肾母细胞瘤基因1在卵巢疾病发病机制中的研究进展

doi:10.3877/cma.j.issn.2095-655X.2023.03.007

卵巢癌(OvCa)、原发性卵巢功能不全(POI)和多囊卵巢综合征(PCOS)是常见的女性卵巢疾病。卵巢疾病具有异质性特点，因此其诊断难，治疗效果及预后较差。肾母细胞瘤基因1(WT1)是一种具有抑癌和促癌双重作用的特殊基因，其编码蛋白通过激活或抑制基因转录调节卵巢细胞的增殖、分化和迁移等过程。WT1突变或表达异常会影响OvCa、POI、PCOS等疾病的发生发展，其与卵巢疾病的关联表明该基因可作为靶点，在诊断、治疗、预后评估方面具有潜力。笔者主要总结WT1在卵巢疾病发生和发展中的调控机制，讨论WT1在卵巢疾病诊断、治疗和预后方面的应用潜力。

关键词: 肾母细胞瘤基因1, 卵巢肿瘤, 原发性卵巢功能不全, 多囊卵巢综合征

Ovarian cancer (OvCa), premature ovarian insufficiency (POI), and polycystic ovary syndrome (PCOS) are all ovarian diseases affecting females. Due to the variability of ovarian diseases, they are challenging to identify and have poor prognosis and therapeutic effect. Wilms′ tumor gene 1 (WT1) is a unique gene that can both suppress and promote cancer. By activating or inhibiting gene transcription, the WT1 coding protein regulates ovarian cell proliferation, differentiation, migration, and other processes. WT1 mutations and abnormal expression impact the onset and progression of OvCa, POI, PCOS, and other diseases. Because WT1 is linked to ovarian diseases, it can be targeted for diagnosis, treatment, and prognosis assessment. This article summarizes WT1′s regulatory mechanism in the occurrence and development of ovarian diseases and discusses its potential application in the diagnosis, treatment, and prognosis of ovarian disease.

Key words: Wilms′ tumor gene 1, Ovarian neoplasms, Premature ovarian insufficiency, Polycystic ovary syndrome

图1 WT1在OvCa中的作用机制图注："+"表示促进，"－"表示抑制；WT1为肾母细胞瘤基因1；WTAP为WT1-结合蛋白；EMT为上皮细胞-间充质转化；HOXA10为同源盒基因A10；ERK为细胞外信号调节激酶；OvCa为卵巢癌；本图由Figdraw绘制

图2 WT1在POI中的作用机制图注："+"表示促进，"－"表示抑制；WT1为肾母细胞瘤基因1；RAP为雷帕霉素；PRMT5为蛋白质精氨酸甲基转移酶5；lncRNA为长链非编码RNA；Bcl-2为B淋巴细胞瘤-2；Bax为B淋巴细胞瘤-2基因相关X蛋白；CYP19A1为细胞色素P450芳香化酶；FSHR为卵泡刺激素受体；POI为原发性卵巢功能不全；本图由Figdraw绘制

图3 WT1在PCOS中的作用机制图注："+"表示促进，"－"表示抑制；WT1为肾母细胞瘤基因1；Bcl-2为B淋巴细胞瘤-2；Bax为B淋巴细胞瘤-2基因相关X蛋白；JAK/STAT3为Janus激酶/信号转导和转录激活因子3；CYP19A1为细胞色素P450芳香化酶；FSHR为卵泡刺激素受体；PCOS为多囊卵巢综合征；本图由Figdraw绘制

