Skip to main content

Advertisement

SpringerLink
Log in

Isocitrate dehydrogenase 2 inhibits gastric cancer cell invasion via matrix metalloproteinase 7

  • Original Article
  • Published:
Tumor Biology

Abstract

Isocitrate dehydrogenase 2 (IDH2) is a mitochondrial NADP-dependent isocitrate dehydrogenase and has been found to be a tumor suppressor in several types of tumors. However, the roles of IDH2 in hepatocellular carcinoma (GC) as well as underlying mechanisms remain unknown. Here, the IDH2 and matrix metalloproteinase 7 (MMP7) levels in the specimens from 30 GC patients were investigated by Western blot and ELISA, respectively. Their relationship was examined by correlation analyses. Patient survival with high IDH2 levels and low IDH2 levels was compared. IDH2 levels, and MMP7 levels were modified in a human GC cell line. The effects of IDH2 or MMP7 modulation on the expression of each other were analyzed. The dependence of nuclear factor κB (NF-κB) signaling was examined using a specific inhibitor. We found that the IDH2 levels significantly decreased in GC, and were even lower in GC with metastases, compared to those without metastases. IDH2 levels inversely correlated with MMP7 levels in GC. GC patients with low IDH2 had lower 5-year survival. MMP7 levels did not regulate IDH2 levels, while IDH2 inhibited MMP7 levels in GC cells, in a NF-κB signaling dependent manner. Together, these data suggest that IDH2 may be a tumor suppressor in that its loss may promote malignant progression of GC via NF-κB-dependent increases in MMP7 activity.

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

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

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

Similar content being viewed by others

References

  1. Wu W, Ding H, Cao J, Zhang W. Fbxl5 inhibits metastasis of gastric cancer through suppressing snail1. Cell Physiol Biochem. 2015;35:1764–72.

    Article  PubMed  Google Scholar 

  2. Liu G, Jiang C, Li D, Wang R, Wang W. Mirna-34a inhibits egfr-signaling-dependent mmp7 activation in gastric cancer. Tumour Biol. 2014;35:9801–6.

    Article  CAS  PubMed  Google Scholar 

  3. Mao D, Zhang Y, Lu H, Zhang H. Molecular basis underlying inhibition of metastasis of gastric cancer by anti-vegfa treatment. Tumour Biol. 2014;35:8217–23.

    Article  CAS  PubMed  Google Scholar 

  4. Ye Y, Zhou X, Li X, Tang Y, Sun Y, Fang J. Inhibition of epidermal growth factor receptor signaling prohibits metastasis of gastric cancer via downregulation of mmp7 and mmp13. Tumour Biol. 2014;35:10891–6.

    Article  CAS  PubMed  Google Scholar 

  5. Zhao Z, Han F, Yang S, Wu J, Zhan W. Oxamate-mediated inhibition of lactate dehydrogenase induces protective autophagy in gastric cancer cells: Involvement of the akt-mtor signaling pathway. Cancer Lett. 2015;358:17–26.

    Article  CAS  PubMed  Google Scholar 

  6. Ge J, Chen Z, Huang J, Chen J, Yuan W, Deng Z, et al. Upregulation of autophagy-related gene-5 (atg-5) is associated with chemoresistance in human gastric cancer. PLoS One. 2014;9:e110293.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Hosogi S, Kusuzaki K, Inui T, Wang X, Marunaka Y. Cytosolic chloride ion is a key factor in lysosomal acidification and function of autophagy in human gastric cancer cell. J Cell Mol Med. 2014;18:1124–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Liu M, Li CM, Chen ZF, Ji R, Guo QH, Li Q, et al. Celecoxib regulates apoptosis and autophagy via the pi3k/akt signaling pathway in sgc-7901 gastric cancer cells. Int J Mol Med. 2014;33:1451–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Tang C, Yang L, Jiang X, Xu C, Wang M, Wang Q, et al. Antibiotic drug tigecycline inhibited cell proliferation and induced autophagy in gastric cancer cells. Biochem Biophys Res Commun. 2014;446:105–12.

    Article  CAS  PubMed  Google Scholar 

  10. Lokody I. Metabolism: Idh2 drives cancer in vivo. Nat Rev Cancer. 2013;13:756–7.

    Article  PubMed  Google Scholar 

  11. Chen C, Liu Y, Lu C, Cross JR, Morris JP, Shroff AS, et al. Cancer-associated idh2 mutants drive an acute myeloid leukemia that is susceptible to brd4 inhibition. Genes Dev. 2013;27:1974–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Lv Q, Xing S, Li Z, Li J, Gong P, Xu X, et al. Altered expression levels of idh2 are involved in the development of colon cancer. Exp Ther Med. 2012;4:801–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Borodovsky A, Seltzer MJ, Riggins GJ. Altered cancer cell metabolism in gliomas with mutant idh1 or idh2. Curr Opin Oncol. 2012;24:83–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Marcucci G, Maharry K, Wu YZ, Radmacher MD, Mrozek K, Margeson D, et al. Idh1 and idh2 gene mutations identify novel molecular subsets within de novo cytogenetically normal acute myeloid leukemia: a cancer and leukemia group b study. J Clin Oncol. 2010;28:2348–55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. van den Bent MJ, Dubbink HJ, Marie Y, Brandes AA, Taphoorn MJ, Wesseling P, et al. Idh1 and idh2 mutations are prognostic but not predictive for outcome in anaplastic oligodendroglial tumors: a report of the european organization for research and treatment of cancer brain tumor group. Clin Cancer Res. 2010;16:1597–604.

