miR‑144 suppresses cell proliferation and invasion in gastric cancer through downregulation of activating enhancer‑binding protein 4

  • Authors:
    • Faheim Mushtaq
    • Jinping Zhang
    • Jiansheng Li
  • View Affiliations

  • Published online on: April 4, 2019     https://doi.org/10.3892/ol.2019.10214
  • Pages: 5686-5692
Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )
Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )


Abstract

Gastric cancer (GC) is the most common malignant disease and its incidence rate is increasing rapidly worldwide. The molecular mechanisms underlying GC tumorigenesis require further investigation. The expression and physiological roles of microRNA‑144 (miR‑144) have been investigated in numerous types of tumor. However, its biological function in GC remains largely unknown. The reverse transcription‑​quantitative polymerase chain reaction was used to determine the expression of miR‑144 in GC cells and normal gastric epithelial cells. An miR‑144 mimic was transfected into HGC‑27 cells. In addition, bioinformatics analysis was performed to identify the potential targets of miR‑144. Protein expression, luciferase and rescue assays were used to confirm the target of miR‑144. It was identified that the expression of miR‑144 was significantly downregulated in GC cells compared with in normal gastric epithelial cells. Furthermore, overexpression of miR‑144 suppressed HGC‑27 cell proliferation, migration and invasion. Additionally, bioinformatics analysis suggested that the activating enhancer‑binding protein 4 (AP4) is a target gene of miR‑144. In addition, it was determined that miR‑144 suppresses the expression of AP4 by binding directly to its 3'‑untranslated regions. Furthermore, restoration of AP4 partially attenuated miR‑144‑induced inhibition of cell proliferation, migration and invasion. Therefore, the results of the present study suggest that miR‑144 serves an important role in GC progression.

References

1 

Global Burden of Disease Cancer Collaboration, Fitzmaurice C, Allen C, Barber RM, Barregard L, Bhutta ZA, Brenner H, Dicker DJ, Chimed-Orchir O, Dandona R, et al: Global, regional, and national cancer incidence, mortality, years of life lost, years lived with disability, and disability-adjusted life-years for 32 cancer groups, 1990 to 2015: A systematic analysis for the global burden of disease study. JAMA Oncol. 3:524–548. 2017. View Article : Google Scholar : PubMed/NCBI

2 

Ambros V: microRNAs: Tiny regulators with great potential. Cell. 107:823–826. 2001. View Article : Google Scholar : PubMed/NCBI

3 

Ke XS, Liu CM, Liu DP and Liang CC: MicroRNAs: Key participants in gene regulatory networks. Curr Opin Chem Biol. 7:516–523. 2003. View Article : Google Scholar : PubMed/NCBI

4 

Ueda T, Volinia S, Okumura H, Shimizu M, Taccioli C, Rossi S, Alder H, Liu CG, Oue N, Yasui W, et al: Relation between microRNA expression and progression and prognosis of gastric cancer: A microRNA expression analysis. Lancet Oncol. 11:136–146. 2010. View Article : Google Scholar : PubMed/NCBI

5 

Guo J, Miao Y, Xiao B, Huan R, Jiang Z, Meng D and Wang Y: Differential expression of microRNA species in human gastric cancer versus non-tumorous tissues. J Gastroenterol Hepatol. 24:652–657. 2009. View Article : Google Scholar : PubMed/NCBI

6 

Pan Y, Zhang J, Fu H and Shen L: miR-144 functions as a tumor suppressor in breast cancer through inhibiting ZEB1/2-mediated epithelial mesenchymal transition process. Onco Targets Ther. 9:6247–6255. 2016. View Article : Google Scholar : PubMed/NCBI

7 

Iwaya T, Yokobori T, Nishida N, Kogo R, Sudo T, Tanaka F, Shibata K, Sawada G, Takahashi Y, Ishibashi M, et al: Downregulation of miR-144 is associated with colorectal cancer progression via activation of mTOR signaling pathway. Carcinogenesis. 33:2391–2397. 2012. View Article : Google Scholar : PubMed/NCBI

