Advertisement

Tumor Biology

, Volume 37, Issue 2, pp 1771–1779 | Cite as

miR-335 directly, while miR-34a indirectly modulate survivin expression and regulate growth, apoptosis, and invasion of gastric cancer cells

  • Bairen Yang
  • Jun Huang
  • Hao Liu
  • Weichang Guo
  • Guoxin Li
Original Article

Abstract

miR-335 and miR-34a are two microRNAs (miRNAs) usually downregulated in gastric cancer (GC). But, their exact regulative roles were not fully elucidated. In this study, we studied the association between miR-335 and/or miR-34a expression and overall survival of GC patients and explored the regulative role of miR-335 and -34a over survivin expression and GC cell growth and invasion. Fifty patients with GC were regularly followed up from 2011 to 2015. miRNA microarray was used to examine the expression trend of miRNAs in eight tumor tissue samples and adjacent normal tissue samples. The possible binding site between miR-335 and survivin messenger RNA (mRNA) was predicted using online database and verified using qRT-PCR, Western blot, and dual luciferase assay. The regulative role of miR-335 and miR-34a over GC cell growth, apoptosis, and invasion was studied using Cell Counting Kit-8 (CCK-8) assay, flow cytometry, and transwell assay, respectively. Among the GC patients, low miR-335 or miR-34a expression is associated with higher clinical stage and lymph node metastasis. Patients with low miR-335 or miR-34a had poor overall survival, while those with combined low miR-335 and miR-34a expression had even poorer overall survival. miR-335 can directly regulate survivin expression through binding to the 3′UTR, while miR-34a has indirect modulating effect. Both miR-335 and miR-34a could inhibit cell proliferation and invasion and enhance cell apoptosis. But, these effects are largely abrogated by overexpression of survivin without 3′UTR. Therefore, besides the targets identified in previous studies, miR-335 and miR-34a can also regulate GC cell growth, apoptosis, and invasion at least partly through survivin.

