Skip to main content

Advertisement

SpringerLink
Log in

LncRNA MALAT1 inhibits apoptosis of endometrial stromal cells through miR-126-5p-CREB1 axis by activating PI3K-AKT pathway

  • Published:
Molecular and Cellular Biochemistry Aims and scope Submit manuscript

Abstract

Endometriosis is a common, chronic and painful disease in women, whose pathogenesis remains not entirely clear. Long non-coding RNA (lncRNA) MALAT1 participates in the development of endometriosis. This study further investigated the regulation of MALAT1-miR-126-5p-CREB1 axis in the pathological process of endometriosis. MALAT1, miR-126-5p, and CREB1 levels in human endometrial stromal cells (HESCs) were detected by quantitative reverse transcription polymerase chain reaction (RT-qPCR). Protein levels were determined by Western blotting. Cell viability and apoptosis was assessed by MTT assay and annexin V-FITC staining, respectively. The interactivity between miR-126-5p and MALAT1 (or CREB1) was assessed by dual luciferase reporter system. Knockdown of MALAT1 or CREB1 restrained proliferation and induced apoptosis as confirmed by upregulating cleaved caspase-3 and Bax, and down-regulating Bcl-2 in HESCs, while inhibition of miR-126-5p presented the opposite results. Moreover, silencing of MALAT1 triggered apoptosis of HESCs via targeting miR-126-5p. In addition, miR-126-5p directly regulated CREB1 expression via binding to its 3′ non-coding region. Finally, miR-126-5p inhibitor-mediated apoptosis inhibition was restrained by CREB1 silencing via inactivation of PI3K-AKT pathway in HESCs. Taken together, our study firstly demonstrates that MALAT1 regulates apoptosis of HESCs through miR-126-5p/CREB1 axis mediated PI3K/AKT pathway. Our findings explained the pathogenesis of endometriosis and offered promising therapeutic option for endometriosis.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

Abbreviations

HESCs:

Human endometrial stromal cells

lncRNAs:

Long non-coding RNAs

miRNA:

MicroRNA

CREB1:

Cyclic AMP response element-binding protein 1

DMSO:

Dimethylsulfoxide

WT:

Wild type

MUT:

Mutant

UTR:

Untranslated regions

RT-qPCR:

Quantitative reverse transcription polymerase chain reaction

References

  1. Vercellini P, Vigano P, Somigliana E, Fedele L (2014) Endometriosis: pathogenesis and treatment. Nat Rev Endocrinol 10:261–275. https://doi.org/10.1038/nrendo.2013.255

    Article  CAS  Google Scholar 

  2. Swiersz LM (2002) Role of endometriosis in cancer and tumor development. Ann N Y Acad Sci 955:281–292. https://doi.org/10.1111/j.1749-6632.2002.tb02788.x

    Article  Google Scholar 

  3. Macer ML, Taylor HS (2012) Endometriosis and infertility: a review of the pathogenesis and treatment of endometriosis-associated infertility. Obstet Gynecol Clin N Am 39:535–549. https://doi.org/10.1016/j.ogc.2012.10.002

    Article  Google Scholar 

  4. Matsuzaki S, Pouly JL, Canis M (2017) Effects of U0126 and MK2206 on cell growth and re-growth of endometriotic stromal cells grown on substrates of varying stiffness. Sci Rep 7:42939. https://doi.org/10.1038/srep42939

    Article  CAS  PubMed Central  Google Scholar 

  5. Santulli P, Marcellin L, Chouzenoux S, Boulard V, Just PA, Nicco C, Chereau C, Tosti C, Chapron C, Batteux F (2016) Role of the protein kinase BRAF in the pathogenesis of endometriosis. Expert Opin Ther Targets 20:1017–1029. https://doi.org/10.1080/14728222.2016.1180367

    Article  CAS  Google Scholar 

  6. Liu S, Qiu J, Tang X, Cui H, Zhang Q, Yang Q (2019) LncRNA-H19 regulates cell proliferation and invasion of ectopic endometrium by targeting ITGB3 via modulating miR-124-3p. Exp Cell Res 381:215–222. https://doi.org/10.1016/j.yexcr.2019.05.010