[1]	Toska E，Roberts SG.Mechanisms of transcriptional regulation by WT1 (Wilms′ tumour 1) [J]．Biochem J，2014，461(1): 15-32.DOI：10.1042/BJ20131587.
[2]	Wang ZY，Qiu QQ，Deuel TF.The Wilms′ tumor gene product WT1 activates or suppresses transcription through separate functional domains[J]．J Biol Chem，1993，268(13): 9172-9175.DOI：10.1016/S0021-9258(18)98329-8.
[3]	Makrigiannakis A，Amin K，Coukos G，et al.Regulated expression and potential roles of p53 and Wilms′ tumor suppressor gene (WT1) during follicular development in the human ovary [J]．J Clin Endocrinol Metab，2000，85(1): 449-459.DOI：10.1210/jcem.85.1.6246.
[4]	Shao T，Ke H，Liu R，et al.Autophagy regulates differentiation of ovarian granulosa cells through degradation of WT1[J]．Autophagy，2022，18(8)：1864-1878.DOI: 10.1080/15548627.2021.2005415.
[5]	Cen C，Chen M，Zhou J，et al.Inactivation of Wt1 causes pre-granulosa cell to steroidogenic cell transformation and defect of ovary development [J]．Biol Reprod，2020，103(1): 60-69.DOI：10.1093/biolre/ioaa042.
[6]	Han Y，Song C，Zhang T，et al.Wilms′ tumor 1 (WT1) promotes ovarian cancer progression by regulating E-cadherin and ERK1/2 signaling [J]．Cell Cycle，2020，19(20): 2662-2675.DOI：10.1080/15384101.2020.1817666.
[7]	Wang Y，Chen Q，Zhang F，et al.Whole exome sequencing identified a rare WT1 loss-of-function variant in a non-syndromic POI patient[J]．Mol Genet Genomic Med，2022，10(1)：e1820.DOI：10.1002/mgg3.1820.
[8]	Wang Q，Huang T，Shu X，et al.Wilms′ tumor 1 overexpression in granulosa cells is associated with polycystic ovaries in polycystic ovary syndrome patients [J]．Gynecol Obstet Invest，2018，83(3): 241-246.DOI：10.1159/000486784.
[9]	Torre LA，Trabert B，DeSantis CE，et al.Ovarian cancer statistics，2018[J]．CA Cancer J Clin，2018，68(4)：284-296.DOI: 10.3322/caac.21456.
[10]	Woad KJ，Watkins WJ，Prendergast D，et al.The genetic basis of premature ovarian failure [J]．Aust N Z J Obstet Gynaecol，2006，46(3): 242-244.DOI：10.1111/j.1479-828X.2006.00585.x.
[11]	Azziz R，Carmina E，Dewailly D，et al.The Androgen Excess and PCOS Society criteria for the polycystic ovary syndrome: the complete task force report [J]．Fertil Steril，2009，91(2): 456-488.DOI：10.1016/j.fertnstert.2008.06.035.
[12]	Balen AH，Morley LC，Misso M，et al.The management of anovulatory infertility in women with polycystic ovary syndrome：an analysis of the evidence to support the development of global WHO guidance[J]．Hum Reprod Update，2016，22(6): 687-708.DOI：10.1093/humupd/dmw025.
[13]	Nakatsuka SI, Oji Y, Horiuchi T, et al. Immunohistochemical detection of WT1 protein in a variety of cancer cells [J]．Mod Pathol，2006，19(6)：804-814.DOI：10.1038/modpathol.3800588.
[14]	Von Gise A, Zhou B, Honor LB, et al. WT1 regulates epicardial epithelial to mesenchymal transition through β-catenin and retinoic acid signaling pathways [J]．Dev Biol，2011，356(2): 421-431.DOI：10.1016/j.ydbio.2011.05.668.
[15]	Zhang Y，Yan WT，Yang ZY，et al.The role of WT1 in breast cancer：clinical implications，biological effects and molecular mechanism[J]．Int J Biol Sci，2020，16(8)：1474-1480.DOI：10.7150/ijbs.39958.