    Article  PubMed  Google Scholar 

  16. Reitman ZJ, Yan H. Isocitrate dehydrogenase 1 and 2 mutations in cancer: alterations at a crossroads of cellular metabolism. J Natl Cancer Inst. 2010;102:932–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Gross S, Cairns RA, Minden MD, Driggers EM, Bittinger MA, Jang HG, et al. Cancer-associated metabolite 2-hydroxyglutarate accumulates in acute myelogenous leukemia with isocitrate dehydrogenase 1 and 2 mutations. J Exp Med. 2010;207:339–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Mao Y, Cheng J, Yu F, Li H, Guo C, Fan X. Ghrelin attenuated lipotoxicity via autophagy induction and nuclear factor-kappab inhibition. Cell Physiol Biochem. 2015;37:563–76.

    Article  CAS  PubMed  Google Scholar 

  19. Orabi AI, Sah S, Javed TA, Lemon KL, Good ML, Guo P, et al. Dynamic imaging of pancreatic nuclear factor kappab (nf-kappab) activation in live mice using adeno-associated virus (aav) infusion and bioluminescence. J Biol Chem. 2015;290:11309–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Moe KT, Khairunnisa K, Yin NO, Chin-Dusting J, Wong P, Wong MC. Tumor necrosis factor-alpha-induced nuclear factor-kappab activation in human cardiomyocytes is mediated by nadph oxidase. J Physiol Biochem. 2014;70:769–79.

    Article  CAS  PubMed  Google Scholar 

  21. Lee SJ, Cho SC, Lee EJ, Kim S, Lee SB, Lim JH, et al. Interleukin-20 promotes migration of bladder cancer cells through extracellular signal-regulated kinase (erk)-mediated mmp-9 protein expression leading to nuclear factor (nf-kappab) activation by inducing the up-regulation of p21(waf1) protein expression. J Biol Chem. 2013;288:5539–52.

    Article  CAS  PubMed  Google Scholar 

  22. Kong D, Li Y, Wang Z, Banerjee S, Sarkar FH. Inhibition of angiogenesis and invasion by 3,3'-diindolylmethane is mediated by the nuclear factor-kappab downstream target genes mmp-9 and upa that regulated bioavailability of vascular endothelial growth factor in prostate cancer. Cancer Res. 2007;67:3310–9.

    Article  CAS  PubMed  Google Scholar 

  23. Li Y, Kucuk O, Hussain M, Abrams J, Cher ML, Sarkar FH. Antitumor and antimetastatic activities of docetaxel are enhanced by genistein through regulation of osteoprotegerin/receptor activator of nuclear factor-kappab (rank)/rank ligand/mmp-9 signaling in prostate cancer. Cancer Res. 2006;66:4816–25.

    Article  CAS  PubMed  Google Scholar 

  24. Ding H, Zhu Y, Chu T, Wang S. Epidermal growth factor induces foxo1 nuclear exclusion to activate mmp7-mediated metastasis of larynx carcinoma. Tumour Biol. 2014;35:9987–92.

    Article  CAS  PubMed  Google Scholar 

  25. Jiang Y, Sun S, Liu G, Yan B, Niu J. Nrdp1 inhibits metastasis of colorectal cancer cells by egfr signaling-dependent mmp7 modulation. Tumour Biol. 2015;36:1129–33.

    Article  CAS  PubMed  Google Scholar 

  26. Feldmann M, Andreakos E, Smith C, Bondeson J, Yoshimura S, Kiriakidis S, et al. Is nf-kappab a useful therapeutic target in rheumatoid arthritis? Ann Rheum Dis. 2002;61 Suppl 2:ii13–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. van Loo G, Beyaert R. Negative regulation of nf-kappab and its involvement in rheumatoid arthritis. Arthritis Res Ther. 2011;13:221.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Roman-Blas JA, Jimenez SA. Nf-kappab as a potential therapeutic target in osteoarthritis and rheumatoid arthritis. Osteoarthritis Cartilage. 2006;14:839–48.

    Article  CAS  PubMed  Google Scholar 

Download references

Conflict of interest

The authors declare that they have no competing interests.

Author information

Authors and Affiliations

  1. Department of Gastroenterology, the First Affiliated Hospital of Liaoning Medical University, No. 2, Section 5, Renmin Road, Jinzhou, 121000, China

    Dandan Wu

Authors
  1. Dandan Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Dandan Wu.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Wu, D. Isocitrate dehydrogenase 2 inhibits gastric cancer cell invasion via matrix metalloproteinase 7. Tumor Biol. 37, 5225–5230 (2016). https://doi.org/10.1007/s13277-015-4358-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13277-015-4358-2

Keywords

Search

Navigation