8 

Zha W, Cao L, Shen Y and Huang M: Roles of Mir-144-ZFX pathway in growth regulation of non-small-cell lung cancer. PLoS One. 8:e741752013. View Article : Google Scholar : PubMed/NCBI

9 

Zhao M, Huang J, Gui K, Xiong M, Cai G, Xu J, Wang K, Liu D, Zhang X and Yin W: The downregulation of miR-144 is associated with the growth and invasion of osteosarcoma cells through the regulation of TAGLN expression. Int J Mol Med. 34:1565–1572. 2014. View Article : Google Scholar : PubMed/NCBI

10 

Guan H, Liang W, Xie Z, Li H, Liu J, Liu L, Xiu L and Li Y: Down-regulation of miR-144 promotes thyroid cancer cell invasion by targeting ZEB1 and ZEB2. Endocrine. 48:566–574. 2015. View Article : Google Scholar : PubMed/NCBI

11 

Zhou S, Ye W, Zhang Y, Yu D, Shao Q, Liang J and Zhang M: miR-144 reverses chemoresistance of hepatocellular carcinoma cell lines by targeting Nrf2-dependent antioxidant pathway. Am J Transl Res. 8:2992–3002. 2016.PubMed/NCBI

12 

Guo Y, Ying L, Tian Y, Yang P, Zhu Y, Wang Z, Qiu F and Lin J: miR-144 downregulation increases bladder cancer cell proliferation by targeting EZH2 and regulating Wnt signaling. FEBS J. 280:4531–4538. 2013. View Article : Google Scholar : PubMed/NCBI

13 

Sureban SM, May R, Mondalek FG, Qu D, Ponnurangam S, Pantazis P, Anant S, Ramanujam RP and Houchen CW: Nanoparticle-based delivery of siDCAMKL-1 increases microRNA-144 and inhibits colorectal cancer tumor growth via a Notch-1 dependent mechanism. J Nanobiotechnology. 9:402011. View Article : Google Scholar : PubMed/NCBI

14 

Zhang LY, Ho-Fun Lee V, Wong AM, Kwong DL, Zhu YH, Dong SS, Kong KL, Chen J, Tsao SW, Guan XY and Fu L: MicroRNA-144 promotes cell proliferation, migration and invasion in nasopharyngeal carcinoma through repression of PTEN. Carcinogenesis. 34:454–463. 2012. View Article : Google Scholar : PubMed/NCBI

15 

Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI

16 

Lewis BP, Burge CB and Bartel DP: Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets. Cell. 120:15–20. 2005. View Article : Google Scholar : PubMed/NCBI

17 

Enright AJ, John B, Gaul U, Tuschl T, Sander C and Marks DS: MicroRNA targets in Drosophila. Genome Biol. 5:R12003. View Article : Google Scholar : PubMed/NCBI

18 

Akiyoshi S, Fukagawa T, Ueo H, Ishibashi M, Takahashi Y, Fabbri M, Sasako M, Maehara Y, Mimori K and Mori M: Clinical significance of miR-144-ZFX axis in disseminated tumour cells in bone marrow in gastric cancer cases. Br J Cancer. 107:13452012. View Article : Google Scholar : PubMed/NCBI

19 

Liu J, Xue H, Zhang J, Suo T, Xiang Y, Zhang W, Ma J, Cai D and Gu X: MicroRNA-144 inhibits the metastasis of gastric cancer by targeting MET expression. J Exp Clin Cancer Res. 34:352015. View Article : Google Scholar : PubMed/NCBI

20 

Kim CH, Kim HK, Rettig RL, Kim J, Lee ET, Aprelikova O, Choi IJ, Munroe DJ and Green JE: miRNA signature associated with outcome of gastric cancer patients following chemotherapy. BMC Med Genomics. 4:792011. View Article : Google Scholar : PubMed/NCBI