[16]	Shih IeM，Kurman RJ.Ovarian tumorigenesis: a proposed model based on morphological and molecular genetic analysis [J]．Am J Pathol，2004，164(5): 1511-1518.DOI：10.1016/S0002-9440(10)63708-X.
[17]	Zamarin D，Burger RA，Sill MW，et al.Randomized phase II trial of nivolumab versus nivolumab and ipilimumab for recurrent or persistent ovarian cancer: an NRG oncology study [J]．J Clin Oncol，2020，38(16): 1814.DOI：10.1200/JCO.19.02059.
[18]	Falzone L, Scandurra G, Lombardo V, et al. A multidisciplinary approach remains the best strategy to improve and strengthen the management of ovarian cancer [J]．Int J Oncol，2021，59(1)：1-14.DOI：10.3892/ijo.2021.5233.
[19]	Carter JH，Deddens JA，Mueller G，et al.Transcription factors WT1 and p53 combined: a prognostic biomarker in ovarian cancer[J]．Br J Cancer，2018，119(4)：462-470.DOI: 10.1038/s41416-018-0191-x.
[20]	Meng K，Cao J，Dong Y，et al.Application of bioinformatics analysis to identify important pathways and Hub genes in ovarian cancer affected by WT1[J]．Front Bioeng Biotechnol，2021(9)：741051.DOI: 10.3389/fbioe.2021.741051.
[21]	Barbolina MV，Adley BP，Shea LD，et al.Wilms tumor gene protein 1 is associated with ovarian cancer metastasis and modulates cell invasion [J]．Cancer，2008，112(7): 1632-1641.DOI：10.1002/cncr.23341.
[22]	Lee GA，Hwang KA，Choi KC.Roles of dietary phytoestrogens on the regulation of epithelial-mesenchymal transition in diverse cancer metastasis [J]．Toxins，2016，8(6): 162.DOI：10.3390/toxins8060162.
[23]	Zeisberg M，Neilson EG.Biomarkers for epithelial-mesenchymal transitions [J]．J Clin Invest，2009，119(6): 1429-1437.DOI：10.1172/JCI36183.
[24]	Kossaï M，Leary A，Scoazec JY，et al.Ovarian cancer: a heterogeneous disease [J]．Pathobiology，2018，85(1-2): 41-49.DOI：10.1159/000479006.
[25]	Ota T，Gilks CB，Longacre T，et al.HOXA7 in epithelial ovarian cancer: interrelationships between differentiation and clinical features[J]．Reprod Sci，2007，14(6)：605-614.DOI: 10.1177/1933719107307781.
[26]	Cheng W，Jiang Y，Liu C，et al.Identification of aberrant promoter hypomethylation of HOXA10 in ovarian cancer [J]．J Cancer Res Clin Oncol，2010，136(8): 1221-1227.DOI：10.1007/s00432-010-0772-4.
[27]	Andikyan V，Taylor HS.WT1 represses HOX gene expression in the regulation of gynaecologic tumour histologic type [J]．J Cell Mol Med，2009，13(11-12)：4522-4531.DOI：10.1111/j.1582-4934.2008.00574.x.
[28]	Little NA，Hastie ND，Davies RC.Identification of WTAP，a novel Wilms′ tumour 1-associating protein [J]．Hum Mol Genet，2000，9(15): 2231-2239.DOI：10.1093/oxfordjournals.hmg.a018914.
[29]	Van Nieuwenhuysen E，Busschaert P，Neven P，et al.The genetic landscape of 87 ovarian germ cell tumors [J]．Gynecol Oncol，2018，151(1): 61-68.DOI：10.1016/j.ygyno.2018.08.013.
[30]	Cooke IE，Shelling AN，Le Meuth VG，et al.Allele loss on chromosome arm 6q and fine mapping of the region at 6q27 in epithelial ovarian cancer [J]．Genes，Chromosomes and Cancer，1996，15(4): 223-233.DOI：10.1002/(SICI)1098-2264(199604)15:4<223::AID-GCC4>3.0.CO;2-3.
