Research Article

Department of Gynecology, the First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, 15000, China

‡Authors contributed equally to this work

Search for more papers by this author

Yanan He‡

Department of Gynecology, the First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, 15000, China

‡Authors contributed equally to this work

Search for more papers by this author

Tian Liang

Department of Gynecology, the First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, 15000, China

Search for more papers by this author

Jing Wang

Department of Gynecology, the First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, 15000, China

Search for more papers by this author

Xinyan Jiang

Department of Gynecology, the First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, 15000, China

Search for more papers by this author

Guangmei Zhang

*Author for correspondence:

E-mail Address: guangmeizhang@126.com

Department of Gynecology, the First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, 15000, China

Search for more papers by this author

Published Online:31 Oct 2022https://doi.org/10.2217/epi-2022-0249

View article

Abstract

Aim: To identify epigenetic alterations of differentially expressed genes and screen out targeted therapeutic drugs in endometriosis. Methods: Based on the Gene Expression Omnibus database and a series of biological information analysis tools, supplemented by validation of clinical samples, aberrant DNA methylation-driven genes and their functions were explored, as well as possible targeted drugs. Results: This study screened out a range of DNA methylation-driven genes that were associated with powerful properties and corresponding pathways. Among them, BDNF and CCL2 were key genes in the development of endometriosis. Four chemical agents have been flagged as potential treatments for endometriosis. Conclusion: These candidate genes and small-molecule agents may be further explored as potential targets and drugs for endometriosis diagnosis and therapy, respectively.

Plain language summary

What is the significance of studying endometriosis? Endometriosis is a common gynecological benign disease affecting an estimated 5–10% of women in their reproductive years. Women with endometriosis suffer from chronic pelvic pain, dyspareunia and dysmenorrhea, and some patients face the possibility of infertility. What were the results of this study? The authors explored a number of key genes that may contribute to the etiology and pathogenesis of endometriosis, discussed the reasons for the changes in the expression levels of these hub genes and then screened for a number of effective small-molecule chemical drugs that may act on endometriosis. What do the results of this study mean? The authors carried out research from the three aspects of etiology, diagnosis and treatment of endometriosis. First, it demonstrated that endometriosis patients did have some differentially expressed genes compared with controls, and then in the analysis of these abnormally expressed genes, it was found that DNA methylation may play an essential role. This is a more meaningful hint, whether the occurrence of endometriosis can be suppressed by targeting methylation modification and then affecting the expression of key genes. In addition, the different severity of endometriosis will also have varying degrees of impact on patients' quality of life. These results are also a good indicator of the severity of endometriosis. Therefore, early detection and timely treatment are guidelines for the treatment of endometriosis. Finally, some of the chemical agents identified to target the cause of endometriosis are expected to become new treatments for endometriosis, supported by the results of follow-up studies, which will lead to more accurate treatments for patients with fewer side effects than existing treatments.

Keywords:

Papers of special note have been highlighted as: •• of considerable interest

References

1. Tapmeier TT, Rahmioglu N, Lin J et al. Neuropeptide S receptor 1 is a nonhormonal treatment target in endometriosis. Sci. Transl. Med. 13(608), eabd6469 (2021).
Medline CASGoogle Scholar
2. Burney RO, Giudice LC. Pathogenesis and pathophysiology of endometriosis. Fertil. Steril. 98(3), 511–519 (2012). •• This is a review on the etiology and pathophysiology of endometriosis and the article elaborates on the existing hypotheses and theories of endometriosis.
Medline CASGoogle Scholar
3. Taylor HS, Kotlyar AM, Flores VA. Endometriosis is a chronic systemic disease: clinical challenges and novel innovations. Lancet 397(10276), 839–852 (2021). •• In this review, they discuss the latest understanding of endometriosis as a systemic disease with multiple manifestations outside the parameters of classic gynecological disease.
Medline CASGoogle Scholar
4. Vallvé-Juanico J, Houshdaran S, Giudice LC. The endometrial immune environment of women with endometriosis. Hum. Reprod. Update 25(5), 564–591 (2019).
MedlineGoogle Scholar
5. Halme J, Hammond MG, Hulka JF, Raj SG, Talbert LM. Retrograde menstruation in healthy women and in patients with endometriosis. Obstet. Gynecol. 64(2), 151–154 (1984).
Medline CASGoogle Scholar
6. Wang Y, Nicholes K, Shih IM. The origin and pathogenesis of endometriosis. Annu. Rev. Pathol. 15, 71–95 (2020).
Medline CASGoogle Scholar
7. Giudice LC. Clinical practice. Endometriosis. N. Engl. J. Med. 362(25), 2389–2398 (2010).
Medline CASGoogle Scholar
8. Tomassetti C, D'Hooghe T. Endometriosis and infertility: insights into the causal link and management strategies. Best Pract. Res. Clin. Obstet. Gynaecol. 51, 25–33 (2018).
MedlineGoogle Scholar
9. Kitawaki J, Ishihara H, Koshiba H et al. Usefulness and limits of CA-125 in diagnosis of endometriosis without associated ovarian endometriomas. Hum. Reprod. 20(7), 1999–2003 (2005).
Medline CASGoogle Scholar
10. Krishnamoorthy K, Decherney AH. Genetics of endometriosis. Clin. Obstet. Gynecol. 60(3), 531–538 (2017).
MedlineGoogle Scholar
11. Saare M, Rekker K, Laisk-Podar T et al. Challenges in endometriosis miRNA studies – from tissue heterogeneity to disease specific miRNAs. Biochim. Biophys. Acta Mol. Basis Dis. 1863(9), 2282–2292 (2017). •• This review focuses on the results of published miRNA studies in endometriosis to reveal the potential impact of tissue heterogeneity on the discovery of disease-specific miRNA alterations in endometriosis. Additionally, functional studies exploring the role of miRNAs involved in endometriosis are discussed.
Medline CASGoogle Scholar
12. Jones A, Lechner M, Fourkala EO, Kristeleit R, Widschwendter M. Emerging promise of epigenetics and DNA methylation for the diagnosis and management of women's cancers. Epigenomics 2(1), 9–38 (2010). •• This article provides an overview of technological development, current markers of risk prediction, early detection, diagnosis, prognosis and response to treatment and highlights the progression of epigenetic therapies.
CASGoogle Scholar
13. Demetriou CA, van Veldhoven K, Relton C, Stringhini S, Kyriacou K, Vineis P. Biological embedding of early-life exposures and disease risk in humans: a role for DNA methylation. Eur. J. Clin. Invest. 45(3), 303–332 (2015).
Medline CASGoogle Scholar
14. Costello JF, Plass C. Methylation matters. J. Med. Genet. 38(5), 285–303 (2001).
Medline CASGoogle Scholar
15. Zhang H, Wu J, Li Y, Jin G, Tian Y, Kang S. Identification of key differentially methylated/expressed genes and pathways for ovarian endometriosis by bioinformatics analysis. Reprod. Sci. 29(5), 1630–1643 (2022).
Medline CASGoogle Scholar
16. Lu Z, Gao Y. Screening differentially expressed genes between endometriosis and ovarian cancer to find new biomarkers for endometriosis. Ann. Med. 53(1), 1377–1389 (2021).
Medline CASGoogle Scholar
17. Nasu K, Kawano Y, Tsukamoto Y et al. Aberrant DNA methylation status of endometriosis: epigenetics as the pathogenesis, biomarker and therapeutic target. J. Obstet. Gynaecol. Res. 37(7), 683–695 (2011).
Medline CASGoogle Scholar
