b1 0.5 \u00b0C) had significant down-regulation of the TGF\u03b21I1 expression of the gene and protein in tilapia ovaries. An miRNA-target gene integrated analysis revealed that miR-33 and TGF\u03b21I1 function in an apoptosis-related signal pathway. The signal transduction of the vascular endothelial growth factor (VEGF) family members VEGFA and its receptor (KDR) in the heat-stressed group decreased significantly compared with the control group. Transcript-levels of the Bax and Caspase-3 as apoptotic promotors were activated and Bcl-2 and Caspase-8 as apoptotic inhibitors were suppressed in the heat-stressed tilapia. These results suggest that heat stress increases the expression of miR-33, which targets TGF\u03b21I1 and inhibits its expression, resulting in decreased levels of follicle-stimulating hormone and 17\u03b2-estradiol and increased apoptosis by suppressing VEGF signaling, eventually inducing follicular atresia. In conclusion, our results show that the miR-33\/TGF\u03b21I1 axis of Nile tilapia is involved in the follicular development of broodstock, and can suppress VEGF signaling to accelerate follicular atresia. Our findings demonstrate the suppressive role of miR-33 during oocyte development in Nile tilapia.<\/jats:p>","DOI":"10.3390\/genes13061009","type":"journal-article","created":{"date-parts":[[2022,6,2]],"date-time":"2022-06-02T11:05:02Z","timestamp":1654167902000},"page":"1009","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Upregulation of miR-33 Exacerbates Heat-Stress-Induced Apoptosis in Granulosa Cell and Follicular Atresia of Nile Tilapia (Oreochromis niloticus) by Targeting TGF\u03b21I1"],"prefix":"10.3390","volume":"13","author":[{"given":"Jun","family":"Qiang","sequence":"first","affiliation":[{"name":"Key Laboratory of Freshwater Fisheries and Germplasm Resources Utilization, Freshwater Fisheries Research Center, Chinese Academy of Fishery Sciences, Ministry of Agriculture, Wuxi 214081, China"},{"name":"Wuxi Fisheries College, Nanjing Agricultural University, Wuxi 214081, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2406-1775","authenticated-orcid":false,"given":"Fan-Yi","family":"Tao","sequence":"additional","affiliation":[{"name":"Key Laboratory of Freshwater Fisheries and Germplasm Resources Utilization, Freshwater Fisheries Research Center, Chinese Academy of Fishery Sciences, Ministry of Agriculture, Wuxi 214081, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qi-Si","family":"Lu","sequence":"additional","affiliation":[{"name":"Key Laboratory of Freshwater Fisheries and Germplasm Resources Utilization, Freshwater Fisheries Research Center, Chinese Academy of Fishery Sciences, Ministry of Agriculture, Wuxi 214081, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"He","sequence":"additional","affiliation":[{"name":"Key Laboratory of Freshwater Fisheries and Germplasm Resources Utilization, Freshwater Fisheries Research Center, Chinese Academy of Fishery Sciences, Ministry of Agriculture, Wuxi 214081, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pao","family":"Xu","sequence":"additional","affiliation":[{"name":"Key Laboratory of Freshwater Fisheries and Germplasm Resources Utilization, Freshwater Fisheries Research Center, Chinese Academy of Fishery Sciences, Ministry of Agriculture, Wuxi 214081, China"},{"name":"Wuxi Fisheries College, Nanjing Agricultural University, Wuxi 214081, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,6,2]]},"reference":[{"key":"ref_1","unstructured":"Bromage, N.R., and Roberts, R.J. (1995). Broodstock Management and Egg and Larval Quality, Blackwell Science."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1023\/A:1018400130692","article-title":"Egg quality in fish: What makes a good egg?","volume":"7","author":"Brooks","year":"1997","journal-title":"Rev. Fish Biol. Fish."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1111\/j.1749-7345.1994.tb00197.x","article-title":"Effects of environmental factors on egg development and hatching of pacific halibut Hippoglossus stenolepis","volume":"25","author":"Liu","year":"1994","journal-title":"J. World Aquac. Soc."