[31]	Yu HL，Ma XD，Tong JF，et al.WTAP is a prognostic marker of high-grade serous ovarian cancer and regulates the progression of ovarian cancer cells[J]．Onco Targets Ther，2019(12)：6191-6201.DOI: 10.2147/OTT.S205730.
[32]	Wang J，Xu J，Li K，et al.Identification of WTAP-related genes by weighted gene co-expression network analysis in ovarian cancer [J]．J Ovarian Res，2020，13(1): 1-11.DOI：10.1186/s13048-020-00710-y.
[33]	Nishida S，Morimoto S，Oji Y，et al.Cellular and humoral immune responses induced by an HLA class I-restricted peptide cancer vaccine targeting WT1 are associated with favorable clinical outcomes in advanced ovarian cancer[J]．J Immunother，2022，45(1)：56-66.DOI: 10.1097/CJI.0000000000000405.
[34]	Sallum LF, Andrade L, Ramalho S, et al. WT1，p53 and p16 expression in the diagnosis of low- and high-grade serous ovarian carcinomas and their relation to prognosis[J]．Oncotarget，2018，9(22)：15818-15827.DOI: 10.18632/oncotarget.24530.
[35]	Zhang L，Conejo-Garcia JR，Katsaros D，et al.Intratumoral T cells，recurrence，and survival in epithelial ovarian cancer [J]．N Engl J Med，2003，348(3): 203-213.DOI：10.1056/NEJMoa020177.
[36]	Kyi C，Doubrovina E，Zhou Q，et al.Phase I dose escalation safety and feasibility study of autologous WT1-sensitized T cells for the treatment of patients with recurrent ovarian cancer [J]．J Immunother Cancer，2021，9(8)．DOI：10.1136/jitc-2021-002752.
[37]	Chapuis AG，Egan DN，Bar M，et al.T cell receptor gene therapy targeting WT1 prevents acute myeloid leukemia relapse post-transplant [J]．Nat Med，2019，25(7): 1064-1072.DOI：10.1038/s41591-019-0472-9.
[38]	Klotz DM，Wimberger P．Overcoming PARP inhibitor resistance in ovarian cancer: what are the most promising strategies? [J]．Arch Gynecol Obstet，2020，302(5): 1087-1102.DOI：10.1007/s00404-020-05677-1.
[39]	Köbel M，Kalloger SE，Boyd N，et al.Ovarian carcinoma subtypes are different diseases: implications for biomarker studies [J]．PLoS Med，2008，5(12): e232.DOI：10.1371/journal.pmed.0050232.
[40]	Taube ET，Denkert C，Sehouli J，et al.Wilms tumor protein 1 (WT1)—not only a diagnostic but also a prognostic marker in high-grade serous ovarian carcinoma [J]．Gynecol Oncol，2016，140(3): 494-502.DOI：10.1016/j.ygyno.2015.12.018.
[41]	Chen Y，Zhang Y，Zhou J，et al.The application of WT1 and P53/Ki-67 to predict the recurrence of epithelial ovarian cancer [J].2021.DOI：10.21203/rs.3.rs-1048180/v1.
[42]	Mondal SK，Basak B，Bhattacharya S，et al.Role of WT1，B-cell lymphoma 2，Ki-67 (Mib1)，and Her2/Neu as diagnostic and prognostic immunomarkers in ovarian serous and endometroid carcinoma[J]．J Canc Res Ther，2021，17(1): 164.DOI：10.4103/jcrt.JCRT_311_19.
[43]	Regan SL，Knight PG，Yovich JL，et al.Granulosa cell apoptosis in the ovarian follicle—a changing view[J]．Front Endocrinol，2018(9)：61.DOI：10.3389/fendo.2018.00061.
[44]	Veitia RA.Primary ovarian insufficiency，meiosis and DNA repair[J]．Biomed J，2020，43(2): 115-123.DOI：10.1016/j.bj.2020.03.005.
