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LINC00152 mediates CD8+ T-cell infiltration in gastric cancer through binding to EZH2 and regulating the CXCL9, 10/CXCR3 axis

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Abstract

This study aimed to annotate the role of long intergenic non-coding RNA 152 (LINC00152) in CD8+ T cells mediated immune responses in gastric cancer (GC) and the underlying mechanism. LINC00152 expression levels were detected through RT-PCR. For tumor engraftment, HGC-27 cells that received LINC00152 shRNA, LINC00152 overexpression vectors, enhancer of zeste homolog 2 (EZH2) shRNA or combination transfection were injected into mice. Chromatin immunoprecipitation (ChIP) assay was used to explore the interaction between LINC00152, Cys-X-cys ligand 9 (CXCL9) and Cys-X-cys ligand 10 (CXCL10). Flow cytometry was adopted to measure the CD8+ T-cell infiltration in tumor issue. In this study, we found increased LINC00152 expression levels are positively associated with the poor prognosis of GC patients and negatively associated with the CD8 levels. ChIP assay verified that LINC00152 recruits EZH2 to the promoters of CXCL9 and CXCL10, thus the silencing of LINC00152 promoted the production of CXCL9 and CXCL10. Knockdown of LINC00152 suppressed tumor cells growth in vivo and in vitro, increased tumor-infiltrating CD8+ T cells numbers and promoted the expression of CXCL9, CXCL10 and C-X-C Motif Chemokine Receptor 3 (CXCR3) in xenograft tumors. While CD8+ T cell depletion reversed the tumor suppression effect of LINC00152 silence. Besides, the silencing of EZH2 partly inhibited the promotion effect LINC00152 on tumor growth. Our study indicated that LINC00152 inhibition suppressed the tumor progress may through promoting CD8+ T-cell infiltration.

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Source data and reagents are available from the corresponding author upon reasonable request.

References

  • Aune TM, Spurlock CF III (2016) Long non-coding RNAs in innate and adaptive immunity. Virus Res 212:146–160

    Article  CAS  Google Scholar 

  • Cao R, Zhang Y (2004) The functions of E (Z)/EZH2-mediated methylation of lysine 27 in histone H3. CurrOpin Genet Dev 14:155–164

    Article  CAS  Google Scholar 

  • Cats A, Jansen EP, van Grieken NC, Sikorska K, Lind P, Nordsmark M, Kranenbarg EM-K, Boot H, Trip AK, Swellengrebel HM (2018) Chemotherapy versus chemoradiotherapy after surgery and preoperative chemotherapy for resectable gastric cancer (CRITICS): an international, open-label, randomised phase 3 trial. Lancet Oncol 19:616–628

    Article  CAS  Google Scholar 

  • Chen Qn, Chen X, Chen Zy, Nie Fq, Wei Cc, Ma Hw, Wan L, Yan S, Ren Sn, Wang Zx (2017) Long intergenic non-coding RNA 00152 promotes lung adenocarcinoma proliferation via interacting with EZH2 and repressing IL24 expression. Mol Cancer 16:17

    Article  CAS  Google Scholar 

  • Chen Wm, D-pS MD, Kong R, Xu Tp, Xia R, Zhang Eb, Shu Y (2016) Long intergenic non-coding RNA 00152 promotes tumor cell cycle progression by binding to EZH2 and repressing p15 and p21 in gastric cancer. Oncotarget 7:9773

    Article  Google Scholar 

  • Chen X, Li D, Gao Y, Tang W, Lao I, Cao Y, Hao B (2018a) Long intergenic noncoding RNA 00152 promotes glioma cell proliferation and invasion by interacting with MiR-16. Cell PhysiolBiochem 46:1055–1064

    CAS  Google Scholar 

  • Chen ZP, Wei JC, Wang Q, Yang P, Li WL, He F, Chen HC, Hu H, Zhong JB, Cao J (2018b) Long non-coding RNA 00152 functions as a competing endogenous RNA to regulate NRP1 expression by sponging with miRNA-206 in colorectal cancer. Int J Oncol 53:1227–1236

    CAS  PubMed  Google Scholar 

  • Cheng WC, Tsui YC, Ragusa S, Koelzer VH, Mina M, Franco F, Läubli H, Tschumi B, Speiser D, Romero P (2019) Uncoupling protein 2 reprograms the tumor microenvironment to support the anti-tumor immune cycle. Nat Immunol 20:206

