Tumor Biology

, Volume 37, Issue 5, pp 6801–6812 | Cite as

Upregulated expression of long noncoding RNA SNHG15 promotes cell proliferation and invasion through regulates MMP2/MMP9 in patients with GC

Original Article

Abstract

Accumulation of data indicates that misregulated long noncoding RNAs (lncRNAs) are implicated in cancer tumorigenesis and progression and might be served as diagnosis and prognosis biomarker or potential therapeutic targets. Identification of cancer-associated lncRNAs and investigation of their biological functions and molecular mechanisms are significant for understanding the development and progression of cancer. In this study, we identified a novel lncRNA SNHG15, whose expression was upregulated in tumor tissues in 106 patients with gastric cancer (GC) compared with those in the adjacent normal tissues (P < 0.001). Furthermore, increased SNHG15 expression was positively correlated with invasion depth (P < 0.001), advanced tumor node metastasis (TNM) stage (P = 0.001), and lymph node metastasis (P = 0.019). SNHG15 levels were robust in differentiating GC tissues from controls (area under the curve (AUC) = 0.722; 95 % confidence interval (CI) = 0.657–0.782, P < 0.01). Kaplan–Meier analysis demonstrated that elevated SNHG15 expression contributed to poor overall survival (P < 0.01) and disease-free survival (P < 0.01) of patients. A multivariate survival analysis also indicated that SNHG15 could be an independent prognostic marker. Furthermore, knockdown of SNHG15 expression by siRNA could inhibit cell proliferation and invasion and induce apoptosis, while ectopic expression of SNHG15 promoted cell proliferation and invasion in GC cells partly via regulating MMP2 and MMP9 protein expression. Our findings present that elevated lncRNA SNHG15 could be identified as a poor prognostic biomarker in GC and regulate cell invasion.

Keywords

Long noncoding RNA SNHG15 Gastric cancer Clinical relevance 

Notes

Compliance with ethical standards

The study was approved by the Ethics Committee on Human Research of the First Affiliated Hospital of Wenzhou Medical University and Yangzhou No.1 People’s Hospital, and written informed consent was obtained from all patients.

Conflicts of interest

None

Supplementary material

13277_2015_4404_MOESM1_ESM.xls (16 kb)
Suppl. Table S1 (XLS 16 kb)