18. Clough E, Barrett T. The Gene Expression Omnibus database. Methods Mol. Biol. 1418, 93–110 (2016). •• The Gene Expression Omnibus database is an international public repository that archives and freely distributes high-throughput gene expression and other functional genomics datasets. This article includes detailed descriptions of methods to query and download Gene Expression Omnibus data and use the analysis and visualization tools.
MedlineGoogle Scholar
19. Li MX, Jin LT, Wang TJ et al. Identification of potential core genes in triple negative breast cancer using bioinformatics analysis. OncoTargets Ther. 11, 4105–4112 (2018).
MedlineGoogle Scholar
20. Zhu W, Shen Y, Liu J et al. Epigenetic alternations of microRNAs and DNA methylation contribute to gestational diabetes mellitus. J. Cell. Mol. Med. 24(23), 13899–13912 (2020).
Medline CASGoogle Scholar
21. Liu J, Li H, Sun L, Wang Z, Xing C, Yuan Y. Aberrantly methylated-differentially expressed genes and pathways in colorectal cancer. Cancer Cell Int. 17, 75 (2017).
MedlineGoogle Scholar
22. Liu J, Wan Y, Li S et al. Identification of aberrantly methylated differentially expressed genes and associated pathways in endometrial cancer using integrated bioinformatic analysis. Cancer Med. 9(10), 3522–3536 (2020).
Medline CASGoogle Scholar
23. Szklarczyk D, Santos A, von Mering C, Jensen LJ, Bork P, Kuhn M. STITCH 5: augmenting protein–chemical interaction networks with tissue and affinity data. Nucleic Acids Res. 44(D1), D380–D384 (2016). •• STITCH database is usually used to explore the relationship between hub genes and drugs, and each compound–protein interaction relation in the STITCH database corresponds to a score indicating its interaction probability or binding affinity and provides the compounds that are similar to the target drug and their similarity scores.
Medline CASGoogle Scholar
24. Song Z, Luo G, Han C, Jia G, Zhang B. Potential targets and action mechanism of gastrodin in the treatment of attention-deficit/hyperactivity disorder: bioinformatics and network pharmacology analysis. Evid. Based Complement. Alternat. Med. 2022, 3607053 (2022).
MedlineGoogle Scholar
25. Vassilopoulou L, Matalliotakis M, Zervou MI et al. Defining the genetic profile of endometriosis. Exp. Ther. Med. 17(5), 3267–3281 (2019).
Medline CASGoogle Scholar
26. Zubrzycka A, Zubrzycki M, Perdas E, Zubrzycka M. Genetic, epigenetic, and steroidogenic modulation mechanisms in endometriosis. J. Clin. Med. 9(5), 1309 (2020).
CASGoogle Scholar
27. Chou JL, Su HY, Chen LY et al. Promoter hypermethylation of FBXO32, a novel TGF-beta/SMAD4 target gene and tumor suppressor, is associated with poor prognosis in human ovarian cancer. Lab. Invest. 90(3), 414–425 (2010).
Medline CASGoogle Scholar
28. Guo W, Zhang M, Shen S et al. Aberrant methylation and decreased expression of the TGF-β/Smad target gene FBXO32 in esophageal squamous cell carcinoma. Cancer 120(16), 2412–2423 (2014).
Medline CASGoogle Scholar
29. Li Y, Gao S, Xue W, Ma Y, Meng Y, Zhang D. miR-19a-3p functions as an oncogene by regulating FBXO32 expression in multiple myeloma. Balkan Med. J. 38(1), 43–49 (2021).
Medline CASGoogle Scholar
30. Zhang L, Li D, Du F et al. A panel of differentially methylated regions enable prognosis prediction for colorectal cancer. Genomics 113(5), 3285–3293 (2021).
Medline CASGoogle Scholar
31. Manzardo AM, Gunewardena S, Butler MG. Over-expression of the miRNA cluster at chromosome 14q32 in the alcoholic brain correlates with suppression of predicted target mRNA required for oligodendrocyte proliferation. Gene 526(2), 356–363 (2013).
Medline CASGoogle Scholar
32. Chang ZW, Dong L, Qin YR, Song M, Guo HY, Zhu QL. Correlations between gastric cancer family history and ROBO2 and RASSF2A gene methylations. J. Cancer Res. Ther. 12(2), 597–600 (2016).
Medline CASGoogle Scholar
33. Kos A, Klein-Gunnewiek T, Meinhardt J et al. MicroRNA-338 attenuates cortical neuronal outgrowth by modulating the expression of axon guidance genes. Mol. Neurobiol. 54(5), 3439–3452 (2017).
Medline CASGoogle Scholar
34. Luo Y, Liu F, Ma J, Fu Y, Gui R. A novel epigenetic regulation of circFoxp1 on Foxp1 in colon cancer cells. Cell. Death Dis. 11(9), 782 (2020).
Medline CASGoogle Scholar
35. Koks CA, Groothuis PG, Dunselman GA, de Goeij AF, Evers JL. Adhesion of menstrual endometrium to extracellular matrix: the possible role of integrin alpha(6)beta(1) and laminin interaction. Mol. Hum. Reprod. 6(2), 170–177 (2000).
