Molecules and Cells

Korean Society for Molecular and Cellular Biology (한국분자세포생물학회)
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Tristetraprolin Overexpression in Gastric Cancer Cells Suppresses PD-L1 Expression and Inhibits Tumor Progression by Enhancing Antitumor Immunity

  • Guo, Jian (Department of General Surgery and Center of Translational Medicine, The Affiliated Wuxi No.2 People's Hospital of Nanjing Medical University) ;
  • Qu, Huiheng (Department of General Surgery and Center of Translational Medicine, The Affiliated Wuxi No.2 People's Hospital of Nanjing Medical University) ;
  • Shan, Ting (Department of General Surgery and Center of Translational Medicine, The Affiliated Wuxi No.2 People's Hospital of Nanjing Medical University) ;
  • Chen, Yigang (Department of General Surgery and Center of Translational Medicine, The Affiliated Wuxi No.2 People's Hospital of Nanjing Medical University) ;
  • Chen, Ye (Department of General Surgery and Center of Translational Medicine, The Affiliated Wuxi No.2 People's Hospital of Nanjing Medical University) ;
  • Xia, Jiazeng (Department of General Surgery and Center of Translational Medicine, The Affiliated Wuxi No.2 People's Hospital of Nanjing Medical University)
  • Received : 2018.01.25
  • Accepted : 2018.05.23
  • Published : 2018.07.31
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Abstract

The RNA-binding protein tristetraprolin (TTP) binds to adenosine-uridine AU-rich elements in the 3'-untranslated region of messenger RNAs and facilitates rapid degradation of the target mRNAs. Therefore, it regulates the expression of multiple cancer and immunity-associated transcripts. Furthermore, a lack of TTP in cancer cells influences cancer progression and predicts poor survival. Although the functions of TTP on cancer cells have previously been researched, the mechanism of TTP on the interaction between cancer cells with their micro-environment remains undiscovered. In this study, we admed to determine the role of cancer cell TTP during the interaction between tumor and immune cells, specifically regulatory T cells (Tregs). We evaluate the capability of TTP to modulate the antitumor immunity of GC and explored the underlying mechanism. The overexpression of TTP in GC cells dramatically increased peripheral blood mononuclear lymphocyte (PBML) -mediated cytotoxicity against GC cells. Increased cytotoxicity against TTP-overexpressed GC cells by PBMLs was determined by Treg development and infiltration. Surprisingly, we found the stabilization of programmed death-ligand 1 (PD-L1) mRNA was declining while TTP was elevated. The PD-L1 protein level was reduced in TTP-abundant GC cells. PD-L1 gas been found to play a pivotal role in Treg development and functional maintenance in immune system. Taken together, our results suggest the overexpression of TTP in GC cells not only affects cell survival and apoptosis but also increases PBMLs -mediated cytotoxicity against GC cells to decelerate tumor progression. Moreover, we identified PD-L1 as a critical TTP-regulated factor that contributes to inhibiting antitumor immunity.

