Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Adenovirus-mediated TIPE2 overexpression inhibits gastric cancer metastasis via reversal of epithelial–mesenchymal transition

Cancer Gene Therapy volume 24, pages 180–188 (2017)Cite this article

Subjects

Abstract

Tumor necrosis factor (TNF)-alpha-induced protein 8-like 2 (TNFAIP8L2; also termed TIPE2) has been shown to be involved in both the immune-negative modulation and cancer. We previously found that TIPE2 is lost in human gastric cancer, and TIPE2 restoration suppresses gastric cancer growth by induction of apoptosis and impairment of protein kinase B (PKB/AKT) and extracellular signal-regulated kinase-1/2 (ERK1/2) signaling. However, its correlation with epithelial–mesenchymal transition (EMT) in gastric cancer is largely elusive. In the present report, we carried out a gain-of-function study in AGS and HGC-27 human gastric cancer cells by adenovirus-mediated human TIPE2 gene transfer (AdVTIPE2). We then examined the effects of AdVTIPE2 on in vitro migration and invasion of AGS and HGC-27 tumor cells by wound-healing assay and Transwell invasion assay, respectively. We also investigated the effects of AdVTIPE2 on in vivo lung metastasis of AGS and HGC-27 tumor cells by intravenous (i.v.) injection in athymic BALB/c nude mice. We demonstrated that AdVTIPE2 remarkably suppressed the migratory, invasive and metastatic potential of AGS and HGC-27 tumor cells in vitro and in vivo in BALB/c nude mouse model. Mechanistically, AdVTIPE2 obviously upregulated E-cadherin epithelial marker in AGS and HGC-27 tumor cells, whereas it downregulated N-cadherin and Vimentin mesenchymal markers, Snail1, Snail2/Slug and Zeb1 EMT-inducing transcription factors (EMT-TFs), and tripartite motif-containing 29 (TRIM29) and phosphatase regenerating liver 3 (PRL-3) gastric cancer-specific metastasis markers. Importantly, glycogen synthase kinase-3β (GSK-3β) inhibitor VIII and 26S proteasome inhibitor MG132 assays revealed that TIPE2 downregulated Snail1 and Snail2/Slug in a GSK-3β- and proteasome-dependent manner possibly by impairing AKT signaling. Our data provided the first evidence that TIPE2 inhibits gastric cancer cell migration, invasion and metastasis very probably via reversal of EMT, revealing that TIPE2 may be a novel therapeutic target for human gastric cancer EMT and metastasis.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6

Similar content being viewed by others

References

  1. Sun H, Gong S, Carmody RJ, Hilliard A, Li L, Sun J et al. TIPE2, a negative regulator of innate and adaptive immunity that maintains immune homeostasis. Cell 2008; 133: 415–426.

    Article  CAS  Google Scholar 

  2. Freundt EC, Bidere N, Lenardo MJ . A different TIPE of immune homeostasis. Cell 2008; 133: 401–402.

    Article  CAS  Google Scholar 

  3. Lou Y, Liu S . The TIPE (TNFAIP8) family in inflammation, immunity, and cancer. Mol Immunol 2011; 49: 4–7.

    Article  CAS  Google Scholar 

  4. Wang Z, Fayngerts S, Wang P, Sun H, Johnson DS, Ruan Q et al. TIPE2 protein serves as a negative regulator of phagocytosis and oxidative burst during infection. Proc Natl Acad Sci USA 2012; 109: 15413–15418.

    Article  CAS  Google Scholar 

  5. Sun H, Zhuang G, Chai L, Wang Z, Johnson D, Ma Y et al. TIPE2 controls innate immunity to RNA by targeting the phosphatidylinositol 3-kinase-Rac pathway. J Immunol 2012; 189: 2768–2773.

    Article  CAS  Google Scholar 

  6. Lou Y, Zhang G, Geng M, Zhang W, Cui J, Liu S . TIPE2 negatively regulates inflammation by switching arginine metabolism from nitric oxide synthase to arginase. PLoS ONE 2014; 9: e96508.

