Advertisement

Inhibition of miR-574-5p suppresses cell growth and metastasis and enhances chemosensitivity by targeting RNA binding protein QKI in cervical cancer cells

  • Rui TongEmail author
  • Jingru Zhang
  • Chunyan Wang
  • Qian Li
  • Ling Wang
  • Mingxiu Ju
Original Article

Abstract

Cervical cancer is the fourth most common female malignancy worldwide and microRNA (miR)-574-5p is a candidate oncogene in multiple cancers. The present study aimed to investigate the role and mechanism of miR-574-5p in cervical cancer. miR-574-5p inhibitors or mimics were transfected into cervical cancer cells to study the function of miR-574-5p. The effects of miR-574-5p on cell growth, invasion, and chemosensitivity were evaluated using CCK8, flow cytometry, transwell, immunofluorescence, and Western blotting analysis. Further depletion or forced expression of QKI was performed to explore the regulatory mechanism of miR-574-5p in cervical cancer. Up-regulation of miR-547-5p and down-regulation of QKI were observed in 30 cervical cancer tissues versus 30 adjacent normal tissues. Silencing of miR-574-5p increased apoptosis, inhibited proliferation, cell cycle progression, and cell invasiveness, as well as enhanced chemosensitivity towards cisplatin and doxorubicin in cervical cancer cells. Overexpression of miR-574-5p exerted promoting effect on cancer progression and metastasis. Knockdown of miR-574-5p induced an up-regulation of E-cadherin and down-regulation of cyclinD1, N-cadherin, matrix metallopeptidase 9 (MMP-9), and β-catenin in cervical cancer cells Moreover, QKI was verified as a target of miR-574-5p and involved in regulation of miR-574-5p-induced cervical cancer cell progression and metastasis. miR-574-5p functions to be oncogenic in cervical cancer, and its inhibition suppresses cervical cancer progression and metastasis as well as enhances chemosensitivity by targeting QKI. Therefore, miR-574-5p is suggested as a potential therapeutic target for cervical cancer treatment.

Keywords

miR-574-5p QKI Cervical cancer Growth Metastasis Chemosensitivity 

Notes

Authors’ contributions

RT conceived, designed, and performed the experiments; JZ, CW, and QL helped perform the experiments; LW drafted the manuscript; MJ revised the manuscript and contributed to data analysis.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

All procedures performed in this study involving human participants were in accordance with ethical standards of Cancer Hospital, Chinese Medical University, China and with the Helsinki declaration.

Informed consent

Informed consent was obtained from all individual participants included in the study.

Supplementary material

210_2019_1772_MOESM1_ESM.doc (49 kb)
ESM 1 (DOC 49 kb)