    Article  CAS  Google Scholar 

  7. Liu J, Wang Y, Chen P, Ma Y, Wang S, Tian Y, Wang A, Wang D (2019) AC002454.1 and CDK6 synergistically promote endometrial cell migration and invasion in endometriosis. Reproduction. https://doi.org/10.1530/REP-19-0005

    Article  PubMed Central  Google Scholar 

  8. Yu J, Chen LH, Zhang B, Zheng QM (2019) The modulation of endometriosis by lncRNA MALAT1 via NF-kappaB/iNOS. Eur Rev Med Pharmacol Sci 23:4073–4080. https://doi.org/10.26355/eurrev_201905_17908

    Article  CAS  Google Scholar 

  9. Liu H, Zhang Z, Xiong W, Zhang L, Du Y, Liu Y, Xiong X (2019) Long non-coding RNA MALAT1 mediates hypoxia-induced pro-survival autophagy of endometrial stromal cells in endometriosis. J Cell Mol Med 23:439–452. https://doi.org/10.1111/jcmm.13947

    Article  CAS  Google Scholar 

  10. Zhou CF, Liu MJ, Wang W, Wu S, Huang YX, Chen GB, Liu LM, Peng DX, Wang XF, Cai XZ, Li XX, Feng WQ, Ma Y (2019) miR-205-5p inhibits human endometriosis progression by targeting ANGPT2 in endometrial stromal cells. Stem Cell Res Ther 10:287. https://doi.org/10.1186/s13287-019-1388-5

    Article  CAS  PubMed Central  Google Scholar 

  11. Zhu H, Cao XX, Liu J, Hua H (2019) MicroRNA-488 inhibits endometrial glandular epithelial cell proliferation, migration, and invasion in endometriosis mice via Wnt by inhibiting FZD7. J Cell Mol Med 23:2419–2430. https://doi.org/10.1111/jcmm.14078

    Article  CAS  PubMed Central  Google Scholar 

  12. Meng X, Liu J, Wang H, Chen P, Wang D (2019) MicroRNA-126-5p downregulates BCAR3 expression to promote cell migration and invasion in endometriosis. Mol Cell Endocrinol 494:110486. https://doi.org/10.1016/j.mce.2019.110486

    Article  CAS  PubMed Central  Google Scholar 

  13. Shabestari RM, Safa M, Alikarami F, Banan M, Kazemi A (2017) CREB knockdown inhibits growth and induces apoptosis in human pre-B acute lymphoblastic leukemia cells through inhibition of prosurvival signals. Biomed Pharmacother 87:274–279. https://doi.org/10.1016/j.biopha.2016.12.070

    Article  CAS  PubMed Central  Google Scholar 

  14. Li Y, Chen D, Jin L, Liu J, Su Z, Qi Z, Shi M, Jiang Z, Ni L, Yang S, Gui Y, Mao X, Chen Y, Lai Y (2016) Oncogenic cAMP responsive element binding protein 1 is overexpressed upon loss of tumor suppressive miR-10b-5p and miR-363-3p in renal cancer. Oncol Rep 35:1967–1978. https://doi.org/10.3892/or.2016.4579

    Article  CAS  PubMed Central  Google Scholar 

  15. Lv X, Wang D, Ma Y, Long Z (2018) Analysis of the oncogene BRAF mutation and the correlation of the expression of wild-type BRAF and CREB1 in endometriosis. Int J Mol Med 41:1349–1356. https://doi.org/10.3892/ijmm.2017.3342

    Article  CAS  PubMed Central  Google Scholar 

  16. Liu H, Zhang Z, Xiong W, Zhang L, Xiong Y, Li N, He H, Du Y, Liu Y (2017) Hypoxia-inducible factor-1alpha promotes endometrial stromal cells migration and invasion by upregulating autophagy in endometriosis. Reproduction 153:809–820. https://doi.org/10.1530/REP-16-0643

    Article  CAS  PubMed Central  Google Scholar 

  17. Kim HS, Kim TH, Chung HH, Song YS (2014) Risk and prognosis of ovarian cancer in women with endometriosis: a meta-analysis. Br J Cancer 110:1878–1890. https://doi.org/10.1038/bjc.2014.29

