多囊卵巢综合征患者颗粒细胞叉头框蛋白O1 mRNA的表达与意义
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摘要
目的探讨转录因子叉头框蛋白O1(FOXO1)在多囊卵巢综合征(PCOS)患者卵巢颗粒细胞中的表达及意义。方法采用逆转录实时定量PCR(qRT-PCR)检测67例PCOS患者(PCOS组)与63例对照患者(对照组)卵巢颗粒细胞中FOXO1的表达,并分析其临床意义。结果PCOS组的体质量指数(BMI)、胰岛素抵抗指数(HOMA-IR)、黄体生成素(LH)、睾酮(T)、抗苗勒氏管激素(AMH)、卵巢基础卵泡数(AFC)明显高于对照组(P均<0. 05),但PCOS组的卵泡刺激素(FSH)低于对照组(P <0. 05)。与对照患者相比,FOXO1在PCOS患者卵巢颗粒细胞中的表达下降(P <0. 05)。采用二元Logistic回归分析发现,FOXO1、AFC、HOMA-IR是影响PCOS的危险因素(P <0. 05)。结论 FOXO1在PCOS患者卵巢颗粒细胞低表达,可能在PCOS的发生发展中发挥重要作用。
Objective To explore the expression and significance of Forkhead box protein O1( FOXO1) in ovarian granulosa cells of patients suffering from polycystic ovary syndrome( PCOS). Methods A total of 130 patients,including 67 PCOS patients and 63 controls,were enrolled. The expression of FOXO1 in ovarian granulosa cells was examined by realtime quantitative reverse transcription PCR( qRT-PCR),and the clinical significance was analyzed. Results PCOS patients had significantly higher body mass index( BMI),homeostasis model assessment-insulin resistance( HOMA-IR),luteotropic hormone( LH),testosterone( T),anti-Mullerian hormone( AMH),average follicle count( AFC) levels( all P < 0. 05),but lower FSH level( P < 0. 05) than controls. Compared with controls,the expression of FOXO1 was much lower in granulosa cells of PCOS patients( P < 0. 05). Binary Logistic regression analysis revealed that FOXO1,AFC and HOMA-IR were risk factors influencing the occurrence of PCOS( P < 0. 05). Conclusion The lower expression of FOXO1 in the granulosa cells of PCOS patients may play an important role in the occurrence and development of PCOS.
Objective To explore the expression and significance of Forkhead box protein O1( FOXO1) in ovarian granulosa cells of patients suffering from polycystic ovary syndrome( PCOS). Methods A total of 130 patients,including 67 PCOS patients and 63 controls,were enrolled. The expression of FOXO1 in ovarian granulosa cells was examined by realtime quantitative reverse transcription PCR( qRT-PCR),and the clinical significance was analyzed. Results PCOS patients had significantly higher body mass index( BMI),homeostasis model assessment-insulin resistance( HOMA-IR),luteotropic hormone( LH),testosterone( T),anti-Mullerian hormone( AMH),average follicle count( AFC) levels( all P < 0. 05),but lower FSH level( P < 0. 05) than controls. Compared with controls,the expression of FOXO1 was much lower in granulosa cells of PCOS patients( P < 0. 05). Binary Logistic regression analysis revealed that FOXO1,AFC and HOMA-IR were risk factors influencing the occurrence of PCOS( P < 0. 05). Conclusion The lower expression of FOXO1 in the granulosa cells of PCOS patients may play an important role in the occurrence and development of PCOS.
引文
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[15]贾月月,刘洪彬,李婧博,等.多囊卵巢综合征患者颗粒细胞microRNA-200b的表达及影响[J].山东大学学报(医学版),2017,55(1):63-68.JIA Yueyue,LIU Hongbin,LI Jingbo,et al. Expressionof microRNA-200b in granulosa cells of PCOS patients andits significance[J]. Journal of Shandong University(Health Sciences),2017,55(1):63-68.
[16]Sanchez AM,Candau RB,Bernardi H. Fox O transcrip-tion factors:their roles in the maintenance of skeletalmuscle homeostasis[J]. Cell Mol Life Sci,2014,71(9):1657-1671.
[17]Anderson MJ,Viars CS,Czekay S,et al. Cloning andcharacterization of three human forkhead genes that com-prise an FKHR-like gene subfamily[J]. Genomics,1998,47(2):187-199.
[18]Sumarac-Dumanovic M,Apostolovic M,Janjetovic K,etal. Downregulation of autophagy gene expression in endo-metria from women with polycystic ovary syndrome[J].Mol Cell Endocrinol,2017,440:116-124. doi:10.1016/j. mce. 2016. 11. 009.