    Article  Google Scholar 

  7. Luan YY, Yao YM, Zhang L, Dong N, Zhang QH, Yu Y et al. Expression of tumor necrosis factor-alpha induced protein 8 like-2 contributes to the immunosuppressive property of CD4(+)CD25(+) regulatory T cells in mice. Mol Immunol 2011; 49: 219–226.

    Article  CAS  Google Scholar 

  8. Luan YY, Yao RQ, Tong S, Dong N, Sheng ZY, Yao YM . Effect of tumor necrosis factor-alpha induced protein 8 like-2 on immune function of dendritic cells in mice following acute insults. Oncotarget 2016; 7: 30178–30192.

    PubMed  PubMed Central  Google Scholar 

  9. Li D, Song L, Fan Y, Li X, Li Y, Chen J et al. Down-regulation of TIPE2 mRNA expression in peripheral blood mononuclear cells from patients with systemic lupus erythematosus. Clin Immunol 2009; 133: 422–427.

    Article  CAS  Google Scholar 

  10. Li F, Zhu X, Yang Y, Huang L, Xu J . TIPE2 alleviates systemic lupus erythematosus through regulating macrophage polarization. Cell Physiol Biochem 2016; 38: 330–339.

    Article  CAS  Google Scholar 

  11. Ma Y, Liu X, Wei Z, Wang X, Wang Z, Zhong W et al. The expression and significance of TIPE2 in peripheral blood mononuclear cells from asthmatic children. Scand J Immunol 2013; 78: 523–528.

    Article  CAS  Google Scholar 

  12. Ding J, Su J, Zhang L, Ma J . Crocetin activates Foxp3 through TIPE2 in asthma-associated treg cells. Cell Physiol Biochem 2015; 37: 2425–2433.

    Article  CAS  Google Scholar 

  13. Lou Y, Liu S, Zhang C, Zhang G, Li J, Ni M et al. Enhanced atherosclerosis in TIPE2-deficient mice is associated with increased macrophage responses to oxidized low-density lipoprotein. J Immunol 2013; 191: 4849–4857.

    Article  CAS  Google Scholar 

  14. Lou Y, Sun H, Morrissey S, Porturas T, Liu S, Hua X et al. Critical roles of TIPE2 protein in murine experimental colitis. J Immunol 2014; 193: 1064–1070.

    Article  CAS  Google Scholar 

  15. Xi W, Hu Y, Liu Y, Zhang J, Wang L, Lou Y et al. Roles of TIPE2 in hepatitis B virus-induced hepatic inflammation in humans and mice. Mol Immunol 2011; 48: 1203–1208.

    Article  CAS  Google Scholar 

  16. Zhang W, Zhang J, Zhao L, Shao J, Cui J, Guo C et al. TIPE2 protein negatively regulates HBV-specific CD8(+) T lymphocyte functions in humans. Mol Immunol 2014; 64: 204–209.

    Article  Google Scholar 

  17. Gus-Brautbar Y, Johnson D, Zhang L, Sun H, Wang P, Zhang S et al. The anti-inflammatory TIPE2 is an inhibitor of the oncogenic Ras. Mol Cell 2012; 45: 610–618.

    Article  CAS  Google Scholar 

  18. Alderton GK . Tumour immunology: suppressing tumorigenic inflammation. Nat Rev Cancer 2012; 12: 228.

    Article  CAS  Google Scholar 

  19. Cao X, Zhang L, Shi Y, Sun Y, Dai S, Guo C et al. Human tumor necrosis factor (TNF)-alpha-induced protein 8-like 2 suppresses hepatocellular carcinoma metastasis through inhibiting Rac1. Mol Cancer 2013; 12: 149.

    Article  Google Scholar 

  20. Li Y, Li X, Liu G, Sun R, Wang L, Wang J et al. Downregulated TIPE2 is associated with poor prognosis and promotes cell proliferation in non-small cell lung cancer. Biochem Biophys Res Commun 2015; 457: 43–49.