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"671","DOI":"10.1111\/j.1749-7345.2008.00197.x","article-title":"Effects of maternal age on fecundity, spawning interval, and egg quality of Nile tilapia, Oreochromis niloticus (L.)","volume":"39","author":"Getinet","year":"2008","journal-title":"J. World Aquac. Soc."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"102889","DOI":"10.1016\/j.jtherbio.2021.102889","article-title":"Optimal combination of temperature and photoperiod for sex steroid hormone secretion and egg development of Oreochromis niloticus as determined by response surface methodology","volume":"97","author":"Qiang","year":"2021","journal-title":"J. Therm. Biol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1016\/S0044-8486(98)00168-9","article-title":"Abrupt changes in photoperiod affect age at maturity, timing of ovulation and plasma testosterone and oestradiol-17b profiles in Atlantic salmon, Salmo salar","volume":"162","author":"Taranger","year":"1998","journal-title":"Aquaculture"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1016\/j.aquaculture.2007.04.027","article-title":"Effect of photoperiod manipulation on rainbow trout (Oncorhynchus mykiss) egg quality: A genomic study","volume":"268","author":"Bonnet","year":"2007","journal-title":"Aquaculture"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"853","DOI":"10.1111\/j.1365-2761.2011.01303.x","article-title":"Evidence that severe acute stress and starvation induce rapid atresia of ovarian vitellogenic follicles in Atlantic bluefin tuna, Thunnus thynnus (L.) (Osteichthyes: Scombridae)","volume":"34","author":"Corriero","year":"2011","journal-title":"J. Fish Dis."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"736278","DOI":"10.1016\/j.aquaculture.2020.736278","article-title":"Some \u2018white\u2019 oocytes undergo atresia and fail to mature during the reproductive cycle in female genetically improved farmed tilapia (Oreochromis niloticus)","volume":"534","author":"Qiang","year":"2021","journal-title":"Aquaculture"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1002\/mrd.20361","article-title":"Large scale real-time PCR analysis of mRNA abundance in rainbow trout eggs in relationship with egg quality and post-ovulatory ageing","volume":"72","author":"Aegerter","year":"2005","journal-title":"Mol. Reprod. Dev."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1140","DOI":"10.1095\/biolreprod47.6.1140","article-title":"Stress reduces the quality of gametes produced by rainbow trout","volume":"47","author":"Campbell","year":"1992","journal-title":"Biol. Reprod."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Schreck, C.B., Contreras-Sanchez, W., and Fitzpatrick, M.S. (2001). Effects of Stress on Fish Reproduction, Gamete Quality, and Progeny. Reproductive Biotechnology in Finfish Aquaculture, Elsevier.","DOI":"10.1016\/S0044-8486(01)00580-4"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"429","DOI":"10.1111\/j.1095-8649.1997.tb01370.x","article-title":"The response to capture and confinement stress of plasma cortisol, plasma sex steroids and vitellogenic oocytes in the marine teleost, red gurnard","volume":"50","author":"Clearwater","year":"1997","journal-title":"J. Fish Biol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1016\/S0044-8486(99)00108-8","article-title":"Preliminary observations on the effects of holding temperature on reproductive performance of female white sturgeon, Acipenser transmontanus Richardson","volume":"176","author":"Molly","year":"1999","journal-title":"Aquaculture"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1016\/S0044-8486(96)01374-9","article-title":"Effect of holding temperature on ovulation, egg fertility, plasma levels of reproductive hormones and in vitro ovarian steroidogenesis in the rainbow trout Oncorhynchus mykiss","volume":"146","author":"Pankhurst","year":"1996","journal-title":"Aquaculture"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1887","DOI":"10.1210\/me.2014-1217","article-title":"TGF\u03b2 signaling promotes juvenile granulosa cell tumorigenesis by suppressing apoptosis","volume":"28","author":"Tripurani","year":"2014","journal-title":"Mol. Endocrinol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"8299","DOI":"10.1074\/jbc.M113.532952","article-title":"Transforming growth factor-\u03b2 signaling participates in the maintenance of the primordial follicle pool in the mouse ovary","volume":"289","author":"Wang","year":"2014","journal-title":"J. Biol. Chem."