Skip to main content

Advertisement

Log in

miR-488 acts as a tumor suppressor gene in gastric cancer

  • Original Article
  • Published:
Tumor Biology

Abstract

MicroRNAs (miRNAs) are small, non-coding RNAs that modulate development, cell proliferation, and apoptosis. The deregulated expression of microRNAs is found in carcinogenesis including gastric cancer (GC). In this study, we showed that the expression levels of miR-488 were downregulated in GC tissues compared to in non-tumor tissues. In addition, the expression of miR-488 was also lower in GC cell lines in contrast with the gastric epithelial cell line (GES). In addition, the expression level of miR-488 was negatively correlated with the TNM stage in GC patients, and lower miR-488 expression was found in tumors with advanced TNM stage. The ectopic expression of miR-488 suppressed the GC cell proliferation, cell cycle, colony information, and migration. PAX6 was identified as a direct target gene of miR-488 in HGC-27. Moreover, we found that the expression level of PAX6 was upregulated in the GC tissues compared with the non-tumor tissues. The PAX6 expression level was correlated with the cancer TNM stage, and higher PAX6 expression was found in tumors with advanced TNM stage. Furthermore, there was an inverse correlation between PAX6 and miR-488 expression levels in GC tissues. Therefore, these studies demonstrated that miR-488 might act as a tumor suppressor miRNA in the development of GC.

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

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

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

Similar content being viewed by others

References

  1. Zhu A, Xia J, Zuo J, Jin S, Zhou H, Yao L, et al. Microrna-148a is silenced by hypermethylation and interacts with DNA methyltransferase 1 in gastric cancer. Med Oncol. 2012;29:2701–9.

    Article  CAS  PubMed  Google Scholar 

  2. Zheng Y, Cui L, Sun W, Zhou H, Yuan X, Huo M, et al. Microrna-21 is a new marker of circulating tumor cells in gastric cancer patients. Cancer Biomark: Section A Dis Markers. 2011;10:71–7.

    Article  CAS  Google Scholar 

  3. Wu Y, Tao Y, Chen Y, Xu W. Rhoc regulates the proliferation of gastric cancer cells through interaction with iqgap1. PLoS One. 2012;7, e48917.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Tsai KW, Hu LY, Wu CW, Li SC, Lai CH, Kao HW, et al. Epigenetic regulation of mir-196b expression in gastric cancer. Genes Chromosomes Cancer. 2010;49:969–80.

    Article  CAS  PubMed  Google Scholar 

  5. Calcagno DQ, de Arruda Cardoso Smith M, Burbano RR. Cancer type-specific epigenetic changes: gastric cancer. Methods Mol Biol. 2015;1238:79–101.

    Article  PubMed  Google Scholar 

  6. Liang J, Liu X, Xue H, Qiu B, Wei B, Sun K. Microrna-103a inhibits gastric cancer cell proliferation, migration and invasion by targeting c-myb. Cell Prolif. 2015;48:78–85.

    Article  CAS  PubMed  Google Scholar 

  7. Bin Z, Dedong H, Xiangjie F, Hongwei X, Qinghui Y. The microrna-367 inhibits the invasion and metastasis of gastric cancer by directly repressing rab23. Genet Test Mol Biomarkers. 2015;19:69–74.

    Article  CAS  PubMed  Google Scholar 

  8. Zhang D, Xiao YF, Zhang JW, Xie R, Hu CJ, Tang B, et al. Mir-1182 attenuates gastric cancer proliferation and metastasis by targeting the open reading frame of htert. Cancer Lett. 2015;360:151–9.

    Article  CAS  PubMed  Google Scholar 

  9. Wang GJ, Liu GH, Ye YW, Fu Y, Zhang XF. The role of microrna-1274a in the tumorigenesis of gastric cancer: accelerating cancer cell proliferation and migration via directly targeting foxo4. Biochemical and biophysical research communications. 2015.

