miR-144-3p increases radiosensibility of gastric cancer cells by targeting inhibition of ZEB1

Abstract

Purpose

This study set out to probe into the effect and mechanism of miR-144-3p on radiosensitivity of gastric cancer (GC) cells.

Methods

Cancer tissue and paracancerous tissue of GC patients admitted to our hospital were collected, their miR-144-3p expression was tested, GC cells were transfected, and survival and biological behavior of those cells under radiation were detected.

Results

After detection, miR-144-3p expression was down-regulated in GC tissue, while ZEB1 was up-regulated. There was no remarkable difference in the survival fraction of cells in each group before receiving radiation, but that of tumor cells decreased obviously (p < 0.05) after radiation exposure. Survival fraction of cells overexpressing miR-144-3p or silencing ZEB1 decreased more obviously, while the inhibition of miR-144-3p or overexpressing ZEB1 was weaker. Biological behavior of cells under 6 Gy radiation was detected. It was found that miR-144-3p overexpression or silencing ZEB1 dramatically inhibited the proliferation activity of GC cells under 6 Gy radiation, increased the levels of pro-apoptotic Bax and caspase-3 proteins (p < 0.05) and decreased the anti-apoptotic protein Bcl-2 level (p < 0.05), resulting in an increase in the apoptosis rate of cells. miR-144-3p was confirmed to be ZEB1 targeting site by dual luciferase report. Moreover, rescue experiments prove that it can increase the radiosensitivity of GC cells by regulating ZEB1 expression.

Conclusion

miR-144-3p expression was down-regulated in GC, and it can increase the radiosensitivity of those cells by inhibiting ZEB1 expression.

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

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

References

  1. 1.

    Van Cutsem E, Sagaert X, Topal B, Haustermans K, Prenen H. Gastric cancer. Lancet. 2016;388:2654–64.

    Article  Google Scholar 

  2. 2.

    Li T, Mo X, Fu L, Xiao B, Guo J. Molecular mechanisms of long noncoding RNAs on gastric cancer. Oncotarget. 2016;7:8601–12.

    Article  Google Scholar 

  3. 3.

    Sitarz R, Skierucha M, Mielko J, Offerhaus GJA, Maciejewski R, Polkowski WP. Gastric cancer: epidemiology, prevention, classification, and treatment. Cancer Manag Res. 2018;10:239–48.

    CAS  Article  Google Scholar 

  4. 4.

    Zhang H, Sun LL, Meng YL, Song GY, Hu JJ, Lu P, Ji B. Survival trends in gastric cancer patients of Northeast China. World J Gastroenterol. 2011;17:3257–62.

    PubMed  PubMed Central  Google Scholar 

  5. 5.

    Zhao EH, Ling TL, Cao H. Current status of surgical treatment of gastric cancer in the era of minimally invasive surgery in China: opportunity and challenge. Int J Surg. 2016;28:45–50.

    Article  Google Scholar 

  6. 6.

    Tan Z. Recent advances in the surgical treatment of advanced gastric cancer: a review. Med Sci Monit. 2019;25:3537–41.

    Article  Google Scholar 

  7. 7.

    Liu JS, Che XM, Chang S, Qiu GL, He SC, Fan L, Zhao W, Zhang ZL, Wang SF. beta-elemene enhances the radiosensitivity of gastric cancer cells by inhibiting Pak1 activation. World J Gastroenterol. 2015;21:9945–56.

    CAS  Article  Google Scholar 

  8. 8.

    Cai M, Chen Q, Shen J, Lv C, Cai L. Epigenetic silenced miR-125a-5p could be self-activated through targeting Suv39H1 in gastric cancer. J Cell Mol Med. 2018;22:4721–31.

    CAS  Article  Google Scholar 

  9. 9.

    Zhu C, Huang Q, Zhu H. miR-383 inhibited the cell cycle progression of gastric cancer cells via targeting Cyclin E2. DNA Cell Biol. 2019;38:849–56.

    CAS  Article  Google Scholar 

  10. 10.

    Wu J, Zhao Y, Li F, Qiao B. MiR-144-3p: a novel tumor suppressor targeting MAPK6 in cervical cancer. J Physiol Biochem. 2019;75:143–52.

    CAS  Article  Google Scholar 

  11. 11.

    Liu F, Chen N, Xiao R, Wang W, Pan Z. miR-144-3p serves as a tumor suppressor for renal cell carcinoma and inhibits its invasion and metastasis by targeting MAP3K8. Biochem Biophys Res Commun. 2016;480:87–93.

    CAS  Article  Google Scholar 

  12. 12.