Keywords

References

  1. Ai, R., Tao, Y., Hao, Y., Jiang, L., Dan, H., Ji, N., Zeng, X., Zhou, Y., and Chen, Q. (2017). Microenvironmental regulation of the progression of oral potentially malignant disorders towards malignancy. Oncotarget 8, 81617-81635.
  2. Becht, E., Giraldo, N.A., Dieu-Nosjean, M.C., Sautes-Fridman, C., and Fridman, W.H. (2016). Cancer immune contexture and immunotherapy. Curr. Opin. Immunol. 39, 7-13. https://doi.org/10.1016/j.coi.2015.11.009
  3. Brooks, S.A. and Blackshear, P.J. (2013) Tristetraprolin (TTP): interactions with mRNA and proteins, and current thoughts on mechanisms of action. Biochim. Biophys. Acta 1829, 666-679. https://doi.org/10.1016/j.bbagrm.2013.02.003
  4. Cho, J., Lee, J., Bang, H., Kim, S.T., Park, S.H., An, J.Y., Choi, M.G., Lee, J.H., Sohn, T.S., Bae, J.M., et al. (2017) Programmed cell deathligand 1 expression predicts survival in patients with gastric carcinoma with microsatellite instability. Oncotarget 8, 13320-13328.
  5. Curiel, T.J., Coukos, G., Zou, L., Alvarez, X., Cheng, P., Mottram, P., Evdemon-Hogan, M., Conejo-Garcia, J.R., Zhang, L., Burow, M., et al. (2004) Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nat. Med. 10, 942-949. https://doi.org/10.1038/nm1093
  6. Das, S., Suarez, G., Beswick, E.J., Sierra, J.C., Graham, D.Y., and Reyes, V.E. (2006). Expression of B7-H1 on gastric epithelial cells: its potential role in regulating T cells during Helicobacter pylori infection. Journal of immunology (Baltimore, Md. : 1950) 176, 3000-3009. https://doi.org/10.4049/jimmunol.176.5.3000
  7. Deng, K., Wang, H., Shan, T., Chen, Y., Zhou, H., Zhao, Q., and Xia, J. (2016). Tristetraprolin inhibits gastric cancer progression through suppression of IL-33. Sci. Rep. 6, 24505. https://doi.org/10.1038/srep24505
  8. Eckert, A.W., Wickenhauser, C., Salins, P.C., Kappler, M., Bukur, J., and Seliger, B. (2016). Clinical relevance of the tumor microenvironment and immune escape of oral squamous cell carcinoma. J. Trans. Med. 14, 85. https://doi.org/10.1186/s12967-016-0828-6
  9. Finn, O.J. (2017). Human tumor antigens yesterday, today, and tomorrow. Cancer Immunol. Res. 5, 347-354. https://doi.org/10.1158/2326-6066.CIR-17-0112
  10. Friedl, P., and Wolf, K. (2003). Tumour-cell invasion and migration: diversity and escape mechanisms. Nature reviews. Cancer 3, 362-374. https://doi.org/10.1038/nrc1075
  11. Geng, Y., Wang, H., Lu, C., Li, Q., Xu, B., Jiang, J., and Wu, C. (2015). Expression of costimulatory molecules B7-H1, B7-H4 and Foxp3+ Tregs in gastric cancer and its clinical significance. Int. J. Clin. Oncol. 20, 273-281. https://doi.org/10.1007/s10147-014-0701-7
  12. Giraldo, N.A., Becht, E., Remark, R., Damotte, D., Sautes-Fridman, C., and Fridman, W.H. (2014). The immune contexture of primary and metastatic human tumours. Curr. Opin. Immunol. 27, 8-15. https://doi.org/10.1016/j.coi.2014.01.001
  13. Guo, J., Qu, H., Chen, Y., and Xia, J. (2017a). The role of RNA-binding protein tristetraprolin in cancer and immunity. Med. Oncol. 34, 196. https://doi.org/10.1007/s12032-017-1055-6
  14. Guo, J., Wang, H., Jiang, S., Xia, J., and Jin, S. (2017b). The cross-talk between tristetraprolin and cytokines in cancer. Anticancer Agents Med. Chem. 17, 1477-1486.
  15. Hatam, L.J., Devoti, J.A., Rosenthal, D.W., Lam, F., Abramson, A.L., Steinberg, B.M., and Bonagura, V.R. (2012). Immune suppression in premalignant respiratory papillomas: enriched functional CD4+Foxp3+ regulatory T cells and PD-1/PD-L1/L2 expression. Clin. Cancer Res. 18, 1925-1935. https://doi.org/10.1158/1078-0432.CCR-11-2941
  16. Heeren, A.M., Koster, B.D., Samuels, S., Ferns, D.M., Chondronasiou, D., Kenter, G.G., Jordanova, E.S., and de Gruijl, T.D. (2015). High and interrelated rates of PD-L1+CD14+ antigen-presenting cells and regulatory T cells mark the microenvironment of metastatic lymph nodes from patients with cervical cancer. Cancer Immunol. Res. 3, 48-58. https://doi.org/10.1158/2326-6066.CIR-14-0149
