Bioinformatics-based study of the ceRNA network and the sub-network of the Ziyin Buyang Formula in premature ovarian failure due to ovarian tumour therapy

Ovarian tumour therapy has been known to cause ovary ageing. The competitive endogenous RNA (ceRNA) network plays an indispensable role in various diseases. We constructed the ceRNA network to examine the role of circular RNA (circRNA) in the ovaries of older women and elucidate the intervention mechanism of the Ziyin Buyang Formula. Ovarian tissue datasets were obtained from the Gene Expression Omnibus (GEO) database and screened for differentially expressed circRNAs (DECs), differentially expressed miRNA (DEMis) and differentially expressed mRNAs (DEMs). The circBase and Cancer-Specific CircRNA Databse 2.0 (CSCD) database were used to predict the miRNA response elements (MREs) of DECs. Interacting miRNAs were obtained by intersecting MREs and DEMis. Based on the interaction between circRNA-miRNA and miRNA-mRNA, the node circRNA, miRNA and mRNA were obtained. The ceRNA network was constructed using the Cytoscape software. The targets of the Ziyin Buyang Formula were obtained from the Traditional Chinese Medicine Systems Pharmacology database and related literature. The sub-networks of the interventions of the Ziyin Buyang Formula were constructed according to the target genes and the corresponding relationships in the ceRNA network. A total of seven circRNAs, six miRNAs and 224 mRNAs were distinguished as nodes from 226 DECs, 35 DEMis, 1697 DEMs, 2320 MREs, 19 intersecting miRNAs and 765 intersecting mRNAs. Moreover, 96 chemical components, 239 targets and four target genes were identified in the ceRNA network of the Ziyin Buyang Formula. This study constructed a ceRNA network for ovary ageing due to ovarian tumour therapy, and the sub-network of the interventions of Ziyin Buyang Formula was predicted, providing a novel perspective for the effective treatment of ovary ageing due to ovarian tumour therapy.

circRNA; ceRNA; The Ziyin Buyang Formula

[1] Torre LA, Trabert B, DeSantis CE, Miller KD, Samimi G, Runowicz CD, Gaudet MM, Jemal A, Siegel RL. Ovarian cancer statistics, 2018. CA Cancer J Clin. 2018; 68: 284-296.

[2] Jang H, Hong K, Choi Y. Melatonin and Fertoprotective Adjuvants: Prevention against Premature Ovarian Failure during Chemotherapy. Int J Mol Sci. 2017; 18: 1221.

[3] Ebrahimi M, Akbari Asbagh F. Pathogenesis and causes of premature ovarian failure: an update. Int J Fertil Steril. 2011 ;5: 54-65.

[4] Salmena L, Poliseno L, Tay Y, Kats L, Pandolfi P. A ceRNA hypothesis: the Rosetta stone of a hidden RNA language? Cell. 2011; 146: 353–358.

[5] Boya Z, Yuxi G, Yefan Y, Xiang Z, Zhihong Z. Regulation of long non-coding Rnas via ceRNA in breast cancer. Chinese Journal of Clinical and Experimental Pathology. 2021; 37: 309–312. (In Chinese)

[6] Yongkang S, Zhijian Z, Xiufen Z, Bo M, Caixi T. Research progress of LncRNA MALAT1 as competitive endogenous RNA in liver cancer. Chinese Journal of Clinical and Experimental Pathology. 2021; 37: 438–440. (In Chinese)

[7] Patop I L, Wust S, Kadener S. Past, present, and future of circRNAs. The EMBO Journal. 2019; 38: e100836.

[8] Lasda E, Parker R. Circular RNAs: diversity of form and function. RNA. 2014; 20: 1829–1842.

[9] Haque S, Ames RM, Moore K, Pilling LC, Peters LL, Bandinelli S, et al. CircRNAs expressed in human peripheral blood are associated with human aging phenotypes, cellular senescence and mouse lifespan. GeroScience. 2020; 42: 183–199.

[10] Knupp D, Miura P. CircRNA accumulation: a new hallmark of aging?Mechanisms of Ageing and Development. 2018; 173: 71–79.

[11] Cheng J, Huang J, Yuan S, Zhou S, Yan W, Shen W, et al. Circular RNA expression profiling of human granulosa cells during maternal aging reveals novel transcripts associated with assisted reproductive technology outcomes. PLoS One. 2017; 12: e177888.

[12] Bahmyari S, Jamali Z, Khatami S H, Vakili O, Roozitalab M, Savardashtaki A, et al. microRNAs in female infertility: an overview. Cell Biochemistry and Function. 2021; 39: 955–969.