  10. Shen J, Niu W, Zhou M, Zhang H, Ma J, Wang L. Microrna-410 suppresses migration and invasion by targeting mdm2 in gastric cancer. PLoS One. 2014;9, e104510.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Li R, Yuan W, Mei W, Yang K, Chen Z. Microrna 520d-3p inhibits gastric cancer cell proliferation, migration, and invasion by downregulating epha2 expression. Mol Cell Biochem. 2014;396:295–305.

    Article  CAS  PubMed  Google Scholar 

  12. Fu Z, Qian F, Yang X, Jiang H, Chen Y, Liu S. Circulating mir-222 in plasma and its potential diagnostic and prognostic value in gastric cancer. Med Oncol. 2014;31:164.

    Article  PubMed  Google Scholar 

  13. Shin VY, Chu KM. Mirna as potential biomarkers and therapeutic targets for gastric cancer. World J Gastroenterol. 2014;20:10432–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Liu HS, Xiao HS. Micrornas as potential biomarkers for gastric cancer. World J Gastroenterol. 2014;20:12007–17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Yu X, Li Z, Yu J, Chan MT, Wu WK. Micrornas predict and modulate responses to chemotherapy in colorectal cancer. Cell Prolif. 2015;48:503–10.

    Article  CAS  PubMed  Google Scholar 

  16. Li Z, Yu X, Shen J, Liu Y, Chan MT, Wu WK. Microrna dysregulation in rhabdomyosarcoma: a new player enters the game. Cell Prolif. 2015;48:511–6.

    Article  CAS  PubMed  Google Scholar 

  17. Yu X, Li Z, Shen J, Wu WK, Liang J, Weng X, et al. Microrna-10b promotes nucleus pulposus cell proliferation through rhoc-akt pathway by targeting hoxd10 in intervetebral disc degeneration. PLoS One. 2013;8, e83080.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Yang Z, Han Y, Cheng K, Zhang G, Wang X. Mir-99a directly targets the mtor signalling pathway in breast cancer side population cells. Cell Prolif. 2014;47:587–95.

    Article  CAS  PubMed  Google Scholar 

  19. Bier A, Giladi N, Kronfeld N, Lee HK, Cazacu S, Finniss S, et al. Microrna-137 is downregulated in glioblastoma and inhibits the stemness of glioma stem cells by targeting rtvp-1. Oncotarget. 2013;4:665–76.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Lee HK, Finniss S, Cazacu S, Bucris E, Ziv-Av A, Xiang C, et al. Mesenchymal stem cells deliver synthetic microrna mimics to glioma cells and glioma stem cells and inhibit their cell migration and self-renewal. Oncotarget. 2013;4:346–61.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Wang Z, Wang N, Liu P, Chen Q, Situ H, Xie T, Zhang J, Peng C, Lin Y, Chen J. Microrna-25 regulates chemoresistance-associated autophagy in breast cancer cells, a process modulated by the natural autophagy inducer isoliquiritigenin. Oncotarget. 2014.

  22. Fu LL, Yang Y, Xu HL, Cheng Y, Wen X, Ouyang L, et al. Identification of novel caspase/autophagy-related gene switch to cell fate decisions in breast cancers. Cell Prolif. 2013;46:67–75.

    Article  CAS  PubMed  Google Scholar 

  23. Xiao Z, Li CH, Chan SL, Xu F, Feng L, Wang Y, Jiang JD, Sung JJ, Cheng CH, Chen Y. A small molecule modulator of the tumor suppressor mirna-34a inhibits the growth of hepatocellular carcinoma. Cancer Res. 2014.

  24. Song Q, Xu Y, Yang C, Chen Z, Jia C, Chen J, et al. Mir-483-5p promotes invasion and metastasis of lung adenocarcinoma by targeting rhogdi1 and alcam. Cancer Res. 2014;74:3031–42.