    Article  CAS  PubMed Central  Google Scholar 

  18. Kao AP, Wang KH, Chang CC, Lee JN, Long CY, Chen HS, Tsai CF, Hsieh TH, Tsai EM (2011) Comparative study of human eutopic and ectopic endometrial mesenchymal stem cells and the development of an in vivo endometriotic invasion model. Fertil Steril 95(1308–15):e1. https://doi.org/10.1016/j.fertnstert.2010.09.064

    Article  CAS  Google Scholar 

  19. Coutinho LM, Vieira EL, Dela Cruz C, Casalechi M, Teixeira AL, Del Puerto HL, Reis FM (2016) Apoptosis modulation by activin A and follistatin in human endometrial stromal cells. Gynecol Endocrinol 32:161–165. https://doi.org/10.3109/09513590.2015.1103222

    Article  CAS  PubMed Central  Google Scholar 

  20. Zhu MB, Chen LP, Hu M, Shi Z, Liu YN (2019) Effects of lncRNA BANCR on endometriosis through ERK/MAPK pathway. Eur Rev Med Pharmacol Sci 23:6806–6812. https://doi.org/10.26355/eurrev_201908_18719

    Article  Google Scholar 

  21. Huang H, Zhu Z, Song Y (2019) Downregulation of lncrna uca1 as a diagnostic and prognostic biomarker for ovarian endometriosis. Rev Assoc Med Bras 65:336–341. https://doi.org/10.1590/1806-9282.65.3.336

    Article  Google Scholar 

  22. Li ZX, Zhu QN, Zhang HB, Hu Y, Wang G, Zhu YS (2018) MALAT1: a potential biomarker in cancer. Cancer Manag Res 10:6757–6768. https://doi.org/10.2147/CMAR.S169406

    Article  CAS  PubMed Central  Google Scholar 

  23. Liang Z, Chen Y, Zhao Y, Xu C, Zhang A, Zhang Q, Wang D, He J, Hua W, Duan P (2017) miR-200c suppresses endometriosis by targeting MALAT1 in vitro and in vivo. Stem Cell Res Ther 8:251. https://doi.org/10.1186/s13287-017-0706-z

    Article  CAS  PubMed Central  Google Scholar 

  24. Zhang H, Li W, Gu W, Yan Y, Yao X, Zheng J (2019) MALAT1 accelerates the development and progression of renal cell carcinoma by decreasing the expression of miR-203 and promoting the expression of BIRC5. Cell Prolif. https://doi.org/10.1111/cpr.12640

    Article  PubMed Central  Google Scholar 

  25. Fang H, Li HF, He MH, Yan JY, Yang M, Zhang FX, Wang RR, Wang QY, Zhang JP (2019) Long non-coding RNA MALAT1 sponges microRNA-429 to regulate apoptosis of hippocampal neurons in hypoxic-ischemic brain damage by regulating WNT1. Brain Res Bull 152:1–10. https://doi.org/10.1016/j.brainresbull.2019.06.004

    Article  CAS  Google Scholar 

  26. Sun Z, Ou C, Liu J, Chen C, Zhou Q, Yang S, Li G, Wang G, Song J, Li Z, Zhang Z, Yuan W, Li X (2019) YAP1-induced MALAT1 promotes epithelial-mesenchymal transition and angiogenesis by sponging miR-126-5p in colorectal cancer. Oncogene 38:2627–2644. https://doi.org/10.1038/s41388-018-0628-y

    Article  CAS  PubMed Central  Google Scholar 

  27. Lima Queiroz A, Zhang B, Comstock DE, Hao Y, Eriksson M, Hydbring P, Vakifahmetoglu-Norberg H, Norberg E (2018) miR-126-5p targets malate dehydrogenase 1 in non-small cell lung carcinomas. Biochem Biophys Res Commun 499:314–320. https://doi.org/10.1016/j.bbrc.2018.03.154

    Article  CAS  Google Scholar 

  28. Villain G, Poissonnier L, Noueihed B, Bonfils G, Rivera JC, Chemtob S, Soncin F, Mattot V (2018) miR-126-5p promotes retinal endothelial cell survival through SetD5 regulation in neurons. Development. https://doi.org/10.1242/dev.156232