[13] Zhang J, Xu Y, Liu H, Pan Z. MicroRNAs in ovarian follicular atresia and granulosa cell apoptosis. Reproductive Biology and Endocrinology. 2019; 17: 9.

[14] Guicheng X. Regulating Menstrual Cycle with Menstrual Cycle Rhythm Induction Method. Journal of Nanjing University of Chinese Medicine (Natural Science Edition). 2000; 11–12. (In Chinese)

[15] Yong T. TAN Yong’s Experience of Effective Prescriptions—Sequential Ziyin Buyang Prescription. Jiangsu Journal of Traditional Chinese Medicine. 2022; 54: 1–2. (In Chinese)

[16] Qianqian L, Guicheng X, Yong T. Fertility reduction stratagies in elderly women. China Journal of Traditional Chinese Medicine and Pharmacy. 2021; 36: 5926–5929. (In Chinese)

[17] Yuying S, Shuping C, Yong T. Effect of Nourishing Yin and Tonifying Yang Sequential therapy combined with western medicine on expression levels of Smad2/Smad3/Smad7 mRNA in rats with diminished ovarian reserve. Acta Medicinae Universitatis Scientiae et Technologiae Huazhong. 2018; 47: 300–304.

[18] Ruxin W, Yong T, Yiqing H. Analysis of experience of Tan Yong in treating diminished ovarian reserve. Clinical Journal of Traditional Chinese Medicine. 2021; 33: 1060–1064. (In Chinese)

[19] Haixia H, Yong T. A probe into Tan Yong’s experience of treating infertility due to premature ovarian dysfunction. Jiangsu Journal of Traditional Chinese Medicine. 2019; 51: 17–19. (In Chinese)

[20] Barrett T, Wilhite S E, Ledoux P, Evangelista C, Kim IF, Tomashevsky M, et al. NCBI GEO: archive for functional genomics data sets—update. Nucleic Acids Research. 2013; 41: D991–D995.

[21] Hongwei L, Yangang C, Lianqi T. Five didfferent processing methods induced variations in composition and content of liposoluble and volatile constituents of Psoralea corylifolia. Chinese Traditional Patent Medicine. 2021; 43: 2418–2427. (In Chinese)

[22] Zifei Q, Peile W, Han X, Han L, Hua B, Jing Y, et al. Effect of prenylated conpounds derived from psoralea corylifolia against human CYP1A1 and corresponding molecular docking validation. Journal of Nanjing University of Traditional Chinese Medicine. 2021; 37: 750–759.

[23] Yali W, Xiaoyan W, Hui Z, Chen YL, Zhang ML, Chen XF, et al. Study on alleviating effect of Glycyrrhizae Radix et Rhizoma on Psoraleae Fructus-induced liver injury based on network pharmacology and cell experiments. China Journal of Chinese Materia Medica. 2022; 47: 176–187. (In Chinese)

[24] Chen L. The expanding regulatory mechanisms and cellular functions of circular RNAs. Nature Reviews Molecular Cell Biology. 2020; 21: 475–490.

[25] Chen L. The biogenesis and emerging roles of circular RNAs. Nature Reviews Molecular Cell Biology. 2016; 17: 205–211.

[26] Maiese K. Disease onset and aging in the world of circular RNAs. Journal of Translational Science. 2016; 2: 327–329.

[27] Fanciulli A, Wenning GK. Multiple-system atrophy. New England Journal of Medicine. 2015; 372: 249–263.

[28] Du WW, Yang W, Chen Y, Wu ZK, Foster FS, Yang Z, et al. Foxo3 circular RNA promotes cardiac senescence by modulating multiple factors associated with stress and senescence responses. European Heart Journal. 2017; 38: 1402–1412.

[29] Rodier F, Campisi J. Four faces of cellular senescence. Journal of Cell Biology. 2011; 192: 547–556.

[30] Perk J, Iavarone A, Benezra R. Id family of helix-loop-helix proteins in cancer. Nature Reviews Cancer. 2005; 5: 603–614.

[31] Iglesias-Ara A, Zenarruzabeitia O, Fernandez-Rueda J, Sánchez-Tilló E, Field SJ, Celada A, et al. Accelerated DNA replication in E2F1-and E2F2-deficient macrophages leads to induction of the DNA damage response and p21CIP1-dependent senescence. Oncogene. 2010; 29: 5579–5590.

[32] Nowicki TS, Zhao H, Darzynkiewicz Z, Moscatello A, Shin E, Schantz S, et al. Downregulation of uPAR inhibits migration, invasion, proliferation, FAK/PI3K/Akt signaling and induces senescence in papillary thyroid carcinoma cells. Cell Cycle. 2011; 10: 100–107.