Medline CASGoogle Scholar
36. Selam B, Kayisli UA, Garcia-Velasco JA, Arici A. Extracellular matrix-dependent regulation of Fas ligand expression in human endometrial stromal cells. Biol. Reprod. 66(1), 1–5 (2002).
Medline CASGoogle Scholar
37. Huan Q, Cheng SC, Du ZH, Ma HF, Li C. lncRNA AFAP1-AS1 regulates proliferation and apoptosis of endometriosis through activating STAT3/TGF-β/Smad signaling via miR-424-5p. J. Obstet. Gynaecol. Res. 47(7), 2394–2405 (2021).
Medline CASGoogle Scholar
38. Chen S, Luo Y, Cui L, Yang Q. miR-96-5p regulated TGF-β/SMAD signaling pathway and suppressed endometrial cell viability and migration via targeting TGFBR1. Cell Cycle 19(14), 1740–1753 (2020).
Medline CASGoogle Scholar
39. Han X, Hu F, Chen F, Wang W. The inhibition of bone morphogenetic protein 1 attenuates endometriosis lesions in vivo and in vitro. Arch. Gynecol. Obstet. 302(2), 415–422 (2020).
Medline CASGoogle Scholar
40. Barjaste N, Shahhoseini M, Afsharian P, Sharifi-Zarchi A, Masoudi-Nejad A. Genome-wide DNA methylation profiling in ectopic and eutopic of endometrial tissues. J. Assist. Reprod. Genet. 36(8), 1743–1752 (2019).
MedlineGoogle Scholar
41. Madanes D, Bilotas MA, Bastón JI et al. PI3K/AKT pathway is altered in the endometriosis patient's endometrium and presents differences according to severity stage. Gynecol. Endocrinol. 36(5), 436–440 (2020).
Medline CASGoogle Scholar
42. Cao L, Zhu T, Lang X et al. Inhibiting DNA methylation improves survival in severe sepsis by regulating NF-κB pathway. Front. Immunol. 11, 1360 (2020).
Medline CASGoogle Scholar
43. Wu W, Wang J, Xiao C et al. SMYD2-mediated TRAF2 methylation promotes the NF-κB signaling pathways in inflammatory diseases. Clin. Transl. Med. 11(11), e591 (2021).
Medline CASGoogle Scholar
44. Chowdhury I, Banerjee S, Driss A et al. Curcumin attenuates proangiogenic and proinflammatory factors in human eutopic endometrial stromal cells through the NF-κB signaling pathway. J. Cell. Physiol. 234(5), 6298–6312 (2019).
Medline CASGoogle Scholar
45. Li MQ, Li HP, Meng YH et al. Chemokine CCL2 enhances survival and invasiveness of endometrial stromal cells in an autocrine manner by activating Akt and MAPK/Erk1/2 signal pathway. Fertil. Steril. 97(4), 919–929 (2012).
Medline CASGoogle Scholar
46. Wang S, Duan H, Li B et al. BDNF and TrKB expression levels in patients with endometriosis and their associations with dysmenorrhoea. J. Ovarian Res. 15(1), 35 (2022).
MedlineGoogle Scholar
47. Kim JM, Kang HJ, Kim SY et al. BDNF promoter methylation associated with suicidal ideation in patients with breast cancer. Int. J. Psychiatry Med. 49(1), 75–94 (2015).
MedlineGoogle Scholar
48. Browne AS, Yu J, Huang RP, Francisco AM, Sidell N, Taylor RN. Proteomic identification of neurotrophins in the eutopic endometrium of women with endometriosis. Fertil. Steril. 98(3), 713–719 (2012).
Medline CASGoogle Scholar
49. Wu PL, Zeng C, Zhou YF, Yin L, Yu XL, Xue Q. Farnesoid X receptor agonist GW4064 inhibits aromatase and ERβ expression in human endometriotic stromal cells. Reprod. Sci. 26(8), 1111–1120 (2019).
Medline CASGoogle Scholar
50. Xiang D, Zhao M, Cai X et al. Betulinic acid inhibits endometriosis through suppression of estrogen receptor β signaling pathway. Front. Endocrinol. (Lausanne) 11, 604648 (2020).
MedlineGoogle Scholar
51. Mama ST. Advances in the management of endometriosis in the adolescent. Curr. Opin. Obstet. Gynecol. 30(5), 326–330 (2018).
MedlineGoogle Scholar
52. Dillon GA, Stanhewicz AE, Serviente C, Flores VA, Stachenfeld N, Alexander LM. Seven days of statin treatment improves nitric-oxide mediated endothelial-dependent cutaneous microvascular function in women with endometriosis. Microvasc. Res. 144, 104421 (2022).
Medline CASGoogle Scholar
53. Ohama Y, Harada T, Iwabe T, Taniguchi F, Takenaka Y, Terakawa N. Peroxisome proliferator-activated receptor-gamma ligand reduced tumor necrosis factor-alpha-induced interleukin-8 production and growth in endometriotic stromal cells. Fertil. Steril. 89(2), 311–317 (2008).
Medline CASGoogle Scholar
54. Herington JL, Crispens MA, Carvalho-Macedo AC et al. Development and prevention of postsurgical adhesions in a chimeric mouse model of experimental endometriosis. Fertil. Steril. 95(4), 1295–301.e1 (2011).
MedlineGoogle Scholar