Keywords

miR-335 miR-34a Gastric cancer Survivin 

Notes

Conflicts of interest

None

References

  1. 1.
    Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin. 2011;61:69–90.CrossRefPubMedGoogle Scholar
  2. 2.
    Pharoah PD, Dunning AM, Ponder BA, Easton DF. Association studies for finding cancer-susceptibility genetic variants. Nat Rev Cancer. 2004;4:850–60.CrossRefPubMedGoogle Scholar
  3. 3.
    Bartel DP. Micrornas: genomics, biogenesis, mechanism, and function. Cell. 2004;116:281–97.CrossRefPubMedGoogle Scholar
  4. 4.
    Cui L, Zhang X, Ye G, Zheng T, Song H, Deng H, et al. Gastric juice micrornas as potential biomarkers for the screening of gastric cancer. Cancer. 2013;119:1618–26.CrossRefPubMedGoogle Scholar
  5. 5.
    Konishi H, Ichikawa D, Komatsu S, Shiozaki A, Tsujiura M, Takeshita H, et al. Detection of gastric cancer-associated micrornas on microrna microarray comparing pre- and post-operative plasma. Br J Cancer. 2012;106:740–7.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Zhang M, Wang X, Li W, Cui Y. Mir-107 and mir-25 simultaneously target lats2 and regulate proliferation and invasion of gastric adenocarcinoma (gac) cells. Biochem Biophys Res Commun. 2015;460:806–12.CrossRefPubMedGoogle Scholar
  7. 7.
    Xu Y, Zhao F, Wang Z, Song Y, Luo Y, Zhang X, et al. Microrna-335 acts as a metastasis suppressor in gastric cancer by targeting bcl-w and specificity protein 1. Oncogene. 2012;31:1398–407.CrossRefPubMedGoogle Scholar
  8. 8.
    Peng Y, Guo JJ, Liu YM, Wu XL. Microrna-34a inhibits the growth, invasion and metastasis of gastric cancer by targeting pdgfr and met expression. Biosci. Rep. 2014;34.Google Scholar
  9. 9.
    Altieri DC. Survivin, cancer networks and pathway-directed drug discovery. Nat Rev Cancer. 2008;8:61–70.CrossRefPubMedGoogle Scholar
  10. 10.
    Sah NK, Khan Z, Khan GJ, Bisen PS. Structural, functional and therapeutic biology of survivin. Cancer Lett. 2006;244:164–71.CrossRefPubMedGoogle Scholar
  11. 11.
    Chen J, Li T, Liu Q, Jiao H, Yang W, Liu X, et al. Clinical and prognostic significance of hif-1alpha, pten, cd44v6, and survivin for gastric cancer: a meta-analysis. PLoS One. 2014;9:e91842.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Krieg A, Werner TA, Verde PE, Stoecklein NH, Knoefel WT. Prognostic and clinicopathological significance of survivin in colorectal cancer: a meta-analysis. PLoS One. 2013;8:e65338.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Kumar B, Yadav A, Lang J, Teknos TN, Kumar P. Dysregulation of microrna-34a expression in head and neck squamous cell carcinoma promotes tumor growth and tumor angiogenesis. PLoS One. 2012;7:e37601.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Geng D, Song X, Ning F, Song Q, Yin H. Mir-34a inhibits viability and invasion of human papillomavirus-positive cervical cancer cells by targeting e2f3 and regulating survivin. Int J Gynecol Cancer Off J Int Gynecol Cancer Soc. 2015.Google Scholar
  15. 15.
    Li H, Xie S, Liu M, Chen Z, Liu X, Wang L, et al. The clinical significance of downregulation of mir-124-3p, mir-146a-5p, mir-155-5p and mir-335-5p in gastric cancer tumorigenesis. Int J Oncol. 2014;45:197–208.PubMedGoogle Scholar
  16. 16.
    Cao W, Fan R, Wang L, Cheng S, Li H, Jiang J, et al. Expression and regulatory function of mirna-34a in targeting survivin in gastric cancer cells. Tumour Biol J Int Soc Oncodev Biol Med. 2013;34:963–71.CrossRefGoogle Scholar
  17. 17.
    Li Z, Li D, Zhang G, Xiong J, Jie Z, Cheng H, et al. Methylation-associated silencing of microrna-335 contributes tumor cell invasion and migration by interacting with rasa1 in gastric cancer. Am J Cancer Res. 2014;4:648–62.PubMedPubMedCentralGoogle Scholar
  18. 18.
    Cao W, Yang W, Fan R, Li H, Jiang J, Geng M, et al. Mir-34a regulates cisplatin-induce gastric cancer cell death by modulating pi3k/akt/survivin pathway. Tumour Biol J Int Soc Oncodev Biol Med. 2014;35:1287–95.CrossRefGoogle Scholar
  19. 19.
    Fukuda S, Pelus LM. Survivin, a cancer target with an emerging role in normal adult tissues. Mol Cancer Ther. 2006;5:1087–98.CrossRefPubMedGoogle Scholar
  20. 20.
    Yamamoto H, Ngan CY, Monden M. Cancer cells survive with survivin. Cancer Sci. 2008;99:1709–14.CrossRefPubMedGoogle Scholar
  21. 21.
    Liu Z, Zhang X, Xu X, Chen L, Li W, Yu H, et al. Runx3 inhibits survivin expression and induces cell apoptosis in gastric cancer. Eur J Cell Biol. 2014;93:118–26.CrossRefPubMedGoogle Scholar
  22. 22.
    Sun XP, Dong X, Lin L, Jiang X, Wei Z, Zhai B, et al. Up-regulation of survivin by akt and hypoxia-inducible factor 1alpha contributes to cisplatin resistance in gastric cancer. FEBS J. 2014;281:115–28.CrossRefPubMedGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2015

Authors and Affiliations

  • Bairen Yang
    • 1
    • 2
  • Jun Huang
    • 2
  • Hao Liu
    • 1
  • Weichang Guo
    • 2
  • Guoxin Li
    • 1
  1. 1.Department of General Surgery, Nanfang HospitalSouthern Medical UniversityGuangzhouChina
  2. 2.Department of General SurgeryThe First People’s Hospital of YibinYibinChina

Personalised recommendations