  17. Hirai, M., Kitahara, H., Kobayashi, Y., Kato, K., Bou-Gharios, G., Nakamura, H., and Kawashiri, S. (2017). Regulation of PD-L1 expression in a high-grade invasive human oral squamous cell carcinoma microenvironment. Int. J. Oncol. 50, 41-48. https://doi.org/10.3892/ijo.2016.3785
  18. Hou, J., Yu, Z., Xiang, R., Li, C., Wang, L., Chen, S., Li, Q., Chen, M., and Wang, L. (2014). Correlation between infiltration of $FOXP^{3+}$ regulatory T cells and expression of B7-H1 in the tumor tissues of gastric cancer. Exp. Mol. Pathol. 96, 284-291. https://doi.org/10.1016/j.yexmp.2014.03.005
  19. Iovanna, J.L., and Closa, D. (2017). Factors released by the tumor far microenvironment are decisive for pancreatic adenocarcinoma development and progression. Oncoimmunology 6, e1358840. https://doi.org/10.1080/2162402X.2017.1358840
  20. Jeltsch, K.M., and Heissmeyer, V. (2016). Regulation of T cell signaling and autoimmunity by RNA-binding proteins. Curr. Opin. Immunol. 39, 127-135. https://doi.org/10.1016/j.coi.2016.01.011
  21. Junttila, M.R., and de Sauvage, F.J. (2013). Influence of tumour micro-environment heterogeneity on therapeutic response. Nature 501, 346-354. https://doi.org/10.1038/nature12626
  22. Kataoka, K., Shiraishi, Y., Takeda, Y., Sakata, S., Matsumoto, M., Nagano, S., Maeda, T., Nagata, Y., Kitanaka, A., Mizuno, S., et al. (2016). Aberrant PD-L1 expression through 3'-UTR disruption in multiple cancers. Nature 534, 402-406. https://doi.org/10.1038/nature18294
  23. Li, Z., Dong, P., Ren, M., Song, Y., Qian, X., Yang, Y., Li, S., Zhang, X., and Liu, F. (2016). PD-L1 Expression Is Associated with Tumor FOXP3(+) Regulatory T-Cell infiltration of breast cancer and poor prognosis of patient. J. Cancer 7, 784-793. https://doi.org/10.7150/jca.14549
  24. Liu, C., Lu, J., Tian, H., Du, W., Zhao, L., Feng, J., Yuan, D., and Li, Z. (2017) Increased expression of PDL1 by the human papillomavirus 16 E7 oncoprotein inhibits anticancer immunity. Mol. Med. Rep. 15, 1063-1070. https://doi.org/10.3892/mmr.2017.6102
  25. Liu, H., Bakthavatsalam, R., Meng, Z., Li, Z., Li, W., Perkins, J.D., and Reyes, J. (2013). PD-L1 signal on liver dendritic cells is critical for Foxp3(+)CD4(+)CD25(+) Treg and liver tolerance induction in mice. Transplant Proc. 45, 1853-1855. https://doi.org/10.1016/j.transproceed.2013.03.015
  26. Liu, X., Yang, Z., Latchoumanin, O., and Qiao, L. (2016). Antagonizing programmed death-1 and programmed death ligand-1 as a therapeutic approach for gastric cancer. Therapeutic advances in gastroenterology 9, 853-860. https://doi.org/10.1177/1756283X16658251
  27. Milke, L., Schulz, K., Weigert, A., Sha, W., Schmid, T., and Brune, B. (2013). Depletion of tristetraprolin in breast cancer cells increases interleukin-16 expression and promotes tumor infiltration with monocytes/macrophages. Carcinogenesis 34, 850-857. https://doi.org/10.1093/carcin/bgs387
  28. Mohamed, M.S., Bishr, M.K., Almutairi, F.M., and Ali, A.G. (2017). Inhibitors of apoptosis: clinical implications in cancer. Apoptosis 22, 1487-1509. https://doi.org/10.1007/s10495-017-1429-4
  29. Newman, R., McHugh, J., and Turner, M. (2016). RNA binding proteins as regulators of immune cell biology. Clin. Exp. Immunol. 183, 37-49. https://doi.org/10.1111/cei.12684
  30. Peligero, C., Argilaguet, J., Guerri-Fernandez, R., Torres, B., Ligero, C., Colomer, P., Plana, M., Knobel, H., Garcia, F., and Meyerhans, A. (2015). PD-L1 blockade differentially impacts regulatory T cells from HIV-infected individuals depending on plasma viremia. PLoS Pathogens 11, e1005270. https://doi.org/10.1371/journal.ppat.1005270
  31. Perez-Ortin, J.E., Alepuz, P., Chavez, S., and Choder, M. (2013). Eukaryotic mRNA decay: methodologies, pathways, and links to other stages of gene expression. J. Mol. Biol. 425, 3750-3775. https://doi.org/10.1016/j.jmb.2013.02.029