References

  1. Bahrami A, Hasanzadeh M, ShahidSales S, Yousefi Z, Kadkhodayan S, Farazestanian M, Joudi Mashhad M, Gharib M, Mahdi Hassanian S, Avan A (2017) Clinical significance and prognosis value of Wnt signaling pathway in cervical Cancer. J Cell Biochem 118(10):3028–3033.  https://doi.org/10.1002/jcb.25992 CrossRefPubMedGoogle Scholar
  2. Biedermann B, Hotz HR, Ciosk R (2010) The quaking family of RNA-binding proteins: coordinators of the cell cycle and differentiation. Cell Cycle 9(10):1929–1933.  https://doi.org/10.4161/cc.9.10.11533 CrossRefPubMedGoogle Scholar
  3. Bracken CP, Scott HS, Goodall GJ (2016) A network-biology perspective of microRNA function and dysfunction in cancer. Nat Rev Genet 17(12):719–732.  https://doi.org/10.1038/nrg.2016.134 CrossRefPubMedGoogle Scholar
  4. Cagel M, Grotz E, Bernabeu E, Moretton MA, Chiappetta DA (2017) Doxorubicin: nanotechnological overviews from bench to bedside. Drug Discov Today 22(2):270–281.  https://doi.org/10.1016/j.drudis.2016.11.005 CrossRefPubMedGoogle Scholar
  5. Cai Z, Liu Q (2017) Cell cycle regulation in treatment of breast Cancer. Adv Exp Med Biol 1026:251–270.  https://doi.org/10.1007/978-981-10-6020-5_12 CrossRefPubMedGoogle Scholar
  6. Chen Y, Ke G, Han D, Liang S, Yang G, Wu X (2014) MicroRNA-181a enhances the chemoresistance of human cervical squamous cell carcinoma to cisplatin by targeting PRKCD. Exp Cell Res 320(1):12–20.  https://doi.org/10.1016/j.yexcr.2013.10.014 CrossRefPubMedGoogle Scholar
  7. Chen C, Lu L, Yan S, Yi H, Yao H, Wu D, He G, Tao X, Deng X (2018) Autophagy and doxorubicin resistance in cancer. Anti-Cancer Drugs 29(1):1–9.  https://doi.org/10.1097/cad.0000000000000572 CrossRefPubMedGoogle Scholar
  8. Cohen PA, Jhingran A, Oaknin A, Denny L (2019) Cervical cancer. Lancet 393(10167):169–182.  https://doi.org/10.1016/s0140-6736(18)32470-x CrossRefPubMedGoogle Scholar
  9. Darbelli L, Richard S (2016) Emerging functions of the quaking RNA-binding proteins and link to human diseases. Wiley Interdiscip Rev RNA 7(3):399–412.  https://doi.org/10.1002/wrna.1344 CrossRefPubMedGoogle Scholar
  10. Dasari S, Tchounwou PB (2014) Cisplatin in cancer therapy: molecular mechanisms of action. Eur J Pharmacol 740:364–378.  https://doi.org/10.1016/j.ejphar.2014.07.025 CrossRefPubMedGoogle Scholar
  11. de Miguel FJ, Pajares MJ, Martinez-Terroba E, Ajona D, Morales X, Sharma RD, Pardo FJ, Rouzaut A, Rubio A, Montuenga LM, Pio R (2016) A large-scale analysis of alternative splicing reveals a key role of QKI in lung cancer. Mol Oncol 10(9):1437–1449.  https://doi.org/10.1016/j.molonc.2016.08.001 CrossRefPubMedPubMedCentralGoogle Scholar
  12. Feng M, Wang Y, Chen K, Bian Z, Jinfang W, Gao Q (2014) IL-17A promotes the migration and invasiveness of cervical cancer cells by coordinately activating MMPs expression via the p38/NF-kappaB signal pathway. PLoS One 9(9):e108502.  https://doi.org/10.1371/journal.pone.0108502 CrossRefPubMedPubMedCentralGoogle Scholar
  13. Foss KM, Sima C, Ugolini D, Neri M, Allen KE, Weiss GJ (2011) miR-1254 and miR-574-5p: serum-based microRNA biomarkers for early-stage non-small cell lung cancer. J Thorac Oncol 6(3):482–488.  https://doi.org/10.1097/JTO.0b013e318208c785 CrossRefPubMedGoogle Scholar
  14. Fu X, Feng Y (2015) QKI-5 suppresses cyclin D1 expression and proliferation of oral squamous cell carcinoma cells via MAPK signalling pathway. Int J Oral Maxillofac Surg 44(5):562–567.  https://doi.org/10.1016/j.ijom.2014.10.001 CrossRefPubMedGoogle Scholar
  15. Gao C, Zhou C, Zhuang J, Liu L, Liu C, Li H, Liu G, Wei J, Sun C (2018) MicroRNA expression in cervical cancer: novel diagnostic and prognostic biomarkers. J Cell Biochem 119(8):7080–7090.  https://doi.org/10.1002/jcb.27029 CrossRefPubMedGoogle Scholar