    Cheng ZX, Song YX, Wang ZY, Wang Y, Dong Y. miR-144-3p serves as a tumor suppressor by targeting FZD7 and predicts the prognosis of human glioblastoma. Eur Rev Med Pharmacol Sci. 2017;21:4079–86.

    PubMed  Google Scholar 

  13. 13.

    Li B, Zhang S, Shen H, Li C. MicroRNA-144-3p suppresses gastric cancer progression by inhibiting epithelial-to-mesenchymal transition through targeting PBX3. Biochem Biophys Res Commun. 2017;484:241–7.

    CAS  Article  Google Scholar 

  14. 14.

    Li LY, Yang CC, Yang JF, Li HD, Zhang BY, Zhou H, Hu S, Wang K, Huang C, Meng XM, Zhou H, Zhang L, Li J, Xu T. ZEB1 regulates the activation of hepatic stellate cells through Wnt/beta-catenin signaling pathway. Eur J Pharmacol. 2019;865:172787.

    Article  Google Scholar 

  15. 15.

    Zhang P, Sun Y, Ma L. ZEB1: at the crossroads of epithelial-mesenchymal transition, metastasis and therapy resistance. Cell Cycle. 2015;14:481–7.

    CAS  Article  Google Scholar 

  16. 16.

    Qin Y, Tang B, Hu CJ, Xiao YF, Xie R, Yong X, Wu YY, Dong H, Yang SM. An hTERT/ZEB1 complex directly regulates E-cadherin to promote epithelial-to-mesenchymal transition (EMT) in colorectal cancer. Oncotarget. 2016;7:351–61.

    Article  Google Scholar 

  17. 17.

    Song Z, Li W, Wang L, Jia N, Chen B. MicroRNA-454 inhibits tumor cell proliferation, migration and invasion by downregulating zinc finger Eboxbinding homeobox 1 in gastric cancer. Mol Med Rep. 2017;16:9067–73.

    CAS  Article  Google Scholar 

  18. 18.

    Zhou X, Wang Y, Shan B, Han J, Zhu H, Lv Y, Fan X, Sang M, Liu XD, Liu W. The downregulation of miR-200c/141 promotes ZEB1/2 expression and gastric cancer progression. Med Oncol. 2015;32:428.

    Article  Google Scholar 

  19. 19.

    Tanioka H, Nagasaka T, Uno F, Inoue M, Okita H, Katata Y, Kanzaki H, Kuramochi H, Satake H, Shindo Y, Doi A, Nasu J, Yamashita H, Yamaguchi Y. The relationship between peripheral neuropathy and efficacy in second-line chemotherapy for unresectable advanced gastric cancer: a prospective observational multicenter study protocol (IVY). BMC Cancer. 2019;19:941.

    Article  Google Scholar 

  20. 20.

    Kim S, Kim JE, Kim N, Joo M, Lee MW, Jeon HJ, Ryu H, Song IC, Song GY, Lee HJ. Decursin inhibits tumor growth, migration, and invasion in gastric cancer by down-regulating CXCR7 expression. Am J Cancer Res. 2019;9:2007–188.

    CAS  PubMed  PubMed Central  Google Scholar 

  21. 21.

    Zhang X, Zheng L, Sun Y, Wang T, Wang B. Tangeretin enhances radiosensitivity and inhibits the radiation-induced epithelial-mesenchymal transition of gastric cancer cells. Oncol Rep. 2015;34:302–10.

    CAS  Article  Google Scholar 

  22. 22.

    Tsubouchi K, Minami K, Hayashi N, Yokoyama Y, Mori S, Yamamoto H, Koizumi M. The CD44 standard isoform contributes to radioresistance of pancreatic cancer cells. J Radiat Res. 2017;58:816–26.

    CAS  Article  Google Scholar 

  23. 23.

    Alfonso JCL, Berk L. Modeling the effect of intratumoral heterogeneity of radiosensitivity on tumor response over the course of fractionated radiation therapy. Radiat Oncol. 2019;14:88.

    CAS  Article  Google Scholar 

  24. 24.

    Borrego-Soto G, Ortiz-Lopez R, Rojas-Martinez A. Ionizing radiation-induced DNA injury and damage detection in patients with breast cancer. Genet Mol Biol. 2015;38:420–32.

    CAS  Article  Google Scholar 

  25. 25.

    Li Y, Qin C. MiR-1179 inhibits the proliferation of gastric cancer cells by targeting HMGB1. Hum Cell. 2019;32:352–9.

    CAS  Article  Google Scholar 

  26. 26.

