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Adenovirus-directed expression of TIPE2 suppresses gastric cancer growth via induction of apoptosis and inhibition of AKT and ERK1/2 signaling

Cancer Gene Therapy volume 23, pages 98–106 (2016)Cite this article

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Abstract

Tumor necrosis factor (TNF)-α-induced protein 8-like 2 (TNFAIP8L2/TIPE2) as a novel anti-inflammatory factor plays an important role in maintaining immune homeostasis. Recently, TIPE2 has been shown to inhibit hepatocarcinoma growth and metastasis through targeting Ras and Rac1. However, its effects in human cancers are poorly understood. In the present study, we analyzed TIPE2 mRNA expression in a panel of human gastric cancer cells (AGS, HGC-27 and SGC-7901) and then examined the cell-autonomous effects of adenovirus-mediated human TIPE2 gene transfer (AdVTIPE2) on AGS and HGC-27 human gastric cancer cells. We found that compared with the GES-1 normal human gastric mucous epithelial cells, human TIPE2 was lost in the AGS, HGC-27 and SGC-7901 gastric cancer cells. Adenovirus-mediated human TIPE2 overexpression significantly inhibited AGS and HGC-27 gastric cancer cell growth and induced AGS and HGC-27 tumor cell apoptosis in vitro. Furthermore, AdVTIPE2 treatment obviously suppressed the growth of AGS gastric cancer subcutaneously xenografted tumors implanted in athymic BALB/c nude mice in vivo. Mechanistically, AdVTIPE2 exhibited marked effects on the upregulation of Bax, cleaved Caspase-9, cleaved Caspase-3, cleaved poly ADP ribose polymerase as well as the downregulation of B-cell lymphoma (Bcl)-XL, phosphorylated-protein kinase B (p-PKB/AKT), phosphorylated-extracellular signal-regulated kinase 1/2 (p-ERK1/2) in AGS gastric cancer cells in vitro and in vivo. Collectively, AdVTIPE2 suppressed gastric cancer growth very possibly by the activation of intrinsic apoptotic pathway and the attenuation of AKT and ERK1/2 signaling. Thus, our data indicated that TIPE2 may be a novel potential therapeutic target for human gastric cancer.

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

    Article  CAS  Google Scholar 

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

    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. 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 

  7. 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 

  8. 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 

  9. 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 

  10. 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 

  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. 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 

  13. 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 

  14. 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 

  15. 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 

  16. 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 

  17. 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 

  18. 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 

  19. 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 

  20. 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 

  21. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D . Global cancer statistics. CA Cancer J Clin 2011; 61: 69–90.

    Article  Google Scholar 

  22. Ushijima T, Sasako M . Focus on gastric cancer. Cancer Cell 2004; 5: 121–125.

    Article  CAS  Google Scholar 

  23. He TC, Zhou S, da Costa LT, Yu J, Kinzler KW, Vogelstein B . A simplified system for generating recombinant adenoviruses. Proc Natl Acad Sci USA 1998; 95: 2509–2514.

    Article  CAS  Google Scholar 

  24. Liu Y, Ye T, Sun D, Maynard J, Deisseroth A . Conditionally replication-competent adenoviral vectors with enhanced infectivity for use in gene therapy of melanoma. Hum Gene Ther 2004; 15: 637–647.

    Article  CAS  Google Scholar 

  25. 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 

  26. Zhang G, Hao C, Lou Y, Xi W, Wang X, Wang Y et al. Tissue-specific expression of TIPE2 provides insights into its function. Mol Immunol 2010; 47: 2435–2442.

    Article  CAS  Google Scholar 

  27. Coussens LM, Zitvogel L, Palucka AK . Neutralizing tumor-promoting chronic inflammation: a magic bullet? Science 2013; 339: 286–291.

    Article  CAS  Google Scholar 

  28. Zhang L, Shi Y, Wang Y, Zhu F, Wang Q, Ma C et al. The unique expression profile of human TIPE2 suggests new functions beyond its role in immune regulation. Mol Immunol 2011; 48: 1209–1215.

    Article  CAS  Google Scholar 

  29. Chappell WH, Steelman LS, Long JM, Kempf RC, Abrams SL, Franklin RA et al. Ras/Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR inhibitors: rationale and importance to inhibiting these pathways in human health. Oncotarget 2011; 2: 135–164.

    Article  Google Scholar 

  30. Saini KS, Loi S, de Azambuja E, Metzger-Filho O, Saini ML, Ignatiadis M et al. Targeting the PI3K/AKT/mTOR and Raf/MEK/ERK pathways in the treatment of breast cancer. Cancer Treat Rev 2013; 39: 935–946.

    Article  CAS  Google Scholar 

  31. Porta C, Paglino C, Mosca A . Targeting PI3K/Akt/mTOR signaling in cancer. Front Oncol 2014; 4: 64.

    Article  Google Scholar 

  32. Zhang G, Zhang W, Lou Y, Xi W, Cui J, Geng M et al. TIPE2 deficiency accelerates neointima formation by downregulating smooth muscle cell differentiation. Cell Cycle 2013; 12: 501–510.

    Article  CAS  Google Scholar 

  33. 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 

  34. Danial NN, Korsmeyer SJ . Cell death: critical control points. Cell 2004; 116: 205–219.

    Article  CAS  Google Scholar 

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Acknowledgements

This research work was supported by grants from the National Natural Science Foundation of China (NNSFC) (Nos. 81372443, 81001016, 81272542 and 81572992), the Science and Technology Department of Jiangsu Province (Nos. BL2014039 and BY2015039), the Science and Technology Development Bureau of Xiangcheng District of Suzhou City (No. XJ201534), the Pushin HK Jiangsu Medical Technology (No. P112200315) and the Wu Jieping Medical Foundation (No. P112200914).

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  1. Y Zhu, M Tao and J Wu: These authors contributed equally to this work.

Authors and Affiliations

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

    Y Zhu, M Tao, J Wu, Y Meng, C Xu, X Zhou & Y Xie

  2. Department of Oncology, Suzhou Xiangcheng People’s Hospital, Suzhou, China

    Y Tian

  3. Cancer Research Unit, Saskatchewan Cancer Agency, Saskatoon, Saskatchewan, Canada

    J Xiang

  4. Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou, China

    H Zhang

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  1. Y Zhu
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Correspondence to H Zhang or Y Xie.

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Zhu, Y., Tao, M., Wu, J. 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 23, 98–106 (2016). https://doi.org/10.1038/cgt.2016.6

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  • DOI: https://doi.org/10.1038/cgt.2016.6

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