  16. Ha M, Kim VN (2014) Regulation of microRNA biogenesis. Nat Rev Mol Cell Biol 15(8):509–524.  https://doi.org/10.1038/nrm3838 CrossRefPubMedGoogle Scholar
  17. Hwang HW, Mendell JT (2006) MicroRNAs in cell proliferation, cell death, and tumorigenesis. Br J Cancer 94(6):776–780.  https://doi.org/10.1038/sj.bjc.6603023 CrossRefPubMedPubMedCentralGoogle Scholar
  18. Ji S, Ye G, Zhang J, Wang L, Wang T, Wang Z, Zhang T, Wang G, Guo Z, Luo Y, Cai J, Yang JY (2013) miR-574-5p negatively regulates Qki6/7 to impact beta-catenin/Wnt signalling and the development of colorectal cancer. Gut 62(5):716–726.  https://doi.org/10.1136/gutjnl-2011-301083 CrossRefPubMedGoogle Scholar
  19. Jonas S, Izaurralde E (2015) Towards a molecular understanding of microRNA-mediated gene silencing. Nat Rev Genet 16(7):421–433.  https://doi.org/10.1038/nrg3965 CrossRefPubMedGoogle Scholar
  20. Kawano M, Mabuchi S, Matsumoto Y, Sasano T, Takahashi R, Kuroda H, Kozasa K, Hashimoto K, Isobe A, Sawada K, Hamasaki T, Morii E, Kimura T (2015) The significance of G-CSF expression and myeloid-derived suppressor cells in the chemoresistance of uterine cervical cancer. Sci Rep 5:18217–18213.  https://doi.org/10.1038/srep18217 CrossRefPubMedPubMedCentralGoogle Scholar
  21. Kelland L (2007) The resurgence of platinum-based cancer chemotherapy. Nat Rev Cancer 7(8):573–584.  https://doi.org/10.1038/nrc2167 CrossRefPubMedGoogle Scholar
  22. Kent OA, Mendell JT (2006) A small piece in the cancer puzzle: microRNAs as tumor suppressors and oncogenes. Oncogene 25(46):6188–6196.  https://doi.org/10.1038/sj.onc.1209913 CrossRefPubMedGoogle Scholar
  23. Kim K, Lu Z, Hay ED (2002) Direct evidence for a role of beta-catenin/LEF-1 signaling pathway in induction of EMT. Cell Biol Int 26(5):463–476CrossRefGoogle Scholar
  24. Kim EJ, Kim JS, Lee S, Lee H, Yoon JS, Hong JH, Chun SH, Sun S, Won HS, Hong SA, Kang K, Jo JY, Choi M, Shin DH, Ahn YH, Ko YH (2019) QKI, a miR-200 target gene, suppresses epithelial-to-mesenchymal transition and tumor growth. Int J Cancer 145(6):1585–1595.  https://doi.org/10.1002/ijc.32372 CrossRefPubMedGoogle Scholar
  25. Kondo T, Furuta T, Mitsunaga K, Ebersole TA, Shichiri M, Wu J, Artzt K, Yamamura K, Abe K (1999) Genomic organization and expression analysis of the mouse qkI locus. Mamm Genome 10(7):662–669CrossRefGoogle Scholar
  26. Lei C, Wang Y, Huang Y, Yu H, Huang Y, Wu L, Huang L (2012) Up-regulated miR155 reverses the epithelial-mesenchymal transition induced by EGF and increases chemo-sensitivity to cisplatin in human Caski cervical cancer cells. PLoS One 7(12):e52310.  https://doi.org/10.1371/journal.pone.0052310 CrossRefPubMedPubMedCentralGoogle Scholar
  27. Li J, Liu Q, Clark LH, Qiu H, Bae-Jump VL, Zhou C (2017) Deregulated miRNAs in human cervical cancer: functional importance and potential clinical use. Future Oncol 13(8):743–753.  https://doi.org/10.2217/fon-2016-0328 CrossRefPubMedGoogle Scholar
  28. Ma DL, Li JY, Liu YE, Liu CM, Li J, Lin GZ, Yan J (2016) Influence of continuous intervention on growth and metastasis of human cervical cancer cells and expression of RNAmiR-574-5p. J Biol Regul Homeost Agents 30(1):91–102PubMedGoogle Scholar
  29. Moghimi-Dehkordi B, Safaee A (2012) An overview of colorectal cancer survival rates and prognosis in Asia. World J Gastrointest Oncol 4(4):71–75.  https://doi.org/10.4251/wjgo.v4.i4.71 CrossRefPubMedPubMedCentralGoogle Scholar
  30. Mukohyama J, Isobe T, Hu Q, Hayashi T, Watanabe T, Maeda M, Yanagi H, Qian X, Yamashita K, Minami H, Mimori K, Sahoo D, Kakeji Y, Suzuki A, Dalerba P, Shimono Y (2019) miR-221 targets QKI to enhance the tumorigenic capacity of human colorectal Cancer stem cells. Cancer Res 79(20):5151–5158.  https://doi.org/10.1158/0008-5472.can-18-3544 CrossRefPubMedGoogle Scholar