[19]Lan ZJ,Krause MS,Redding SD,et al. Selective dele-tion of Pten in theca-interstitial cells leads to androgen ex-cess and ovarian dysfunction in mice[J]. Mol Cell Endo-crinol,2017,444:26-37. doi:10. 1016/j. mce. 2017.01. 043.
[20]Kajihara T,Uchino S,Suzuki M,et al. Increased ovarianfollicle atresia in obese Zucker rats is associated with en-hanced expression of the forkhead transcription factorFOXO1[J]. Med Mol Morphol,2009,42(4):216-221.
[21]Liu Z,Ren YA,Pangas SA,et al. FOXO1/3 and PTENdepletion in granulosa cells promotes ovarian granulosacell tumor developmen[J]. Mol Endocrinol,2015,29(7):1006-1024.
[22] Gebremedhn S,Salilew-Wondim D,Hoelker M,et al.MicroRNA-183-96-182 cluster regulates bovine granulosacell proliferation and cell cycle transition by coordinatelytargeting FOXO1[J]. Biol Reprod,2016,94(6):127.doi:10. 1095/biolreprod. 115. 137539.
[23]Shen M,Liu Z,Li B,et al. Involvement of Fox O1 in theeffects of follicle-stimulating hormone on inhibition of ap-optosis in mouse granulosa cells[J]. Cell Death Dis,2014,5:e1475-e1475. doi:10. 1038/cddis. 2014. 400.
[24]Chang RJ,Cook-Andersen H. Disordered follicle develop-ment[J]. Mol Cell Endocrinol,2013,373(1-2):51-60.
[25]Fang D,Huang Z,Guan H,et al. The Akt/Fox O1/p27pathway mediates the proliferative action of liraglutide inbeta cells[J]. Mol Med Rep,2012,5(1):233-238.
[26]Han DF,Zhang JX,Wei WJ,et al. Fenofibrate inducesG0/G1 phase arrest by modulating the PPARalpha/Fox O1/p27 kip pathway in human glioblastoma cells[J].Tumour Biol,2015,36(5):3823-3829.
[27]Alikhani M,Alikhani Z,Graves DT. FOXO1 functions asa master switch that regulates gene expression necessaryfor tumor necrosis factor-induced fibroblast apoptosis[J].J Biol Chem,2005,280(13):12096-12102.
[2]Webber LJ,Stubbs S,Stark J,et al. Formation and earlydevelopment of follicles in the polycystic ovary[J]. Lan-cet,2003,362(9389):1017-1021.
[3]Maciel GA,Baracat EC,Benda JA,et al. Stockpiling oftransitional and classic primary follicles in ovaries of womenwith polycystic ovary syndrome[J]. J Clin EndocrinolMetab,2004,89(11):5321-5327.
[4]Das M,Djahanbakhch O,Hacihanefioglu B,et al. Granu-losa cell survival and proliferation are altered in polycysticovary syndrome[J]. J Clin Endocrinol Metab,2008,93(3):881-887.
[5]Stubbs SA,Stark J,Dilworth SM,et al. Abnormal prean-tral folliculogenesis in polycystic ovaries is associated withincreased granulosa cell division[J]. J Clin EndocrinolMetab,2007,92(11):4418-4426.
[6]Webber LJ,Stubbs SA,Stark J,et al. Prolonged survivalin culture of preantral follicles from polycystic ovaries[J].J Clin Endocrinol Metab,2007,92(5):1975-1978.
[7]Song HM,Song JL,Li DF,et al. Inhibition of FOXO1 bysmall interfering RNA enhances proliferation and inhibitsapoptosis of papillary thyroid carcinoma cells via Akt/FOXO1/Bim pathway[J]. Onco Targets Ther,2015,8:3565-3573. doi:10. 2147/OTT. S95395.
[8]Prasad SB,Yadav SS,Das M,et al. Down regulation ofFOXO1 promotes cell proliferation in cervical cancer[J]. JCancer,2014,5(8):655-662.
[9]He W,Lin F,Xia D,et al. MiR-374a promotes the prolif-eration of human osteosarcoma by downregulating FOXO1expression[J]. Int J Clin Exp Med,2014,8(3):3482-3489.
[10] Shi F,La Polt PS. Relationship between Fox O1 proteinlevels and follicular development,atresia,and luteiniza-tion in the rat ovary[J]. J Endocrinol,2003,179(2):195-203.