Vol. 14, No. 19

Supplemental Materials

Metrics

Downloaded 183 times

History

Received 17 July 2022

Accepted 13 October 2022

Published online 31 October 2022

Published in print October 2022

Information

Keywords

Supplementary data

To view the supplementary data that accompany this paper please visit the journal website at: www.futuremedicine.com/doi/suppl/10.2217/epi-2022-0249

Author contributions

GM Zhang designed and directed all the research. JX Li and YN He conducted the data processing and experimental analysis. T Liang, J Wang and XY Jiang drafted the manuscript. All authors reviewed and approved the final version of the manuscript.

Acknowledgments

The authors would like to thank the staff members of the Gene Expression Omnibus database and the Turku Endometriosis Database, as well as all the authors for making their valuable research data public.

Financial & competing interests disclosure

This study was supported by the National Natural Science Foundation of China (grant no. 81971359), the Natural Science Foundation of Heilongjiang Province (grant no. LH2019H027), the Heilongjiang Postdoctoral Program Foundation (LBH-Z19085) and the Outstanding Young Medical Talents Training Fund project of the First Affiliated Hospital of Harbin Medical University (HYD2020YQ0021). All clinical samples were obtained with informed consent and approved by the Ethics Commission of Harbin Medical University (202105). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

PDF download

Identification of potential differentially methylated gene-related biomarkers in endometriosis

Abstract

Plain language summary

References