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"144","DOI":"10.1016\/j.dci.2018.07.018","article-title":"Identification and functional analysis of transforming growth factor-\u03b2 type I receptor (T \u03b2 R1) from Scylla paramamosain: The first evidence of T \u03b2 R1 Check for involved in development and innate immunity in crustaceans","volume":"88","author":"Zhou","year":"2018","journal-title":"Dev. Comp. Immunol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1792","DOI":"10.1016\/j.molimm.2007.09.027","article-title":"Grass carp transforming growth factor-\u03b2 1 (TGF-\u03b2 1): Molecular cloning, tissue distribution and immunobiological activity in teleost peripheral blood lymphocytes","volume":"45","author":"Yang","year":"2008","journal-title":"Mol. Immunol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1016\/j.fsi.2020.07.002","article-title":"Identification and functional analysis of transforming growth factor-\u03b2 type III receptor (T\u03b2R3) from Scylla paramamosain: The first evidence of T\u03b2R3 involved in development and innate immunity in invertebrates","volume":"105","author":"Li","year":"2020","journal-title":"Fish Shellfish Immunol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"649","DOI":"10.1163\/1937240X-00002458","article-title":"Appendage Regeneration After Autotomy is Mediated by Baboon in the Crayfish Procambarus Fallax F. Virginalis Martin, Dorn, Kawai, Heiden and Scholtz, 2010 (Decapoda: Astacoidea: Cambaridae)","volume":"36","author":"Shinji","year":"2016","journal-title":"J. Crustacean Biol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1931","DOI":"10.1210\/en.2002-0126","article-title":"Cloning of transforming growth factor-\u03b21 (TGF-\u03b21) and its type II receptor from zebrafish ovary and role of TGF-\u03b21 in oocyte maturation","volume":"144","author":"Kohli","year":"2003","journal-title":"Endocrinology"},{"key":"ref_23","first-page":"3","article-title":"Potential targets of transforming growth factor-beta1 during inhibition of oocyte maturation in zebrafish","volume":"53","author":"Kohli","year":"2005","journal-title":"Reprod. Biol. Endocrinol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1016\/j.mce.2009.03.011","article-title":"Regulation of membrane progestin receptors in the zebrafish ovary by gonadotropin, activin, TGF-\u03b2 and BMP-15","volume":"312","author":"Tan","year":"2009","journal-title":"Mol. Cell. Endocrinol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"738171","DOI":"10.1016\/j.aquaculture.2022.738171","article-title":"Effects of heat stress on follicular development and atresia in Nile tilapia (Oreochromis niloticus) during one reproductive cycle and its potential regulation by autophagy and apoptosis","volume":"555","author":"Qiang","year":"2022","journal-title":"Aquaculture"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"449","DOI":"10.1002\/jcp.21706","article-title":"Transforming growth factor-\u03b2 1 (TGF-\u03b21) induces angiogenesis through vascular endothelial growth factor (VEGF)-mediated apoptosis","volume":"219","author":"Ferrari","year":"2009","journal-title":"J. Cell. Physiol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"17220","DOI":"10.18632\/oncotarget.7948","article-title":"Apatinib inhibits VEGF signaling and promotes apoptosis in intrahepatic cholangiocarcinoma","volume":"7","author":"Peng","year":"2016","journal-title":"Oncotarget"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"534171","DOI":"10.3389\/fphar.2020.534171","article-title":"Quercetin induces apoptosis via downregulation of vascular endothelial growth factor\/Akt signaling pathway in acute myeloid leukemia cells","volume":"11","author":"Shi","year":"2020","journal-title":"Front. Pharmacol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"17260","DOI":"10.1073\/pnas.0605556103","article-title":"VEGF, a prosurvival factor, acts in concert with TGF-1 to induce endothelial cell apoptosis","volume":"103","author":"Ferrari","year":"2006","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"4497","DOI":"10.1016\/j.febslet.2014.10.021","article-title":"MiR-92a inhibits porcine ovarian granulosa cell apoptosis by targeting Smad7 gene","volume":"588","author":"Liu","year":"2014","journal-title":"FEBS Lett."