Abstract
The inner myometrium, also called the junctional zone (JZ), is believed to play a major role in the development of adenomyosis. Recently, we found that the lethal-7a (Let-7a) microRNA (miRNA) was clearly downregulated in the miRNA expression profiles of JZ smooth muscle cells (JZSMCs) of patients with adenomyosis. Lin28, including Lin28A and Lin28B, is responsible for the post-transcriptional downregulation of the Let-7 miRNA family. However, the expression pattern of Lin28 and the function of the Lin28/Let-7 axis in adenomyosis have not yet been identified. In this study, we aim to explore the potential roles of the Lin28/Let-7 axis in the development of adenomyosis. Immunohistochemistry, western blot, and reverse transcription polymerase chain reaction (RT-qPCR) were used to evaluate the Lin28 expression, respectively. The correlation between Let-7a, Lin28A, and Lin28B expression was further examined using Pearson’s correlation analysis. RNA interference was used to inhibit Lin28B gene, and then Cell Counting Kit (CCK-8) assay was performed to detect the cell proliferation capacity. The results revealed that the expression levels of Lin28B were upregulated in the JZ of adenomyosis whatever about proteins or mRNA (P < 0.0001); furthermore, its mRNA expression level was negatively correlated with Let-7a (r = − 0.749, P < 0.0001). After inhibiting Lin28B gene, the proliferation capacity of JZSMCs in adenomyosis group decreased after 48 h (P < 0.05). These results indicated that Lin28B may be involved in the pathogenesis of adenomyosis by promoting the proliferation capacity of JZSMCs via regulating Let-7a.
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References
Yen CF, Huang SJ, Lee CL, Wang HS, Liao SK. Molecular characteristics of the endometrium in uterine adenomyosis and its biochemical microenvironment. Reprod Sci. 2017;24(6):1933719117691141.
Nelsen LM, Lenderking WR, Pokrzywinski R, et al. Experience of symptoms and disease impact in patients with denomyosis. Patient. 2017;11(373):1–10.
Struble J, Reid S, Bedaiwy MA. Adenomyosis: a clinical review of a challenging gynecologic condition. J Minim Invasive Gynecol. 2016;23(2):164–85.
Fusi L, Cloke B, Brosens JJ. The uterine junctional zone. Best Pract Res Clin Obstet Gynaecol. 2006;20(4):479–91.
Barker FG. Uterine junctional zone: function and disease. Lancet. 1995;346(8974):558–60.
Mehasseb MK, Bell SC, Pringle JH, Habiba MA. Uterine adenomyosis is associated with ultrastructural features of altered contractility in the inner myometrium. Fertil Steril. 2010;93(7):2130–6.
Zhang Y, Zhou L, Li TC, Duan H, Yu P, Wang HY. Ultrastructural features of endometrial-myometrial interface and its alteration in adenomyosis. Int J Clin Exp Pathol. 2014;7(4):1469–77.
Bartel DP. MicroRNAs: genomics, biogenesis, mechanism, and function. Cell. 2004;116(2):0–297.
Baek D, Villén J, Shin C, Camargo FD, Gygi SP, Bartel DP. The impact of microRNAs on protein output. Nature. 2008;455(7209):64.
Hwang HW, Mendell JT. MicroRNAs in cell proliferation, cell death, and tumorigenesis. Br J Cancer. 2006;94(6):776–80.
Nothnick WB. The role of micro-RNAs in the female reproductive tract. Reproduction. 2012;143(5):559–76.
Roush S, Slack FJ. The Let-7 family of microRNAs. Trends Cell Biol. 2008;18(10):505–16.
Lin S, Gregory RI. Identification of small molecule inhibitors of Zcchc11 TUTase activity. RNA Biol. 2015;12(8):792–800.
Viswanathan SR, Daley GQ, Gregory RI. Selective blockade of microRNA processing by Lin28. Science. 2008;320(5872):97–100.
Nguyen LH, Zhu H. Lin28 and Let-7 in cell metabolism and cancer. Transl Pediatr. 2015;4(1):4–11.
Balzeau J, Menezes MR, Cao S, Hagan JP. The LIN28/Let-7 pathway in Cancer. Front Genet. 2017;8:31.
Gordts S, Grimbizis G, Campo R. Symptoms and classification of uterine adenomyosis, including the place of hysteroscopy in diagnosis. Fertil Steril. 2018;109(3):380–388.e1.
Sheng J, Zhang WY, Zhang JP, Lu D. The LNG-IUS study on adenomyosis: a 3-year follow-up study on the efficacy and side effects of the use of levonorgestrel intrauterine system for the treatment of dysmenorrhea associated with adenomyosis. Contraception. 2009;79(3):189–93.
Zheng D, Duan H, Wang S, Xu Q, Gan L, Li J, et al. FAK regulates epithelialmesenchymal transition in adenomyosis. Mol Med Rep. 2018;18(6):5461–72.
Carrarelli P, Yen CF, Arcuri F, et al. Myostatin, follistatin and activin type II receptors are highly expressed in adenomyosis. Fertil Steril. 2015;104(3):744–752.e1.