    Article  CAS  Google Scholar 

  21. Liu QQ, Zhang FF, Wang F, Qiu JH, Luo CH, Zhu GY et al. TIPE2 Inhibits Lung Cancer Growth Attributing to Promotion of Apoptosis by Regulating Some Apoptotic Molecules Expression. PLoS ONE 2015; 10: e0126176.

    Article  Google Scholar 

  22. Deng B, Feng Y . TIPE2 mediates the suppressive effects of Shikonin on MMP13 in osteosarcoma cells. Cell Physiol Biochem 2015; 37: 2434–2443.

    Article  CAS  Google Scholar 

  23. Zhao Q, Zhao M, Dong T, Zhou C, Peng Y, Zhou X et al. Tumor necrosis factor-alpha-induced protein-8 like-2 (TIPE2) upregulates p27 to decrease gastic cancer cell proliferation. J Cell Biochem 2015; 116: 1121–1129.

    Article  CAS  Google Scholar 

  24. Zhu Y, Tao M, Wu J, Meng Y, Xu C, Tian Y et al. Adenovirus-directed expression of TIPE2 suppresses gastric cancer growth via induction of apoptosis and inhibition of AKT and ERK1/2 signaling. Cancer Gene Ther 2016; 23: 98–106.

    Article  CAS  Google Scholar 

  25. Peng Y, Zhao Q, Zhang H, Han B, Liu S, Han M . TIPE2, a negative regulator of TLR signaling, regulates p27 through IRF4-induced signaling. Oncol Rep 2016; 35: 2480–2486.

    Article  CAS  Google Scholar 

  26. Zhang YH, Yan HQ, Wang F, Wang YY, Jiang YN, Wang YN et al. TIPE2 inhibits TNF-alpha-induced hepatocellular carcinoma cell metastasis via Erk1/2 downregulation and NF-kappaB activation. Int J Oncol 2015; 46: 254–264.

    Article  Google Scholar 

  27. Li XM, Su JR, Yan SP, Cheng ZL, Yang TT, Zhu Q . A novel inflammatory regulator TIPE2 inhibits TLR4-mediated development of colon cancer via caspase-8. Cancer Biomark 2014; 14: 233–240.

    Article  Google Scholar 

  28. Zhang Z, Qi H, Hou S, Jin X . TIPE2 mRNA overexpression correlates with TNM staging in renal cell carcinoma tissues. Oncol Lett 2013; 6: 571–575.

    Article  CAS  Google Scholar 

  29. Li X . TIPE2 regulates tumor-associated macrophages in skin squamous cell carcinoma. Tumour Biol 2016; 37: 5585–5590.

    Article  CAS  Google Scholar 

  30. Xie Y, Sheng W, Miao J, Xiang J, Yang J . Enhanced antitumor activity by combining an adenovirus harboring ING4 with cisplatin for hepatocarcinoma cells. Cancer Gene Ther 2011; 18: 176–188.

    Article  CAS  Google Scholar 

  31. Zhang H, Zhou X, Xu C, Yang J, Xiang J, Tao M et al. Synergistic tumor suppression by adenovirus-mediated ING4/PTEN double gene therapy for gastric cancer. Cancer Gene Ther 2016; 23: 13–23.

    Article  CAS  Google Scholar 

  32. Hanahan D, Weinberg RA . Hallmarks of cancer: the next generation. Cell 2011; 144: 646–674.

    Article  CAS  Google Scholar 

  33. Lamouille S, Xu J, Derynck R . Molecular mechanisms of epithelial-mesenchymal transition. Nat Rev Mol Cell Biol 2014; 15: 178–196.

    Article  CAS  Google Scholar 

  34. Kosaka Y, Inoue H, Ohmachi T, Yokoe T, Matsumoto T, Mimori K et al. Tripartite motif-containing 29 (TRIM29) is a novel marker for lymph node metastasis in gastric cancer. Ann Surg Oncol 2007; 14: 2543–2549.

    Article  Google Scholar 

  35. Dai N, Lu AP, Shou CC, Li JY . Expression of phosphatase regenerating liver 3 is an independent prognostic indicator for gastric cancer. World J Gastroenterol 2009; 15: 1499–1505.