21 

Hu YF, Lüscher B, Admon A, Mermod N and Tjian R: Transcription factor AP4 contains multiple dimerization domains that regulate dimer specificity. Genes Dev. 4:1741–1752. 1990. View Article : Google Scholar : PubMed/NCBI

22 

Edmondson DG and Olson EN: A gene with homology to the myc similarity region of MyoD1 is expressed during myogenesis and is sufficient to activate the muscle differentiation program. Genes Dev. 3:628–640. 1989. View Article : Google Scholar : PubMed/NCBI

23 

Murre C, McCaw PS and Baltimore D: A new DNA binding and dimerization motif in immunoglobulin enhancer binding, daughterless, MyoD, and myc proteins. Cell. 56:777–783. 1989. View Article : Google Scholar : PubMed/NCBI

24 

Jung P and Hermeking H: The c-MYC-AP4-p21 cascade. Cell Cycle. 8:982–989. 2009. View Article : Google Scholar : PubMed/NCBI

25 

Tsujimoto K, Ono T, Sato M, Nishida T, Oguma T and Tadakuma T: Regulation of the expression of caspase-9 by the transcription factor activator protein-4 in glucocorticoid-induced apoptosis. J Biol Chem. 280:27638–27644. 2005. View Article : Google Scholar : PubMed/NCBI

26 

Kim MY, Jeong BC, Lee JH, Kee HJ, Kook H, Kim NS, Kim YH, Kim JK, Ahn KY and Kim KK: A repressor complex, AP4 transcription factor and geminin, negatively regulates expression of target genes in nonneuronal cells. Proc Natl Acad Sci USA. 103:13074–13079. 2006. View Article : Google Scholar : PubMed/NCBI

27 

Cao J, Tang M, Li WL, Xie J, Du H, Tang WB, Wang H, Chen XW, Xiao H and Li Y: Upregulation of activator protein-4 in human colorectal cancer with metastasis. Int J Surg Pathol. 17:16–21. 2009. View Article : Google Scholar : PubMed/NCBI

28 

Lin T, et al: Identification of Transcription Factor AP4 as the Regulator that Upregulates the Expression of L-plastin in Hormone-Independent Prostate Cancer. J Sun Yat-Sen Univ (Med Sci). 19–23. 2006.

29 

Buechler S: Low expression of a few genes indicates good prognosis in estrogen receptor positive breast cancer. BMC Cancer. 9:2432009. View Article : Google Scholar : PubMed/NCBI

30 

Xinghua L, Bo Z, Yan G, Lei W, Changyao W, Qi L, Lin Y, Kaixiong T, Guobin W and Jianying C: The overexpression of AP4 as a prognostic indicator for gastric carcinoma. Med Oncol. 29:871–877. 2012. View Article : Google Scholar : PubMed/NCBI

31 

Jung P, Menssen A, Mayr D and Hermeking H: AP4 encodes a c-MYC-inducible repressor of p21. Proc Natl Acad Sci USA. 105:15046–15051. 2008. View Article : Google Scholar : PubMed/NCBI

Related Articles

Journal Cover

June 2019
Volume 17 Issue 6

Print ISSN: 1792-1074
Online ISSN:1792-1082

Sign up for eToc alerts

Recommend to Library

Copy and paste a formatted citation
APA
Mushtaq, F., Zhang, J., & Li, J. (2019). miR‑144 suppresses cell proliferation and invasion in gastric cancer through downregulation of activating enhancer‑binding protein 4. Oncology Letters, 17, 5686-5692. https://doi.org/10.3892/ol.2019.10214
MLA
Mushtaq, F., Zhang, J., Li, J."miR‑144 suppresses cell proliferation and invasion in gastric cancer through downregulation of activating enhancer‑binding protein 4". Oncology Letters 17.6 (2019): 5686-5692.
Chicago
Mushtaq, F., Zhang, J., Li, J."miR‑144 suppresses cell proliferation and invasion in gastric cancer through downregulation of activating enhancer‑binding protein 4". Oncology Letters 17, no. 6 (2019): 5686-5692. https://doi.org/10.3892/ol.2019.10214