[45]	Wang H，Li G，Zhang J，et al.Novel WT1 missense mutations in Han Chinese women with premature ovarian failure[J]．Sci Rep，2015，5(1): 1-7.DOI：10.1038/srep13983.
[46]	Kranc W，Brᶏzert M，Budna J，et al.Genes responsible for proliferation，differentiation，and junction adhesion are significantly up-regulated in human ovarian granulosa cells during a long-term primary in vitro culture [J]．Histochem Cell Biol，2019，151(2): 125-143.DOI：10.1007/s00418-018-1750-1.
[47]	Peters AE，Mihalas BP，Bromfield EG，et al.Autophagy in female fertility: a role in oxidative stress and aging [J]．Antioxid Redox Signal，2020，32(8): 550-568.DOI：10.1089/ars.2019.7986.
[48]	Gao F，Zhang J，Wang X，et al.Wt1 functions in ovarian follicle development by regulating granulosa cell differentiation[J]．Hum Mol Genet，2014，23(2)：333-341.DOI: 10.1093/hmg/ddt423.
[49]	Li D，Xu W，Wang X，et al.lncRNA DDGC participates in premature ovarian insufficiency through regulating RAD51 and WT1 [J]．Mol Ther Nucleic Acids，2021(26)：1092-1106.DOI：10.1016/j.omtn.2021.10.015.
[50]	Chen M，Dong F，Shen Z，et al.PRMT5 regulates ovarian follicle development by facilitating Wt1 translation[J]．Elife，2021(10)：e68930.DOI：10.7554/eLife.68930.
[51]	Kunze MM，Benz F，Brauβ TF，et al.sST2 translation is regulated by FGF2 via an hnRNP A1-mediated IRES-dependent mechanism[J]．BBA-Gene Regul Mech，2016，1859(7): 848-859.DOI：10.1016/j.bbagrm.2016.05.005.
[52]	Elfayomy AK，Almasry SM，El-Tarhouny SA，et al.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 [J]．Tissue Cell，2016，48(4): 370-382.DOI：10.1016/j.tice.2016.05.001Get.
[53]	Wang J，Bo L，Xu W，et al.Mitigation of premature ovarian failure by over-expression of lentivirus vector-mediated Wilms tumor-suppressor gene [J]．Trop J Pharm Res，2018，17(9): 1745-1751.DOI：10.4314/tjpr.v17i9.9.
[54]	Alam MH，Miyano T．Interaction between growing oocytes and granulosa cells in vitro [J]．Reprod Med Biol，2020，19(1): 13-23.DOI：10.1002/rmb2.12292.
[55]	Shao S，Wang H，Shao W，et al.miR-199a-5p stimulates ovarian granulosa cell apoptosis in polycystic ovary syndrome [J]．J Mol Endocrinol，2020，65(4): 187-201.DOI：10.1530/JME-20-0077.
[56]	Zhang L，Gao J，Cui S．miR-21 is involved in norepinephrine-mediated rat granulosa cell apoptosis by targeting SMAD7 [J]．J Mol Endocrinol，2017，58(4): 199-210.DOI：10.1530/JME-16-0248.
[57]	Musalı N，Özmen B，Şükür YE，et al.Follicular fluid norepinephrine and dopamine concentrations are higher in polycystic ovary syndrome[J]．Gynecol Endocrinol，2016，32(6): 460-463.DOI：10.3109/09513590.2015.1130808.
[58]	王群．多囊卵巢综合征患者WT1基因研究[D]．济南：山东大学，2018.
[59]	Gonzalez D，Thackeray H，Lewis P，et al.Loss of WT1 expression in the endometrium of infertile PCOS patients: a hyperandrogenic effect? [J]. J Clin Endocrinol Metab，2012，97(3): 957-966.DOI：10.1210/jc.2011-2366.

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Research progress of Wilms' tumor gene 1 in the pathogenesis of ovarian diseases

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Research progress of Wilms' tumor gene 1 in the pathogenesis of ovarian diseases