    Article  CAS  PubMed  Google Scholar 

  25. Li Z, Yu X, Shen J, Wu WK, Chan MT. Microrna expression and its clinical implications in Ewing’s sarcoma. Cell Prolif. 2015;48:1–6.

    Article  PubMed  Google Scholar 

  26. Chow TF, Mankaruos M, Scorilas A, Youssef Y, Girgis A, Mossad S, et al. The mir-17-92 cluster is over expressed in and has an oncogenic effect on renal cell carcinoma. J Urol. 2010;183:743–51.

    Article  CAS  PubMed  Google Scholar 

  27. Chakravarthi BV, Pathi SS, Goswami MT, Cieslik M, Zheng H, Nallasivam S, et al. The mir-124-prolyl hydroxylase p4ha1-mmp1 axis plays a critical role in prostate cancer progression. Oncotarget. 2014;5:6654–69.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Li Z, Lei H, Luo M, Wang Y, Dong L, Ma Y, et al. DNA methylation downregulated mir-10b acts as a tumor suppressor in gastric cancer. Gastric Cancer: Off J Int Gastric Cancer Assoc Jpn Gastric Cancer Assoc. 2015;18:43–54.

    Article  CAS  Google Scholar 

  29. Li Z, Yu X, Wang Y, Shen J, Wu WK, Liang J, et al. By downregulating tiam1 expression, microrna-329 suppresses gastric cancer invasion and growth. Oncotarget. 2015;6:17559–69.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Perilli L, Vicentini C, Agostini M, Pizzini S, Pizzi M, D’Angelo E, et al. Circulating mir-182 is a biomarker of colorectal adenocarcinoma progression. Oncotarget. 2014;5:6611–9.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Huang J, Zhang SY, Gao YM, Liu YF, Liu YB, Zhao ZG, et al. Micrornas as oncogenes or tumour suppressors in oesophageal cancer: potential biomarkers and therapeutic targets. Cell Prolif. 2014;47:277–86.

    Article  CAS  PubMed  Google Scholar 

  32. Li M, Yu M, Liu C, Zhu H, He X, Peng S, et al. Mir-34c works downstream of p53 leading to dairy goat male germline stem-cell (mgscs) apoptosis. Cell Prolif. 2013;46:223–31.

    Article  CAS  PubMed  Google Scholar 

  33. Muinos-Gimeno M, Espinosa-Parrilla Y, Guidi M, Kagerbauer B, Sipila T, Maron E, et al. Human micrornas mir-22, mir-138-2, mir-148a, and mir-488 are associated with panic disorder and regulate several anxiety candidate genes and related pathways. Biol Psychiatry. 2011;69:526–33.

    Article  CAS  PubMed  Google Scholar 

  34. Patnaik SK, Kannisto E, Knudsen S, Yendamuri S. Evaluation of microrna expression profiles that may predict recurrence of localized stage I non-small cell lung cancer after surgical resection. Cancer Res. 2010;70:36–45.

    Article  CAS  PubMed  Google Scholar 

  35. Tong HX, Zhou YH, Hou YY, Zhang Y, Huang Y, Xie B, et al. Expression profile of micrornas in gastrointestinal stromal tumors revealed by high throughput quantitative rt-pcr microarray. World J Gastroenterol. 2015;21:5843–55.

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Liu Y, Guo R, Hao G, Xiao J, Bao Y, Zhou J, et al. The expression profiling and ontology analysis of noncoding rnas in peritoneal fibrosis induced by peritoneal dialysis fluid. Gene. 2015;564:210–9.

    Article  CAS  PubMed  Google Scholar 

  37. de Cubas AA, Leandro-Garcia LJ, Schiavi F, Mancikova V, Comino-Mendez I, Inglada-Perez L, et al. Integrative analysis of mirna and mrna expression profiles in pheochromocytoma and paraganglioma identifies genotype-specific markers and potentially regulated pathways. Endocr Relat Cancer. 2013;20:477–93.