    Article  CAS  Google Scholar 

  • Chheda ZS, Sharma RK, Jala VR, Luster AD, Haribabu B (2016) Chemoattractant receptors BLT1 and CXCR3 regulate antitumor immunity by facilitating CD8+ T cell migration into tumors. J Immunol 197(5):2016–2026

    Article  CAS  Google Scholar 

  • Christofides A, Karantanos T, Bardhan K, Boussiotis VA (2016) Epigenetic regulation of cancer biology and anti-tumor immunity by EZH2. Oncotarget 7:85624

    Article  Google Scholar 

  • Curran MA, Montalvo W, Yagita H, Allison JP (2010) PD-1 and CTLA-4 combination blockade expands infiltrating T cells and reduces regulatory T and myeloid cells within B16 melanoma tumors. ProcNatlAcadSci 107:4275–4280

    Article  CAS  Google Scholar 

  • Djebali S, Davis CA, Merkel A, Dobin A, Lassmann T, Mortazavi A, Tanzer A, Lagarde J, Lin W, Schlesinger F et al (2012) Landscape of transcription in human cells. Nature 489:101–108

    Article  CAS  Google Scholar 

  • Dolcetti R, De Re V, Canzonieri V (2018) Immunotherapy for gastric cancer: time for a personalized approach? Int J MolSci 19:1602

    Google Scholar 

  • Fulton AM (2009) The chemokine receptors CXCR4 and CXCR3 in cancer. CurrOncol Rep 11:125–131

    CAS  Google Scholar 

  • Gajewski TF (2015) The next hurdle in cancer immunotherapy: overcoming the non–T-cell–inflamed tumor microenvironment. Semi Oncol 42:663–671

    Article  Google Scholar 

  • Gorbachev AV, Kobayashi H, Kudo D, Tannenbaum CS, Finke JH, Shu S, Farber JM, Fairchild RL (2007) CXC chemokine ligand 9/monokine induced by IFN-γ production by tumor cells is critical for T cell-mediated suppression of cutaneous tumors. J Immunol 178:2278–2286

    Article  CAS  Google Scholar 

  • Guan D, Zhang W, Zhang W, Liu GH, Belmonte JC (2013) Switching cell fate, ncRNAs coming to play. Cell Death Dis 4:e464

    Article  CAS  Google Scholar 

  • He W, Zhang H, Han F, Chen X, Lin R, Wang W, Qiu H, Zhuang Z, Liao Q, Zhang W (2017) CD155T/TIGIT signaling regulates CD8+ T-cell metabolism and promotes tumor progression in human gastric cancer. Can Res 77:6375–6388

    Article  CAS  Google Scholar 

  • Hu G, Tang Q, Sharma S, Yu F, Escobar TM, Muljo SA, Zhu J, Zhao K (2013) Expression and regulation of intergenic long noncoding RNAs during T cell development and differentiation. Nat Immunol 14:1190

    Article  CAS  Google Scholar 

  • Huarte M (2015) The emerging role of lncRNAs in cancer. Nat Med 21:1253

    Article  CAS  Google Scholar 

  • Kung JT, Colognori D, Lee JT (2013) Long noncoding RNAs: past, present, and future. Genetics 193:651–669

    Article  CAS  Google Scholar 

  • Li S, Wen D, Che S, Cui Z, Sun Y, Ren H, Hao J (2018) Knockdown of long noncoding RNA 00152 (LINC00152) inhibits human retinoblastoma progression. OncoTargetsTher 11:3215

    Google Scholar 

  • Neves H, Kwok HF (2015) Recent advances in the field of anti-cancer immunotherapy. BBA Clin 3:280–288

    Article  Google Scholar 

  • Peng D, Kryczek I, Nagarsheth N, Zhao L, Wei S, Wang W, Sun Y, Zhao E, Vatan L, Szeliga W (2015) Epigenetic silencing of T H 1-type chemokines shapes tumour immunity and immunotherapy. Nature 527:249

    Article  CAS  Google Scholar 

  • Peng W, Liu C, Xu C, Lou Y, Chen J, Yang Y, Yagita H, Overwijk WW, Lizée G, Radvanyi L (2012) PD-1 blockade enhances T-cell migration to tumors by elevating IFN-γ inducible chemokines. Cancer Res 72:5209–5218