References

  1. 1.
    Moore MA, Attasara P, Khuhaprema T, Le TN, Nguyen TH, Raingsey PP, et al. Cancer epidemiology in mainland South-East Asia—past, present and future. Asian Pac J Cancer Prev. 2010;11 Suppl 2:67–80.PubMedGoogle Scholar
  2. 2.
    Jemal A, Siegel R, Xu J, Ward E. Cancer statistics, 2010. CA Cancer J Clin. 2010;60:277–300.CrossRefPubMedGoogle Scholar
  3. 3.
    Sapari NS, Loh M, Vaithilingam A, Soong R. Clinical potential of DNA methylation in gastric cancer: a meta-analysis. Plos One. 2012;7:e36275.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Milne AN, Carneiro F, O’Morain C, Offerhaus GJA. Nature meets nurture: molecular genetics of gastric cancer. Hum Genet. 2009;126:615–28.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Muers M. RNA genome-wide views of long non-coding RNAs. Nat Rev Genet. 2011;12:742.CrossRefPubMedGoogle Scholar
  6. 6.
    Ponting CP, Oliver PL, Reik W. Evolution and functions of long noncoding RNAs. Cell. 2009;136:629–41.CrossRefPubMedGoogle Scholar
  7. 7.
    Rinn JL, Kertesz M, Wang JK, Squazzo SL, Xu X, Brugmann SA, et al. Functional demarcation of active and silent chromatin domains in human HOX loci by noncoding RNAs. Cell. 2007;129:1311–23.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Hirata H, Hinoda Y, Shahryari V, Deng GR, Nakajima K, Tabatabai ZL, et al. Long noncoding RNA MALAT1 promotes aggressive renal cell carcinoma through Ezh2 and interacts with miR-205. Cancer Res. 2015;75:1322–31.CrossRefPubMedGoogle Scholar
  9. 9.
    Okugawa Y, Toiyama Y, Hur K, Toden S, Saigusa S, Tanaka K, et al. Metastasis-associated long non-coding RNA drives gastric cancer development and promotes peritoneal metastasis. Carcinogenesis. 2014;35:2731–9.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Sun M, Jin FY, Xia R, Kong R, Li JH, Xu TP, et al. Decreased expression of long noncoding RNA GAS5 indicates a poor prognosis and promotes cell proliferation in gastric cancer. BMC Cancer. 2014;14:319.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Sun M, Xia R, Jin FY, Xu TP, Liu ZJ, De W, et al. Downregulated long noncoding RNA MEG3 is associated with poor prognosis and promotes cell proliferation in gastric cancer. Tumor Biol. 2014;35:1065–73.CrossRefGoogle Scholar
  12. 12.
    Kong R, Zhang EB, Yin DD, You LH, Xu TP, Chen WM, et al. Long noncoding RNA PVT1 indicates a poor prognosis of gastric cancer and promotes cell proliferation through epigenetically regulating p15 and p16. Mol Cancer. 2015;14:82.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Qi P, Du X. The long non-coding RNAs, a new cancer diagnostic and therapeutic gold mine. Mod Pathol. 2013;26:155–65.CrossRefPubMedGoogle Scholar
  14. 14.
    Risueno A, Fontanillo C, Dinger ME, De Las Rivas J. GATExplorer: genomic and transcriptomic explorer; mapping expression probes to gene loci, transcripts, exons and ncRNAs. BMC Bioinformatics. 2010;11:221.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Pang KC, Stephen S, Dinger ME, Engstrom PG, Lenhard B, Mattick JS. RNAdb 2.0-an expanded database of mammalian non-coding RNAs. Nucleic Acids Res. 2007;35:D178–82.CrossRefPubMedGoogle Scholar
  16. 16.
    Gupta RA, Shah N, Wang KC, Kim J, Horlings HM, Wong DJ, et al. Long non-coding RNA HOTAIR reprograms chromatin state to promote cancer metastasis. Nature. 2010;464:1071–6.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Kotake Y, Nakagawa T, Kitagawa K, Suzuki S, Liu N, Kitagawa M, et al. Long non-coding RNA ANRIL is required for the PRC2 recruitment to and silencing of p15(INK4B) tumor suppressor gene. Oncogene. 2011;30:1956–62.CrossRefPubMedGoogle Scholar
  18. 18.
    Fan Y, Shen B, Tan M, Mu X, Qin Y, Zhang F, et al. TGF-beta-induced upregulation of malat1 promotes bladder cancer metastasis by associating with suz12. Clin Cancer Res: Off J Am Assoc Cancer Res. 2014;20:1531–41.CrossRefGoogle Scholar
  19. 19.
    Prensner JR, Chen W, Iyer MK, Cao Q, Ma T, Han S, et al. PCAT-1, a long noncoding RNA, regulates BRCA2 and controls homologous recombination in cancer. Cancer Res. 2014;74:1651–60.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Xu TP, Huang MD, Xia R, Liu XX, Sun M, Yin L, et al. Decreased expression of the long non-coding RNA FENDRR is associated with poor prognosis in gastric cancer and FENDRR regulates gastric cancer cell metastasis by affecting fibronectin1 expression. J Hematol Oncol. 2014;7:63.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Tani H, Torimura M. Identification of short-lived long non-coding RNAs as surrogate indicators for chemical stress response. Biochem Biophys Res Commun. 2013;439:547–51.CrossRefPubMedGoogle Scholar
  22. 22.
    Tani H, Torimura M. Development of cytotoxicity-sensitive human cells using overexpression of long non-coding RNAs. J Biosci Bioeng. 2015;119:604–8.CrossRefPubMedGoogle Scholar
  23. 23.
    Kessenbrock K, Plaks V, Werb Z. Matrix metalloproteinases: regulators of the tumor microenvironment. Cell. 2010;141:52–67.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Lynch CC. Matrix metalloproteinases as master regulators of the vicious cycle of bone metastasis. Bone. 2011;48:44–53.CrossRefPubMedGoogle Scholar
  25. 25.
    Hadler-Olsen E, Winberg J-O, Uhlin-Hansen L. Matrix metalloproteinases in cancer: their value as diagnostic and prognostic markers and therapeutic targets. Tumour Biol: J Int Soc Oncodev Biol Med. 2013;34:2041–51.CrossRefGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2015

Authors and Affiliations

  • Su-xiu Chen
    • 1
  • Jun-feng Yin
    • 2
  • Bao-chai Lin
    • 3
  • Hua-fang Su
    • 3
  • Zhen Zheng
    • 3
  • Cong-ying Xie
    • 3
  • Zheng-hua Fei
    • 3
  1. 1.Department of Tumor RehabilitationThe 1st Affiliated Hospital of Wenzhou Medical UniversityWenzhouChina
  2. 2.Department of General Surgery, Yangzhou No 1 People’s HospitalThe Second Clinical School of Yangzhou UniversityYangzhouChina
  3. 3.Radiotherapy and Chemotherapy DepartmentThe 1st Affiliated Hospital of Wenzhou Medical UniversityWenzhouChina

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