    Article  PubMed  Google Scholar 

  38. Sikand K, Slaibi JE, Singh R, Slane SD, Shukla GC. Mir 488* inhibits androgen receptor expression in prostate carcinoma cells. Int J Cancer. 2011;129:810–9.

    Article  CAS  PubMed  Google Scholar 

  39. Song J, Kim D, Lee CH, Lee MS, Chun CH, Jin EJ. Microrna-488 regulates zinc transporter slc39a8/zip8 during pathogenesis of osteoarthritis. J Biomed Sci. 2013;20:31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Mishra S, Maurya SK, Srivastava K, Shukla S, Mishra R. Pax6 influences expression patterns of genes involved in neuro- degeneration. Ann Neurosci. 2015;22:226–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Thomas MG, Welch C, Stone L, Allan P, Barker RA, White RB. Pax6 expression may be protective against dopaminergic cell loss in Parkinson’s disease. CNS & neurological disorders drug targets. 2015.

  42. Manuel MN, Mi D, Mason JO, Price DJ. Regulation of cerebral cortical neurogenesis by the pax6 transcription factor. Front Cell Neurosci. 2015;9:70.

    PubMed  PubMed Central  Google Scholar 

  43. Huettl RE, Eckstein S, Stahl T, Petricca S, Ninkovic J, Gotz M, Huber AB. Functional dissection of the pax6 paired domain: roles in neural tube patterning and peripheral nervous system development. Dev Biol. 2015.

  44. Lai JP, Mertens RB, Mirocha J, Koo J, Venturina M, Chung F, et al. Comparison of pax6 and pax8 as immunohistochemical markers for pancreatic neuroendocrine tumors. Endocr Pathol. 2015;26:54–62.

    Article  CAS  PubMed  Google Scholar 

  45. Shubham K, Mishra R. Pax6 interacts with sparc and tgf-beta in murine eyes. Mol Vis. 2012;18:951–6.

    PubMed  PubMed Central  Google Scholar 

  46. Bai SW, Li B, Zhang H, Jonas JB, Zhao BW, Shen L, et al. Pax6 regulates proliferation and apoptosis of human retinoblastoma cells. Invest Ophthalmol Vis Sci. 2011;52:4560–70.

    Article  CAS  PubMed  Google Scholar 

  47. van Bever Y, van Hest L, Wolfs R, Tibboel D, van den Hoonaard TL, Gischler SJ. Exclusion of a pax6, foxc1, pitx2, and mycn mutation in another patient with apple peel intestinal atresia, ocular anomalies and microcephaly and review of the literature. Am J Med Genet A. 2008;146A:500–4.

    Article  PubMed  Google Scholar 

  48. Meng Y, Zou Q, Liu T, Cai X, Huang Y, Pan J. Microrna-335 inhibits proliferation, cell-cycle progression, colony formation, and invasion via targeting pax6 in breast cancer cells. Mol Med Rep. 2015;11:379–85.

    CAS  PubMed  Google Scholar 

  49. Shahi MH, Afzal M, Sinha S, Eberhart CG, Rey JA, Fan X, et al. Regulation of sonic hedgehog-gli1 downstream target genes ptch1, cyclin d2, plakoglobin, pax6 and nkx2.2 and their epigenetic status in medulloblastoma and astrocytoma. BMC Cancer. 2010;10:614.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Zhao X, Yue W, Zhang L, Ma L, Jia W, Qian Z, et al. Downregulation of pax6 by shrna inhibits proliferation and cell cycle progression of human non-small cell lung cancer cell lines. PLoS One. 2014;9, e85738.

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding authors

Correspondence to Mudan Ren or Shuixiang He.

Ethics declarations

Conflicts of interest

None

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zhao, Y., Lu, G., Ke, X. et al. miR-488 acts as a tumor suppressor gene in gastric cancer. Tumor Biol. 37, 8691–8698 (2016). https://doi.org/10.1007/s13277-015-4645-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13277-015-4645-y

Keywords

Navigation