    Article  Google Scholar 

  29. Rao M, Zhu Y, Cong X, Li Q (2017) Knockdown of CREB1 inhibits tumor growth of human gastric cancer in vitro and in vivo. Oncol Rep 37:3361–3368. https://doi.org/10.3892/or.2017.5636

    Article  CAS  Google Scholar 

  30. Yan L, You WQ, Sheng NQ, Gong JF, Hu LD, Tan GW, Chen HQ, Wang ZG (2018) A CREB1/miR-433 reciprocal feedback loop modulates proliferation and metastasis in colorectal cancer. Aging (Albany NY) 10:3774–3793. https://doi.org/10.18632/aging.101671

    Article  CAS  Google Scholar 

  31. Kong WQ, Bai R, Liu T, Cai CL, Liu M, Li X, Tang H (2012) MicroRNA-182 targets cAMP-responsive element-binding protein 1 and suppresses cell growth in human gastric adenocarcinoma. FEBS J 279:1252–1260. https://doi.org/10.1111/j.1742-4658.2012.08519.x

    Article  CAS  Google Scholar 

  32. Chhabra A, Fernando H, Watkins G, Mansel RE, Jiang WG (2007) Expression of transcription factor CREB1 in human breast cancer and its correlation with prognosis. Oncol Rep 18:953–958

    CAS  Google Scholar 

  33. Zhao Y, Sun H, Feng M, Zhao J, Zhao X, Wan Q, Cai D (2018) Metformin is associated with reduced cell proliferation in human endometrial cancer by inbibiting PI3K/AKT/mTOR signaling. Gynecol Endocrinol 34:428–432. https://doi.org/10.1080/09513590.2017.1409714

    Article  CAS  Google Scholar 

  34. Lee MS, Jeong MH, Lee HW, Han HJ, Ko A, Hewitt SM, Kim JH, Chun KH, Chung JY, Lee C, Cho H, Song J (2015) PI3K/AKT activation induces PTEN ubiquitination and destabilization accelerating tumourigenesis. Nat Commun 6:7769. https://doi.org/10.1038/ncomms8769

    Article  CAS  PubMed Central  Google Scholar 

  35. Xu X, Zhu Y, Liang Z, Li S, Wang X, Wu J, Hu Z, Meng S, Liu B, Qin J, Xie L, Zheng X (2016) c-Met and CREB1 are involved in miR-433-mediated inhibition of the epithelial-mesenchymal transition in bladder cancer by regulating Akt/GSK-3beta/Snail signaling. Cell Death Dis 7:e2088. https://doi.org/10.1038/cddis.2015.274

    Article  CAS  PubMed Central  Google Scholar 

  36. Rosa E, Fahnestock M (2015) CREB expression mediates amyloid beta-induced basal BDNF downregulation. Neurobiol Aging 36:2406–2413. https://doi.org/10.1016/j.neurobiolaging.2015.04.014

    Article  CAS  PubMed Central  Google Scholar 

Download references

Funding

None.

Author information

Authors and Affiliations

  1. Department of Obstetrics and Gynecology, Donghu District, the Second Affiliated Hospital of Nanchang University, No. 1, Minde Road, Nanchang, 330006, Jiangxi Province, China

    Ying Feng & Bu-Zhen Tan

Authors
  1. Ying Feng
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Bu-Zhen Tan
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

YF contributed to the study conception and design. Material preparation, data collection and analysis were performed by YF and B-ZT. The first draft of the manuscript was written by YF and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Bu-Zhen Tan.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Ethics approval

The experiment was carried out in accordance with the ethical standards as laid down in the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards, and approved by the Ethics Committee of the Second Affiliated Hospital of Nanchang University.

Informed consent

All patients signed written informed consent. The informed consent was obtained from study participants.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Feng, Y., Tan, BZ. LncRNA MALAT1 inhibits apoptosis of endometrial stromal cells through miR-126-5p-CREB1 axis by activating PI3K-AKT pathway. Mol Cell Biochem 475, 185–194 (2020). https://doi.org/10.1007/s11010-020-03871-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11010-020-03871-y

Keywords

Search

Navigation