  31. Schiffman M, Castle PE, Jeronimo J, Rodriguez AC, Wacholder S (2007) Human papillomavirus and cervical cancer. Lancet 370(9590):890–907.  https://doi.org/10.1016/s0140-6736(07)61416-0 CrossRefPubMedGoogle Scholar
  32. Shang S, Hua F, Hu ZW (2017) The regulation of beta-catenin activity and function in cancer: therapeutic opportunities. Oncotarget 8(20):33972–33989.  https://doi.org/10.18632/oncotarget.15687 CrossRefPubMedPubMedCentralGoogle Scholar
  33. Small W Jr, Bacon MA, Bajaj A, Chuang LT, Fisher BJ, Harkenrider MM, Jhingran A, Kitchener HC, Mileshkin LR, Viswanathan AN, Gaffney DK (2017) Cervical cancer: a global health crisis. Cancer 123(13):2404–2412.  https://doi.org/10.1002/cncr.30667 CrossRefPubMedGoogle Scholar
  34. Srivastava SK, Ahmad A, Zubair H, Miree O, Singh S, Rocconi RP, Scalici J, Singh AP (2017) MicroRNAs in gynecological cancers: Small molecules with big implications. Cancer Lett 407:123–138.  https://doi.org/10.1016/j.canlet.2017.05.011 CrossRefPubMedPubMedCentralGoogle Scholar
  35. Svoronos AA, Engelman DM, Slack FJ (2016) OncomiR or tumor suppressor? The duplicity of MicroRNAs in Cancer. Cancer Res 76(13):3666–3670.  https://doi.org/10.1158/0008-5472.can-16-0359 CrossRefPubMedPubMedCentralGoogle Scholar
  36. Tse JC, Kalluri R (2007) Mechanisms of metastasis: epithelial-to-mesenchymal transition and contribution of tumor microenvironment. J Cell Biochem 101(4):816–829.  https://doi.org/10.1002/jcb.21215 CrossRefPubMedGoogle Scholar
  37. Wang X, Lu X, Geng Z, Yang G, Shi Y (2017) LncRNA PTCSC3/miR-574-5p governs cell proliferation and migration of papillary thyroid carcinoma via Wnt/beta-catenin signaling. J Cell Biochem 118(12):4745–4752.  https://doi.org/10.1002/jcb.26142 CrossRefPubMedGoogle Scholar
  38. Xiong Y, Sun F, Dong P, Watari H, Yue J, Yu MF, Lan CY, Wang Y, Ma ZB (2017) iASPP induces EMT and cisplatin resistance in human cervical cancer through miR-20a-FBXL5/BTG3 signaling. J Exp Clin Cancer Res 36(1):48.  https://doi.org/10.1186/s13046-017-0520-6 CrossRefPubMedPubMedCentralGoogle Scholar
  39. Yang G, Fu H, Zhang J, Lu X, Yu F, Jin L, Bai L, Huang B, Shen L, Feng Y, Yao L, Lu Z (2010) RNA-binding protein quaking, a critical regulator of colon epithelial differentiation and a suppressor of colon cancer. Gastroenterology 138(1):231–40.e1-5.  https://doi.org/10.1053/j.gastro.2009.08.001 CrossRefPubMedGoogle Scholar
  40. Zhang Z, Li X, Xiao Q, Wang Z (2018) MiR-574-5p mediates the cell cycle and apoptosis in thyroid cancer cells via Wnt/beta-catenin signaling by repressing the expression of quaking proteins. Oncol Lett 15(4):5841–5848.  https://doi.org/10.3892/ol.2018.8067 CrossRefPubMedPubMedCentralGoogle Scholar
  41. Zhao Y, Zhang G, Wei M, Lu X, Fu H, Feng F, Wang S, Lu W, Wu N, Lu Z, Yuan J (2014) The tumor suppressing effects of QKI-5 in prostate cancer: a novel diagnostic and prognostic protein. Cancer Biol Ther 15(1):108–118.  https://doi.org/10.4161/cbt.26722 CrossRefPubMedGoogle Scholar
  42. Zhou X, Li X, Sun C, Shi C, Hua D, Yu L, Wen Y, Hua F, Wang Q, Zhou Q, Yu S (2017) Quaking-5 suppresses aggressiveness of lung cancer cells through inhibiting beta-catenin signaling pathway. Oncotarget 8(47):82174–82184.  https://doi.org/10.18632/oncotarget.19066 CrossRefPubMedPubMedCentralGoogle Scholar
  43. Zhu H, Luo H, Zhang W, Shen Z, Hu X, Zhu X (2016) Molecular mechanisms of cisplatin resistance in cervical cancer. Drug Des Devel Ther 10:1885–1895.  https://doi.org/10.2147/dddt.s106412 CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of GynecologyCancer Hospital of China Medical University, Liaoning Cancer Hospital and InstituteShenyangPeople’s Republic of China

Personalised recommendations