    Article  CAS  Google Scholar 

  36. Zhou BP, Deng J, Xia W, Xu J, Li YM, Gunduz M et al. Dual regulation of Snail by GSK-3beta-mediated phosphorylation in control of epithelial-mesenchymal transition. Nat Cell Biol 2004; 6: 931–940.

    Article  CAS  Google Scholar 

  37. Yook JI, Li XY, Ota I, Hu C, Kim HS, Kim NH et al. A Wnt-Axin2-GSK3beta cascade regulates Snail1 activity in breast cancer cells. Nat Cell Biol 2006; 8: 1398–1406.

    Article  CAS  Google Scholar 

  38. Kao SH, Wang WL, Chen CY, Chang YL, Wu YY, Wang YT et al. GSK3beta controls epithelial-mesenchymal transition and tumor metastasis by CHIP-mediated degradation of Slug. Oncogene 2014; 33: 3172–3182.

    Article  CAS  Google Scholar 

  39. Fayngerts SA, Wu J, Oxley CL, Liu X, Vourekas A, Cathopoulis T et al. TIPE3 is the transfer protein of lipid second messengers that promote cancer. Cancer Cell 2014; 26: 465–478.

    Article  CAS  Google Scholar 

  40. Moniz LS, Vanhaesebroeck B . A new TIPE of phosphoinositide regulator in cancer. Cancer Cell 2014; 26: 443–444.

    Article  CAS  Google Scholar 

  41. Zhang Z, Liang X, Gao L, Ma H, Liu X, Pan Y et al. TIPE1 induces apoptosis by negatively regulating Rac1 activation in hepatocellular carcinoma cells. Oncogene 2015; 34: 2566–2574.

    Article  CAS  Google Scholar 

  42. Chaffer CL, Weinberg RA . A perspective on cancer cell metastasis. Science 2011; 331: 1559–1564.

    Article  CAS  Google Scholar 

  43. De Craene B, Berx G . Regulatory networks defining EMT during cancer initiation and progression. Nat Rev Cancer 2013; 13: 97–110.

    Article  CAS  Google Scholar 

  44. Mendez MG, Kojima S, Goldman RD . Vimentin induces changes in cell shape, motility, and adhesion during the epithelial to mesenchymal transition. FASEB J 2010; 24: 1838–1851.

    Article  CAS  Google Scholar 

  45. Puisieux A, Brabletz T, Caramel J . Oncogenic roles of EMT-inducing transcription factors. Nat Cell Biol 2014; 16: 488–494.

    Article  CAS  Google Scholar 

  46. Peinado H, Olmeda D, Cano A . Snail, Zeb and bHLH factors in tumour progression: an alliance against the epithelial phenotype? Nat Rev Cancer 2007; 7: 415–428.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This research work was supported by grants from the National Natural Science Foundation of China (NNSFC) (No. 81372443, 81001016, 81272542 and 81572992), the Science and Technology Department of Jiangsu Province (No. BL2014039 and BY2015039-03), the Pushin HK Jiangsu Medical Technology. (No. P112200315) and the Wu Jieping Medical Foundation (No. P112200914).

Author information

Author notes

  1. H Yin and X Huang: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Oncology, The First Affiliated Hospital of Soochow University, Suzhou, China

    H Yin, X Huang, M Tao, Q Hu, J Qiu, J Wu & Y Xie

  2. Department of Gastroenterology, The First Affiliated Hospital of Soochow University, Suzhou, China

    W Chen

Authors
  1. H Yin
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. X Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. M Tao
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Q Hu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. J Qiu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. W Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. J Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Y Xie
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to J Wu or Y Xie.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Yin, H., Huang, X., Tao, M. et al. Adenovirus-mediated TIPE2 overexpression inhibits gastric cancer metastasis via reversal of epithelial–mesenchymal transition. Cancer Gene Ther 24, 180–188 (2017). https://doi.org/10.1038/cgt.2017.3

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/cgt.2017.3

This article is cited by

Search

Advanced search

Quick links