[11]Richards JS,Sharma SC,Falender AE,et al. Expressionof FKHR,FKHRL1,and AFX genes in the rodent ovary:evidence for regulation by IGF-I,estrogen,and the gona-dotropins[J]. Mol Endocrinol,2002,16(3):580-599.
[12]Cunningham MA,Zhu Q,Unterman TG,et al. Follicle-stimulating hormone promotes nuclear exclusion of theforkhead transcription factor Fox O1a via phosphatidylinos-itol 3-kinase in porcine granulosa cells[J]. Endocrinolo-gy,2003,144(12):5585-5594.
[13]Gebremedhn S,Salilewwondim D,Hoelker M,et al. Mi-croRNA-183-96-182 cluster regulates bovine granulosacell proliferation and cell cycle transition by coordinatelytargeting FOXO1[J]. Biol Reprod,2016,94(6):127.doi:10. 1095/biolreprod. 115. 137539.
[14]夏雅仙.多囊卵巢综合征(PCOS)诊断—中华人民共和国卫生行业标准[S]. 2012浙江省计划生育与生殖医学学术年会论文集[C]. 2012:130-137.
[15]贾月月,刘洪彬,李婧博,等.多囊卵巢综合征患者颗粒细胞microRNA-200b的表达及影响[J].山东大学学报(医学版),2017,55(1):63-68.JIA Yueyue,LIU Hongbin,LI Jingbo,et al. Expressionof microRNA-200b in granulosa cells of PCOS patients andits significance[J]. Journal of Shandong University(Health Sciences),2017,55(1):63-68.
[16]Sanchez AM,Candau RB,Bernardi H. Fox O transcrip-tion factors:their roles in the maintenance of skeletalmuscle homeostasis[J]. Cell Mol Life Sci,2014,71(9):1657-1671.
[17]Anderson MJ,Viars CS,Czekay S,et al. Cloning andcharacterization of three human forkhead genes that com-prise an FKHR-like gene subfamily[J]. Genomics,1998,47(2):187-199.
[18]Sumarac-Dumanovic M,Apostolovic M,Janjetovic K,etal. Downregulation of autophagy gene expression in endo-metria from women with polycystic ovary syndrome[J].Mol Cell Endocrinol,2017,440:116-124. doi:10.1016/j. mce. 2016. 11. 009.
[19]Lan ZJ,Krause MS,Redding SD,et al. Selective dele-tion of Pten in theca-interstitial cells leads to androgen ex-cess and ovarian dysfunction in mice[J]. Mol Cell Endo-crinol,2017,444:26-37. doi:10. 1016/j. mce. 2017.01. 043.
[20]Kajihara T,Uchino S,Suzuki M,et al. Increased ovarianfollicle atresia in obese Zucker rats is associated with en-hanced expression of the forkhead transcription factorFOXO1[J]. Med Mol Morphol,2009,42(4):216-221.
[21]Liu Z,Ren YA,Pangas SA,et al. FOXO1/3 and PTENdepletion in granulosa cells promotes ovarian granulosacell tumor developmen[J]. Mol Endocrinol,2015,29(7):1006-1024.
[22] Gebremedhn S,Salilew-Wondim D,Hoelker M,et al.MicroRNA-183-96-182 cluster regulates bovine granulosacell proliferation and cell cycle transition by coordinatelytargeting FOXO1[J]. Biol Reprod,2016,94(6):127.doi:10. 1095/biolreprod. 115. 137539.
[23]Shen M,Liu Z,Li B,et al. Involvement of Fox O1 in theeffects of follicle-stimulating hormone on inhibition of ap-optosis in mouse granulosa cells[J]. Cell Death Dis,2014,5:e1475-e1475. doi:10. 1038/cddis. 2014. 400.
[24]Chang RJ,Cook-Andersen H. Disordered follicle develop-ment[J]. Mol Cell Endocrinol,2013,373(1-2):51-60.
[25]Fang D,Huang Z,Guan H,et al. The Akt/Fox O1/p27pathway mediates the proliferative action of liraglutide inbeta cells[J]. Mol Med Rep,2012,5(1):233-238.
[26]Han DF,Zhang JX,Wei WJ,et al. Fenofibrate inducesG0/G1 phase arrest by modulating the PPARalpha/Fox O1/p27 kip pathway in human glioblastoma cells[J].Tumour Biol,2015,36(5):3823-3829.
[27]Alikhani M,Alikhani Z,Graves DT. FOXO1 functions asa master switch that regulates gene expression necessaryfor tumor necrosis factor-induced fibroblast apoptosis[J].J Biol Chem,2005,280(13):12096-12102.