    He Y, Jing Y, Wei F, Tang Y, Yang L, Luo J, Yang P, Ni Q, Pang J, Liao Q, Xiong F, Guo C, Xiang B, Li X, Zhou M, Li Y, Xiong W, Zeng Z, Li G. Long non-coding RNA PVT1 predicts poor prognosis and induces radioresistance by regulating DNA repair and cell apoptosis in nasopharyngeal carcinoma. Cell Death Dis. 2018;9:235.

    Article  Google Scholar 

  27. 27.

    Gao F, Liu P, Narayanan J, Yang M, Fish BL, Liu Y, Liang M, Jacobs ER, Medhora M. Changes in miRNA in the lung and whole blood after whole thorax irradiation in rats. Sci Rep. 2017;7:44132.

    CAS  Article  Google Scholar 

  28. 28.

    Song L, Peng L, Hua S, Li X, Ma L, Jie J, Chen D, Wang Y, Li D. miR-144-5p enhances the radiosensitivity of non-small-cell lung cancer cells via targeting ATF2. Biomed Res Int. 2018;2018:5109497.

    PubMed  PubMed Central  Google Scholar 

  29. 29.

    Wang P, Yang Z, Ye T, Shao F, Li J, Sun N, He J. lncTUG1/miR-144-3p affect the radiosensitivity of esophageal squamous cell carcinoma by competitively regulating c-MET. J Exp Clin Cancer Res. 2020;39:7.

    CAS  Article  Google Scholar 

  30. 30.

    Zhang P, Wang L, Rodriguez-Aguayo C, Yuan Y, Debeb BG, Chen D, Sun Y, You MJ, Liu Y, Dean DC, Woodward WA, Liang H, Yang X, Lopez-Berestein G, Sood AK, Hu Y, Ang KK, Chen J, Ma L. miR-205 acts as a tumour radiosensitizer by targeting ZEB1 and Ubc13. Nat Commun. 2014;5:5671.

    CAS  Article  Google Scholar 

  31. 31.

    Kowalski-Chauvel A, Modesto A, Gouaze-Andersson V, Baricault L, Gilhodes J, Delmas C, Lemarie A, Toulas C, Cohen-Jonathan-Moyal E, Seva C. Alpha-6 integrin promotes radioresistance of glioblastoma by modulating DNA damage response and the transcription factor Zeb1. Cell Death Dis. 2018;9:872.

    Article  Google Scholar 

  32. 32.

    Shao M, Bi T, Ding W, Yu C, Jiang C, Yang H, Sun X, Yang M. OCT4 potentiates radio-resistance and migration activity of rectal cancer cells by improving epithelial-mesenchymal transition in a ZEB1 dependent manner. Biomed Res Int. 2018;2018:3424956.

    PubMed  PubMed Central  Google Scholar 

  33. 33.

    El Bezawy R, Cominetti D, Fenderico N, Zuco V, Beretta GL, Dugo M, Arrighetti N, Stucchi C, Rancati T, Valdagni R, Zaffaroni N, Gandellini P. miR-875-5p counteracts epithelial-to-mesenchymal transition and enhances radiation response in prostate cancer through repression of the EGFR-ZEB1 axis. Cancer Lett. 2017;395:53–62.

    Article  Google Scholar 

  34. 34.

    Jiang Y, Jin S, Tan S, Shen Q, Xue Y. MiR-203 acts as a radiosensitizer of gastric cancer cells by directly targeting ZEB1. Onco Targets Ther. 2019;12:6093–104.

    CAS  Article  Google Scholar 

Download references

Author information

Affiliations

Authors

Contributions

ZG is responsible for the conception or design of the work. ZG, HL and ZZ contribute the acquisition, analysis, or interpretation of data for the work. HL provides the tissue samples. ZG helps in the follow-up of the patients. HL helps in reviewing the histopathology slides. All authors finally approved the manuscript version to be published. ZG is the guarantor of the article.

Corresponding author

Correspondence to Z. Y. Gao.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

The study was approved by Ethical Committee of Binzhou Central Hospital and conducted in accordance with the ethical standards.

Informed consent

Yes.

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

Verify currency and authenticity via CrossMark

Cite this article

Gao, Z.Y., Liu, H. & Zhang, Z. miR-144-3p increases radiosensibility of gastric cancer cells by targeting inhibition of ZEB1. Clin Transl Oncol (2020). https://doi.org/10.1007/s12094-020-02436-1

Download citation

Keywords

  • miR-144-3p
  • ZEB1
  • Gastric cancer
  • Radiosensitivity