Sun FQ, Duan H, Wang S, Li JJ. 17beta-estradiol induces overproliferation in adenomyotic human uterine smooth muscle cells of the junctional zone through hyperactivation of the estrogen receptor-enhanced RhoA/ROCK signaling pathway. Reprod Sci. 2015;22(11):1436–44.
Streuli I, Santulli P, Chouzenoux S, et al. Activation of the MAPK/ERK cell-signaling pathway in uterine smooth muscle cells of women with adenomyosis. Reprod Sci. 2015;22(12):1549.
Büssing I, Slack FJ, Grosshans H. Let-7 microRNAs in development, stem cells and cancer. Trends Mol Med. 2008;14(9):400–9.
Thornton JE, Gregory RI. How does Lin28 Let-7 control development and disease? Trends Cell Biol. 2012;22(9):474–82.
Nam Y, Chen C, Gregory RI, Chou JJ, Sliz P. Molecular basis for interaction of Let-7 microRNAs with Lin28. Cell. 2011;147(5):1080–91.
Piskounova E, Polytarchou C, Thornton JE, LaPierre R, Pothoulakis C, Hagan JP, et al. Lin28A and Lin28B inhibit Let-7 microRNA biogenesis by distinct mechanisms. Cell. 2011;147(5):1066–79.
Shyh-Chang N, Daley GQ. Lin28: primal regulator of growth and metabolism in stem cells. Cell Stem Cell. 2013;12(4):395–406.
Murray MJ, Saini HK, Siegler CA, et al. LIN28 expression in malignant germ cell tumors downregulates Let-7 and increases oncogene levels. Cancer Res. 2013;73(15):4872–84.
Guo M, Zhao X, Yuan X, Jiang J, Li P. MiR-let-7a inhibits cell proliferation, migration, and invasion by down-regulating PKM2 in cervical cancer. Oncotarget. 2017;8(17):28226–36.
Hai-Xia D, Yu Y-Y, et al. Yangzheng Sanjie decoction regulates proliferation and apoptosis of gastric cancer cells by enhancing Let-7a expression. World J Gastroenterol. 2017;23(30):5538.
Qi L, Liu F, Zhang F, et al. lncRNA NEAT1 competes against Let-7a to contribute to non-small cell lung cancer proliferation and metastasis. Biomed Pharmacother. 2018:1507–15.
Wu J, Feng X, Du Y, et al. Beta-catenin/LIN28B promotes the proliferation of human choriocarcinoma cells via Let-7a repression. Acta Biochim Biophys Sin. 2019;51(5):455–62.
Peng S, Chen LL, Lei XX, et al. Genome-wide studies reveal that Lin28 enhances the translation of genes important for growth and survival of human embryonic stem cells. Stem Cells. 2011;29(3):496–504.
Hanna J, Saha K, Pando B, van Zon J, Lengner CJ, Creyghton MP, et al. Direct cell reprogramming is a stochastic process amenable to acceleration. Nature. 2009;462(7273):595–601.
Yu J, Vodyanik MA, Smugaotto K, et al. Induced pluripotent stem cell lines derived from human somatic cells. Science. 2008;318(5858):1917–20.
Zhu H, Shah S, Shyh-Chang N, Shinoda G, Einhorn WS, Viswanathan SR, et al. Lin28a transgenic mice manifest size and puberty phenotypes identified in human genetic association studies. Nat Genet. 2010;42(7):626–30.
Liu Y, Li H, Feng J, Cui X, Huang W, Li Y, et al. Lin28 induces epithelial-to-mesenchymal transition and stemness via downregulation of let-7a in breast cancer cells. PLoS One. 2013;8(12):e83083.
García-Solares J, Donnez J, et al. Pathogenesis of uterine adenomyosis: invagination or metaplasia? Fertil Steril. 2018;109(3):371–9.
Funding
The present study was supported by the National Natural Science Foundation of China (grant no. 81571412), Beijing Municipal Administration of Hospitals Clinical Medicine Development of Special Funding Support (grant no. ZYLX201406), and the Basic-Clinic Cooperation Fund of Capital Medical University (grant no. 16JL44).
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Si-Li Lin performed the experiments and wrote the manuscript. Hua Duan made substantial contributions to the conception and experimental design. Sha Wang and Jin-Jiao Li participated in analyzing the data. All authors approved the final version of the article.
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This study was strictly carried out in accordance with the principles of the Declaration of Helsinki and approved by the Ethics Committee for Clinical Research of Beijing Obstetrics and Gynecology Hospital, Capital Medical University (approval no. 2016-KY-012). All participants signed informed consent before surgery.
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Lin, SL., Duan, H., Wang, S. et al. Overexpression of Lin28B Promoted the Proliferation of Adenomyotic Smooth Muscle Cells of the Junctional Zone via Regulating Let-7a. Reprod. Sci. 27, 1156–1163 (2020). https://doi.org/10.1007/s43032-019-00107-3
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DOI: https://doi.org/10.1007/s43032-019-00107-3