The Korean Journal of Physiology and Pharmacology

The Korean Society of Pharmacology (대한약리학회)
권호 표지
DOI QR코드

DOI QR Code

MicroRNA-186 targets SKP2 to induce p27Kip1-mediated pituitary tumor cell cycle deregulation and modulate cell proliferation

  • He, Zongze (Department of Neurosurgery, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China) ;
  • Chen, Longyi (Department of Neurosurgery, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China) ;
  • Wang, Qi (Department of Neurosurgery, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China) ;
  • Yin, Cheng (Department of Neurosurgery, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China) ;
  • Hu, Junting (Department of Neurosurgery, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China) ;
  • Hu, Xiao (Department of Neurosurgery, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China) ;
  • Fei, Fan (Department of Neurosurgery, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China) ;
  • Tang, Jian (Department of Neurosurgery, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China)
  • Received : 2018.06.04
  • Accepted : 2018.12.21
  • Published : 2019.05.01
Download PDF
⟨ Previous Next ⟩

Abstract

Pituitary tumors are usually benign but can occasionally exhibit hormonal and proliferative behaviors. Dysregulation of the G1/S restriction point largely contributes to the over-proliferation of pituitary tumor cells. F-box protein S-phase kinase-interacting protein-2 (SKP2) reportedly targets and inhibits the expression of $p27^{Kip1}$, a well-known negative regulator of G1 cell cycle progression. In this study, SKP2 expression was found to be upregulated while $p27^{Kip1}$ expression was determined to be downregulated in rat and human pituitary tumor cells. Furthermore, SKP2 knockdown induced upregulation of $p27^{Kip1}$ and cell growth inhibition in rat and human pituitary tumor cells, while SKP2overexpression elicited opposite effects on $p27^{Kip1}$ expression and cell growth. The expression of microRNA-186 (miR-186) was reported to be reduced in pituitary tumors. Online tools predicted SKP2 to be a direct downstream target of miR-186, which was further confirmed by luciferase reporter gene assays. Moreover, miR-186 could modulate the cell proliferation and $p27^{Kip1}$-mediated cell cycle alternation of rat and human pituitary tumor cells through SKP2. As further confirmation of these findings, miR-186 and $p27^{Kip1}$ expression were downregulated, while SKP2 expression was upregulated in human pituitary tumor tissue samples; thus, SKP2 expression negatively correlated with miR-186 and $p27^{Kip1}$ expression. In contrast, miR-186 expression positively associated with $p27^{Kip1}$ expression. Taken together, we discovered a novel mechanism by which miR-186/SKP2 axis modulates pituitary tumor cell proliferation through $p27^{Kip1}$-mediated cell cycle alternation.