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1038\/s42003-020-0864-x","article-title":"NORFA, long intergenic noncoding RNA, maintains sow fertility by inhibiting granulosa cell death","volume":"3","author":"Du","year":"2020","journal-title":"Commun. Biol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"94","DOI":"10.1016\/j.theriogenology.2021.12.014","article-title":"MiR-31 targets HSD17B14 and FSHR, and miR-20b targets HSD17B14 to affect apoptosis and steroid hormone metabolism of porcine ovarian granulosa cells","volume":"180","author":"Gao","year":"2022","journal-title":"Theriogenology"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"670","DOI":"10.3389\/fphys.2020.00670","article-title":"miR-34a regulates the activity of HIF-1a and P53 signaling pathways by promoting GLUT1 in genetically improved farmed tilapia (GIFT, Oreochromis niloticus) under hypoxia stress","volume":"11","author":"Qiang","year":"2020","journal-title":"Front. Physiol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"146023","DOI":"10.1016\/j.gene.2021.146023","article-title":"Transcriptional inhibition of steroidogenic factor 1 in vivo in Oreochromis niloticus increased weight and suppressed gonad development","volume":"809","author":"Cao","year":"2022","journal-title":"Gene"},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Reading, J.B., Andersen, K.L., Ryu, Y.W., Mushirobira, Y.J., Todo, T., and Hiramatsu, N. (2018). Oogenesis and egg quality in finfish: Yolk formation and other factors influencing female fertility. Fishes, 3.","DOI":"10.3390\/fishes3040045"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"193","DOI":"10.2108\/zsj.20.193","article-title":"Correlation of mitogen-activated protein kinase activities with cell survival and apoptosis in porcine granulosa cells","volume":"20","author":"Shiota","year":"2003","journal-title":"Zool. Sci."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1111\/rda.13551","article-title":"miR-17-5p effects porcine granulosa cell growth and oestradiol synthesis by targeting E2F1 gene","volume":"54","author":"Zhang","year":"2019","journal-title":"Reprod. Domest. Anim."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"2019","DOI":"10.1016\/S2095-3119(16)61582-4","article-title":"MicroRNA-34c regulates porcine granulosa cell function by targeting forkhead box O3a","volume":"16","author":"Xu","year":"2017","journal-title":"J. Integr. Agric."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1095\/biolreprod.115.130690","article-title":"miR-23a and miR-27a promote human granulosa cell apoptosis by targeting SMAD5","volume":"93","author":"Nie","year":"2015","journal-title":"Biol. Reprod."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1016\/j.repbio.2017.09.005","article-title":"MicroRNA-27a-3p affects estradiol and androgen imbalance by targeting Creb1 in the granulosa cells in mouse polycytic ovary syndrome model","volume":"17","author":"Wang","year":"2017","journal-title":"Biol. Reprod."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"365","DOI":"10.1007\/s11626-015-9977-9","article-title":"MicroRNA-764-3p regulates 17\u03b2-estradiol synthesis of mouse ovarian granulosa cells by targeting steroidogenic factor-1","volume":"52","author":"Wang","year":"2016","journal-title":"Vitr. Cell. Dev. Biol. Anim."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"2281","DOI":"10.1016\/j.ymthe.2021.03.014","article-title":"Targeting of miR-33 ameliorates phenotypes linked to age-related macular degeneration","volume":"29","author":"Gnanaguru","year":"2021","journal-title":"Mol. Ther."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"112443","DOI":"10.1016\/j.yexcr.2020.112443","article-title":"Endothelium-specific endothelin-1 expression promotes pro-inflammatory macrophage activation by regulating miR-33\/NR4A axis","volume":"399","author":"Zhao","year":"2021","journal-title":"Exp. Cell. Res."