    Article  CAS  Google Scholar 

  • Ribas A, Wolchok JD (2018) Cancer immunotherapy using checkpoint blockade. Science 359:1350–1355

    Article  CAS  Google Scholar 

  • Sharma P, Hu-Lieskovan S, Wargo JA, Ribas A (2017) Primary, adaptive, and acquired resistance to cancer immunotherapy. Cell 168:707–723

    Article  CAS  Google Scholar 

  • Sitarz R, Skierucha M, Mielko J, Offerhaus GJA, Maciejewski R, Polkowski WP (2018) Gastric cancer: epidemiology, prevention, classification, and treatment. Cancer Manag Res 10:239

    Article  CAS  Google Scholar 

  • Tumeh PC, Harview CL, Yearley JH, Shintaku IP, Taylor EJ, Robert L, Chmielowski B, Spasic M, Henry G, Ciobanu V (2014) PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature 515:568

    Article  CAS  Google Scholar 

  • Wang Y, Liu J, Bai H, Dang Y, Lv P, Wu S (2017) Long intergenic non-coding RNA 00152 promotes renal cell carcinoma progression by epigenetically suppressing P16 and negatively regulates miR-205. Am J Cancer Res 7:312

    CAS  PubMed  PubMed Central  Google Scholar 

  • Wu K, Zhao Z, Liu K, Zhang J, Li G, Wang L (2017) Long noncoding RNA lnc-sox5 modulates CRC tumorigenesis by unbalancing tumor microenvironment. Cell Cycle 16:1295–1301

    Article  CAS  Google Scholar 

  • Xue J, Yu X, Xue L, Ge X, Zhao W, Peng W (2019) Intrinsic β-catenin signaling suppresses CD8+ T-cell infiltration in colorectal cancer. Biomed Pharmacother 115:108921

    Article  CAS  Google Scholar 

  • Yang G, Lu X, Yuan L (2014) LncRNA: a link between RNA and cancer. BiochimetBiophysActa (BBA) 1839(11):1097–1109

    CAS  Google Scholar 

  • Yang T, Zeng H, Chen W, Zheng R, Zhang Y, Li Z, Qi J, Wang M, Chen T, Lou J (2016) Helicobacter pylori infection, H19 and LINC00152 expression in serum and risk of gastric cancer in a Chinese population. Cancer Epidemiol 44:147–153

    Article  CAS  Google Scholar 

  • Yu WD, Wang H, He QF, Xu Y, Wang XC (2018) Long noncoding RNAs in cancer-immunity cycle. J Cell Physiol 233:6518–6523

    Article  CAS  Google Scholar 

  • Yu Y, Yang J, Li Q, Xu B, Lian Y, Miao L (2017) LINC 00152: a pivotal oncogenic long non-coding RNA in human cancers. Cell Prolif 50:e12349

    Article  Google Scholar 

  • Zhao E, Maj T, Kryczek I, Li W, Wu K, Zhao L, Wei S, Crespo J, Wan S, Vatan L et al (2016) Cancer mediates effector T cell dysfunction by targeting microRNAs and EZH2 via glycolysis restriction. Nat Immunol 17:95–103

    Article  CAS  Google Scholar 

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Acknowledgements

The study was funded by Scientific Research Project of baoan district science and innovation bureau (2019JD254)

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  1. Jinqing Ou and Pingguang Lei contributed equally and regarded as co-first author.

Authors and Affiliations

  1. Department of Gastroenterology, Songgang People’s Hospital of Baoan, Shajiang Road NO.2, Shenzhen, 518000, China

    Jinqing Ou, Pingguang Lei, Zhenling Yang, Man Yang, Lingmin Luo, Hongdan Mo, Guijin Luo & Junhui He

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  1. Jinqing Ou
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  2. Pingguang Lei
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  7. Guijin Luo
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  8. Junhui He
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Contributions

GL and JH: designed the experiments. JO, PL, ZY, MY, LL and HM: performed the experiments. JO and PL: analyzed the data.

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Correspondence to Guijin Luo or Junhui He.

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Ou, J., Lei, P., Yang, Z. et al. LINC00152 mediates CD8+ T-cell infiltration in gastric cancer through binding to EZH2 and regulating the CXCL9, 10/CXCR3 axis. J Mol Histol 52, 611–620 (2021). https://doi.org/10.1007/s10735-021-09967-z

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