Keywords

References

  1. Shimon I, Melmed S. Genetic basis of endocrine disease: pituitary tumor pathogenesis. J Clin Endocrinol Metab. 1997;82:1675-1681. https://doi.org/10.1210/jcem.82.6.3987
  2. Coire CI, Horvath E, Kovacs K, Smyth HS, Ezzat S. Cushing's syndrome from an ectopic pituitary adenoma with peliosis: a histological, immunohistochemical, and ultrastructural study and review of the literature. Endocr Pathol. 1997;8:65-74. https://doi.org/10.1007/BF02739709
  3. Asa SL, Ezzat S. The cytogenesis and pathogenesis of pituitary adenomas. Endocr Rev. 1998;19:798-827. https://doi.org/10.1210/er.19.6.798
  4. Palumbo T, Faucz FR, Azevedo M, Xekouki P, Iliopoulos D, Stratakis CA. Functional screen analysis reveals miR-26b and miR-128 as central regulators of pituitary somatomammotrophic tumor growth through activation of the PTEN-AKT pathway. Oncogene. 2013;32:1651-1659. https://doi.org/10.1038/onc.2012.190
  5. Tang FY, Shih CJ, Cheng LH, Ho HJ, Chen HJ. Lycopene inhibits growth of human colon cancer cells via suppression of the Akt signaling pathway. Mol Nutr Food Res. 2008;52:646-654. https://doi.org/10.1002/mnfr.200700272
  6. Li W, Zhang G, Wang HL, Wang L. Analysis of expression of cyclin E, p27kip1 and Ki67 protein in colorectal cancer tissues and its value for diagnosis, treatment and prognosis of disease. Eur Rev Med Pharmacol Sci. 2016;20:4874-4879.
  7. Berton S, Cusan M, Segatto I, Citron F, D'Andrea S, Benevol S, Avanzo M, Dall'Acqua A, Schiappacassi M, Bristow RG, Belletti B, Baldassarre G. Loss of p27kip1 increases genomic instability and induces radio-resistance in luminal breast cancer cells. Sci Rep. 2017;7:595. https://doi.org/10.1038/s41598-017-00734-3
  8. Kim GJ, Kim DH, Min KW, Kim YH, Oh YH. Loss of p27kip1 expression is associated with poor prognosis in patients with taxanetreated breast cancer. Pathol Res Pract. 2018;214:565-571. https://doi.org/10.1016/j.prp.2018.02.004
  9. Haddad NF, Teodoro AJ, Leite de Oliveira F, Soares N, de Mattos RM, Hecht F, Dezonne RS, Vairo L, Goldenberg RC, Gomes FC, de Carvalho DP, Gadelha MR, Nasciutti LE, Miranda-Alves L. Lycopene and beta-carotene induce growth inhibition and proapoptotic effects on ACTH-secreting pituitary adenoma cells. PLoS One. 2013;8:e62773. https://doi.org/10.1371/journal.pone.0062773
  10. Kulinski M, Achkar IW, Haris M, Dermime S, Mohammad RM, Uddin S. Dysregulated expression of SKP2 and its role in hematological malignancies. Leuk Lymphoma. 2018;59:1051-1063. https://doi.org/10.1080/10428194.2017.1359740
  11. Ma Y, Yan M, Huang H, Zhang L, Wang Q, Zhao Y, Zhao J. Associations and prognostic significance of p27Kip1, Jab1 and Skp2 in non-Hodgkin lymphoma. Mol Clin Oncol. 2016;5:357-364. https://doi.org/10.3892/mco.2016.986
  12. Borriello A, Naviglio S, Bencivenga D, Caldarelli I, Tramontano A, Speranza MC, Stampone E, Sapio L, Negri A, Oliva A, Sinisi AA, Spina A, Della Ragione F. Histone deacetylase inhibitors increase p27(Kip1) by affecting its ubiquitin-dependent degradation through Skp2 downregulation. Oxid Med Cell Longev. 2016;2016:2481865.
  13. Frescas D, Pagano M. Deregulated proteolysis by the F-box proteins SKP2 and beta-TrCP: tipping the scales of cancer. Nat Rev Cancer. 2008;8:438-449. https://doi.org/10.1038/nrc2396
  14. Croce CM, Calin GA. miRNAs, cancer, and stem cell division. Cell. 2005;122:6-7. https://doi.org/10.1016/j.cell.2005.06.036
  15. Iorio MV, Ferracin M, Liu CG, Veronese A, Spizzo R, Sabbioni S, Magri E, Pedriali M, Fabbri M, Campiglio M, Menard S, Palazzo JP, Rosenberg A, Musiani P, Volinia S, Nenci I, Calin GA, Querzoli P, Negrini M, Croce CM. MicroRNA gene expression deregulation in human breast cancer. Cancer Res. 2005;65:7065-7070. https://doi.org/10.1158/0008-5472.CAN-05-1783
  16. Bandres E, Bitarte N, Arias F, Agorreta J, Fortes P, Agirre X, Zarate R, Diaz-Gonzalez JA, Ramirez N, Sola JJ, Jimenez P, Rodriguez J, Garcia-Foncillas J. microRNA-451 regulates macrophage migration inhibitory factor production and proliferation of gastrointestinal cancer cells. Clin Cancer Res. 2009;15:2281-2290. https://doi.org/10.1158/1078-0432.CCR-08-1818
  17. Stilling G, Sun Z, Zhang S, Jin L, Righi A, Kovacs G, Korbonits M, Scheithauer BW, Kovacs K, Lloyd RV. MicroRNA expression in ACTH-producing pituitary tumors: up-regulation of microRNA-122 and -493 in pituitary carcinomas. Endocrine. 2010;38:67-75. https://doi.org/10.1007/s12020-010-9346-0