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"107198","DOI":"10.1016\/j.intimp.2020.107198","article-title":"Exosome-mediated miR-33 transfer induces M1 polarization in mouse macrophages and exerts antitumor effect in 4T1 breast cancer cell line","volume":"90","author":"Bandehpour","year":"2021","journal-title":"Int. Immunopharmacol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1292","DOI":"10.1095\/biolreprod.103.023531","article-title":"The modulatory role of transforming growth factor beta1 and androstenedione on follicle-stimulating hormone-induced gelatinase secretion and steroidogenesis in rat granulosa cells","volume":"70","author":"Ke","year":"2004","journal-title":"Biol. Reprod."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"969","DOI":"10.1530\/REP-08-0365","article-title":"Transforming growth factor-beta1 inhibits luteinization and promotes apoptosis in bovine granulosa cells","volume":"137","author":"Zheng","year":"2009","journal-title":"Reproduction"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"407","DOI":"10.1016\/j.theriogenology.2020.08.015","article-title":"miR-130a\/TGF-b1 axis is involved in sow fertility by controlling granulosa cell apoptosis","volume":"157","author":"Du","year":"2020","journal-title":"Theriogenology"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1038\/nature07203","article-title":"From endoplasmic-reticulum stress to the inflammatory response","volume":"454","author":"Zhang","year":"2008","journal-title":"Nature"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1608","DOI":"10.1002\/jcp.22491","article-title":"Potential role of follicle-stimulating hormone (FSH) and transforming growth factor (TGFbeta1) in the regulation of ovarian angiogenesis","volume":"226","author":"Kuo","year":"2011","journal-title":"J. Cell. Physiol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"S195","DOI":"10.1111\/j.1440-169X.2008.01019.x","article-title":"Regulation of oocyte maturation in fish","volume":"50","author":"Nagahama","year":"2008","journal-title":"Dev. Growth Differ."},{"key":"ref_51","unstructured":"Liu, N.N., Cheng, X.K., Yang, Y., Liu, J., Gu, H.R., and Wang, Z.J. (2021). Effects of low temperature on the ovarian development of Sinibrama taeniatus. J. Fish. China, Available online: https:\/\/kns.cnki.net\/kcms\/detail\/31.1283.S.20210415.1036.004.html."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"3034","DOI":"10.1093\/jas\/skz164","article-title":"Hormonal regulation of vascular endothelial growth factor A (VEGFA) gene expression in granulosa and theca cells of cattle","volume":"97","author":"Nichols","year":"2019","journal-title":"J. Anim. Sci."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1016\/j.mce.2010.04.018","article-title":"Direct survival role of vascular endothelial growth factor (VEGF) on rat ovarian follicular cells","volume":"325","author":"Irusta","year":"2010","journal-title":"Mol. Cell. Endocrinol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1186\/s13048-018-0384-1","article-title":"The molecular mechanism of ovarian granulosa cell tumors","volume":"11","author":"Li","year":"2018","journal-title":"J. Ovarian Res."},{"key":"ref_55","unstructured":"Qin, L. (2012). Overexpression of VEGF-A Isoform-VEGF164 in Mouse Ovarian Granulosa Cells by Lentiviral Vector-Mediated, Nanjing Agricultural University."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"733","DOI":"10.1016\/j.bbrc.2007.09.061","article-title":"Vascular endothelial growth factor (VEGF) suppresses ovarian granulosa cell apoptosis in vitro","volume":"363","author":"Kosaka","year":"2007","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"1101","DOI":"10.1016\/j.fertnstert.2004.03.036","article-title":"Direct injection of vascular endothelial growth factor into the ovary of mice promotes follicular development","volume":"82","author":"Quintana","year":"2004","journal-title":"Fertil. Steril."}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/13\/6\/1009\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T23:23:57Z","timestamp":1760138637000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/13\/6\/1009"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,6,2]]},"references-count":57,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2022,6]]}},"alternative-id":["genes13061009"],"URL":"https:\/\/doi.org\/10.3390\/genes13061009","relation":{},"ISSN":["2073-4425"],"issn-type":[{"value":"2073-4425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,6,2]]}}}