[33] Holdt LM, Stahringer A, Sass K, Pichler G, Kulak NA, Wilfert W, et al. Circular non-coding RNA ANRIL modulates ribosomal RNA maturation and atherosclerosis in humans. Nature Communications. 2016; 7: 12429.

[34] Du WW, Yang W, Liu E, Yang Z, Dhaliwal P, Yang BB. Foxo3 circular RNA retards cell cycle progression via forming ternary complexes with p21 and CDK2. Nucleic Acids Research. 2016; 44: 2846–2858.

[35] Sandhu C, Donovan J, Bhattacharya N, Stampfer M, Worland P, Slingerland J. Reduction of Cdc25a contributes to cyclin E1-Cdk2 inhibition at senescence in human mammary epithelial cells. Oncogene. 2000; 19: 5314–5323.

[36] Persson JL, Zhang Q, Wang XY, Ravnik SE, Muhlrad S, Wolgemuth DJ. Distinct roles for the mammalian A-type cyclins during oogenesis. Reproduction. 2005; 130: 411–422.

[37] Wang R, Wu Z, Liu R, Bai L, Lin Y, Ba Y, et al. Age-related miRNAs dysregulation and abnormal BACE1 expression following Pb exposure in adolescent mice. Environmental Toxicology. 2022; 37: 1902–1913.

[38] Yan R, Fan Q, Zhou J, Vassar R. Inhibiting BACE1 to reverse synaptic dysfunctions in Alzheimer’s disease. Neuroscience & Biobehavioral Reviews. 2016; 65: 326–340.

[39] Agca C, Klakotskaia D, Stopa EG, Schachtman TR, Agca Y. Ovariectomy influences cognition and markers of Alzheimer’s disease. Journal of Alzheimer’S Disease. 2020; 73: 529–541.

[40] Cong H, Xianglong M, Chenxu N, Xiaojuan S, Shuosheng Z. Research progress of Chinese Yam and its network pharmacological analysis of anti-aging. Modernization of Traditional Chinese Medicine and Materia Medica—World Science and Technology. 2020; 22: 2348–2365. (In Chinese)

[41] Piette PCM. Questionable recommendation for LPS for IVF/ICSI in ESHRE guideline 2019: ovarian stimulation for IVF/ICSI. Human Reproduction Open. 2021; 2021: hoab005.

[42] Ovarian ST, Bosch E, Broer S, Griesinger G, Grynberg M, Humaidan P, et al. ESHRE guideline: ovarian stimulation for IVF/IC†. Human Reproduction Open. 2020; 2020: hoaa009.

[43] Graziano S, Johnston R, Deng O, Zhang J, Gonzalo S. Vitamin D/vitamin D receptor axis regulates DNA repair during oncogene-induced senescence. Oncogene. 2016; 35: 5362–5376.

[44] Sever R, Glass CK. Signaling by nuclear receptors. Cold Spring Harbor Perspectives in Biology. 2013; 5: a016709–a016709.

[45] Ma X, Warnier M, Raynard C, Ferrand M, Kirsh O, Defossez P, et al. The nuclear receptor RXRA controls cellular senescence by regulating calcium signaling. Aging Cell. 2018; 17: e12831.

[46] Olmos G, Martínez-Miguel P, Alcalde-Estevez E, Medrano D, Sosa P, Rodríguez-Mañas L, et al. Hyperphosphatemia induces senescence in human endothelial cells by increasing endothelin-1 production. Aging Cell. 2017; 16: 1300–1312.

[47] Hansen KE, Johnson MG, Carter TC, Mayer J, Keuler NS, Blank RD. The− 839 (A/C) polymorphism in the ECE1 isoform b promoter associates with osteoporosis and fractures. Journal of the Endocrine Society. 2019; 3: 2041–2050.

[48] Zhu T, Yuan J, Wang Y, Gong C, Xie Y, Li H. MiR-661 contributed to cell proliferation of human ovarian cancer cells by repressing INPP5J expression. Biomedicine & Pharmacotherapy. 2015; 75: 123–128.

[49] Yoshioka S. Endothelin-converting enzyme-1 is expressed on human ovarian follicles and corpora lutea of menstrual cycle and early pregnancy. Journal of Clinical Endocrinology & Metabolism. 1998; 83: 3943–3950.

[50] Xie S, Batnasan E, Zhang Q, Li Y. MicroRNA expression is altered in granulosa cells of ovarian hyperresponders. Reproductive Sciences. 2016; 23: 1001–1010.