  18. Bottoni A, Piccin D, Tagliati F, Luchin A, Zatelli MC, degli Uberti EC. miR-15a and miR-16-1 down-regulation in pituitary adenomas. J Cell Physiol . 2005;204:280-285. https://doi.org/10.1002/jcp.20282
  19. Wierinckx A, Roche M, Legras-Lachuer C, Trouillas J, Raverot G, Lachuer J. MicroRNAs in pituitary tumors. Mol Cell Endocrinol. 2017;456:51-61. https://doi.org/10.1016/j.mce.2017.01.021
  20. Zhang QJ, Xu C. The role of microRNAs in the pathogenesis of pituitary tumors. Front Biosci (Landmark Ed). 2016;21:1-7. https://doi.org/10.2741/4371
  21. Sapochnik M, Nieto LE, Fuertes M, Arzt E. Molecular mechanisms underlying pituitary pathogenesis. Biochem Genet. 2016;54:107-119. https://doi.org/10.1007/s10528-015-9709-6
  22. Dweep H, Gretz N, Sticht C. miRWalk database for miRNA-target interactions. Methods Mol Biol. 2014;1182:289-305. https://doi.org/10.1007/978-1-4939-1062-5_25
  23. John B, Enright AJ, Aravin A, Tuschl T, Sander C, Marks DS. Human MicroRNA targets. PLoS Biol. 2004;2:e363. https://doi.org/10.1371/journal.pbio.0020363
  24. Agarwal V, Bell GW, Nam JW, Bartel DP. Predicting effective microRNA target sites in mammalian mRNAs. Elife. 2015;4:e05005. https://doi.org/10.7554/eLife.05005
  25. Molatore S, Marinoni I, Lee M, Pulz E, Ambrosio MR, degli Uberti EC, Zatelli MC, Pellegata NS. A novel germline CDKN1B mutation causing multiple endocrine tumors: clinical, genetic and functional characterization. Hum Mutat. 2010;31:E1825-1835. https://doi.org/10.1002/humu.21354
  26. An J, Pei X, Zang Z, Zhou Z, Hu J, Zheng X, Zhang Y, He J, Duan L, Shen R, Zhang W, Zhu F, Li S, Yang H. Metformin inhibits proliferation and growth hormone secretion of GH3 pituitary adenoma cells. Oncotarget. 2017;8:37538-37549. https://doi.org/10.18632/oncotarget.16556
  27. Sherr CJ, Roberts JM. Inhibitors of mammalian G1 cyclin-dependent kinases. Genes Dev. 1995;9:1149-1163. https://doi.org/10.1101/gad.9.10.1149
  28. Sherr CJ, Roberts JM. CDK inhibitors: positive and negative regulators of G1-phase progression. Genes Dev. 1999;13:1501-1512. https://doi.org/10.1101/gad.13.12.1501
  29. Musat M, Vax VV, Borboli N, Gueorguiev M, Bonner S, Korbonits M, Grossman AB. Cell cycle dysregulation in pituitary oncogenesis. Front Horm Res . 2004;32:34-62. https://doi.org/10.1159/000079037
  30. Craig C, Wersto R, Kim M, Ohri E, Li Z, Katayose D, Lee SJ, Trepel J, Cowan K, Seth P. A recombinant adenovirus expressing p27Kip1 induces cell cycle arrest and loss of cyclin-Cdk activity in human breast cancer cells. Oncogene. 1997;14:2283-2289. https://doi.org/10.1038/sj.onc.1201064
  31. Katayose Y, Kim M, Rakkar AN, Li Z, Cowan KH, Seth P. Promoting apoptosis: a novel activity associated with the cyclin-dependent kinase inhibitor p27. Cancer Res. 1997;57:5441-5445.
  32. Bartel DP. MicroRNAs: genomics, biogenesis, mechanism, and function. Cell. 2004;116:281-297. https://doi.org/10.1016/S0092-8674(04)00045-5
  33. Liang HQ, Wang RJ, Diao CF, Li JW, Su JL, Zhang S. The PTTG1-targeting miRNAs miR-329, miR-300, miR-381, and miR-655 inhibit pituitary tumor cell tumorigenesis and are involved in a p53/PTTG1 regulation feedback loop. Oncotarget. 2015;6:29413-29427. https://doi.org/10.18632/oncotarget.5003
  34. Renjie W, Haiqian L. MiR-132, miR-15a and miR-16 synergistically inhibit pituitary tumor cell proliferation, invasion and migration by targeting Sox5. Cancer Lett. 2015;356:568-578. https://doi.org/10.1016/j.canlet.2014.10.003
  35. Cai J, Wu J, Zhang H, Fang L, Huang Y, Yang Y, Zhu X, Li R, Li M. miR-186 downregulation correlates with poor survival in lung adenocarcinoma, where it interferes with cell-cycle regulation. Cancer Res. 2013;73:756-766. https://doi.org/10.1158/0008-5472.CAN-12-2651
  36. Yang J, Yuan D, Li J, Zheng S, Wang B. miR-186 downregulates protein phosphatase PPM1B in bladder cancer and mediates G1-S phase transition. Tumour Biol. 2016;37:4331-4341. https://doi.org/10.1007/s13277-015-4117-4
  37. Hua X, Xiao Y, Pan W, Li M, Huang X, Liao Z, Xian Q, Yu L. miR-186 inhibits cell proliferation of prostate cancer by targeting GOLPH3. Am J Cancer Res. 20161;6:1650-1660.

Cited by

  1. Age-related transcriptome changes in Sox2+ supporting cells in the mouse cochlea vol.10, pp.1, 2019, https://doi.org/10.1186/s13287-019-1437-0
  2. Overview of Evidence-Based Chemotherapy for Oral Cancer: Focus on Drug Resistance Related to the Epithelial-Mesenchymal Transition vol.11, pp.6, 2021, https://doi.org/10.3390/biom11060893
  3. The role of noncoding RNAs in pituitary adenoma vol.13, pp.17, 2019, https://doi.org/10.2217/epi-2021-0165