  32. Pollack, S.M., He, Q., Yearley, J.H., Emerson, R., Vignali, M., Zhang, Y., Redman, M.W., Baker, K.K., Cooper, S., Donahue, B., et al. (2017). T-cell infiltration and clonality correlate with programmed cell death protein 1 and programmed death-ligand 1 expression in patients with soft tissue sarcomas.
  33. Robert, J. (2013). [Biology of cancer metastasis]. Bulletin du Cancer 100, 333-342.
  34. Sanduja, S., Blanco, F.F., and Dixon, D.A. (2011). The roles of TTP and BRF proteins in regulated mRNA decay. Wiley interdisciplinary reviews. RNA 2, 42-57. https://doi.org/10.1002/wrna.28
  35. Sanduja, S., Blanco, F.F., Young, L.E., Kaza, V., and Dixon, D.A. (2012). The role of tristetraprolin in cancer and inflammation. Frontiers in bioscience (Landmark edition) 17, 174-188. https://doi.org/10.2741/3920
  36. Schreiber, R.D., Old, L.J., and Smyth, M.J. (2011). Cancer immunoediting: integrating immunity's roles in cancer suppression and promotion. Science (New York, N.Y.) 331, 1565-1570. https://doi.org/10.1126/science.1203486
  37. Seo, G.S., Jiang, W.Y., Chi, J.H., Jin, H., Park, W.C., Sohn, D.H., Park, P.H., and Lee, S.H. (2015). Heme oxygenase-1 promotes tumor progression and metastasis of colorectal carcinoma cells by inhibiting antitumor immunity. Oncotarget 6, 19792-19806.
  38. Siegel, R., Naishadham, D., and Jemal, A. (2012). Cancer statistics, 2012. CA: a cancer journal for clinicians 62, 10-29. https://doi.org/10.3322/caac.20138
  39. Tan, M.P., Dolton, G.M., Gerry, A.B., Brewer, J.E., Bennett, A.D., Pumphrey, N.J., Jakobsen, B.K., and Sewell, A.K. (2017). Human leucocyte antigen class I-redirected anti-tumour CD4(+) T cells require a higher T cell receptor binding affinity for optimal activity than CD8(+) T cells. Clin. Exp. Immunol. 187, 124-137. https://doi.org/10.1111/cei.12828
  40. Tian, M., Zhang, Y., Liu, Z., Sun, G., Mor, G., and Liao, A. (2016). The PD-1/PD-L1 inhibitory pathway is altered in pre-eclampsia and regulates T cell responses in pre-eclamptic rats. Sci. Rep. 6, 27683. https://doi.org/10.1038/srep27683
  41. Tripathi, S., and Guleria, I. (2015). Role of PD1/PDL1 pathway, and TH17 and treg cells in maternal tolerance to the fetus. Biomed. J. 38, 25-31. https://doi.org/10.4103/2319-4170.143511
  42. Yuan, J., Zhang, J., Zhu, Y., Li, N., Tian, T., Li, Y., Li, Y., Li, Z., Lai, Y., Gao, J., et al. (2016). Programmed death-ligand-1 expression in advanced gastric cancer detected with RNA in situ hybridization and its clinical significance. Oncotarget 7, 39671-39679.
  43. Yuan, X.L., Chen, L., Zhang, T.T., Ma, Y.H., Zhou, Y.L., Zhao, Y., Wang, W.W., Dong, P., Yu, L., Zhang, Y.Y., et al. (2011). Gastric cancer cells induce human CD4+Foxp3+ regulatory T cells through the production of TGF-beta1. World J. Gastroenterol. 17, 2019-2027. https://doi.org/10.3748/wjg.v17.i15.2019
  44. Zeng, B., Zhu, D., Su, Z., Li, Z., and Yu, Z. (2016). Tristetraprolin exerts tumor suppressive functions on the tumorigenesis of glioma by targeting IL-13. Int. Immunopharmacol. 39, 63-70. https://doi.org/10.1016/j.intimp.2016.07.001
  45. Zhang, M., Dong, Y., Liu, H., Wang, Y., Zhao, S., Xuan, Q., Wang, Y., and Zhang, Q. (2016). The clinicopathological and prognostic significance of PD-L1 expression in gastric cancer: a meta-analysis of 10 studies with 1,901 patients. Sci. Rep. 6, 37933. https://doi.org/10.1038/srep37933
  46. Zheng, X.T., Xiao, X.Q., and Dai, J.J. (2016). Corrigendum to "Sodium butyrate down-regulates tristetraprolin-mediated cyclin B1expression independent of the formation of processing bodies" [Int. J. Biochem. Cell Biol. 69 (2015) 241-248]. Int. J. Biochem. Cell Biol. 74, 161. https://doi.org/10.1016/j.biocel.2016.02.024

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