Expression and significance of novel tumour-testis antigens CT10, SSX1 induced by low dose of 5-aza-2’-deoxycytidine in hepatocellular carcinoma cell HepG2
ZHANG He ZHAO Huixia ZENG Zhiyan LI Qingyan YUN Chao GUAN Na LI Quiwen XIAO Wenhua
Department of Oncology, Fourth Medical Center of People’s Liberation Army General Hospital, Beijing 100048, China
Abstract：Objective To explore expression and significance of novel tumour-testis antigens CT10, SSX1 induced by low dose of 5-aza-2’-deoxycytidine(5-aza-CdR) in hepatocellular carcinoma cell HepG2. Methods The six mRNA expression of MAGE1, MAGE3, CT10, CTp11, NE-ESO-1, and SSX1 in HepG2, SMMC-7721, BEL-7402, MHCC97L and MHCC97M3 liver cancer cell lines were detected by RT-PCR. HepG2 cells that do not express CT10 and SSX1 were selected as the study object as nCTAs, and HepG2 cells were treated with 0, 0.5, 1.0, and 1.5 μmol/L 5-aza-CdR. The control group did not contain 5-aza-CdR, from low to high concentration, they were experiment 1, 2, and 3 groups respectively, the mRNA and protein expressions of CT10 and SSX1 were detected by RT-PCR and Western blot, respectively. Results Different nCTAs expression was found in five hepatocellular cells, the expression was heterogeneous, among them MAGE1, MAGE3, CTp11, and NY-ESO-1 expression in HepG2; MAGE1, MAGE3, CT10, CTp11, and SSX1 expression in both MHCC97L and MHCC97M3; MAGE1, MAGE3, and CTp11 expression in BEL-7402; however, SMMC-7721 only expresses MAGE1 and MAGE3. Experimental 1, 2, and 3 groups could induce the expression of CTA-CT10 and SSX1, among them, 0.5 μmol/L small dose of experiment group 1 could also induce the expression of nCTAs, the relative expression of nCTAs induced in experiment 3 group was significantly higher than that in experiment 1 and 2 group, and the differences were statistically significant (P＜0.05). Conclusion Different hepatocellular carcinoma cells expressed different CTAs, and a small dose of 5-aza-CdR could induce the expression of nCTAs in hepatocellular carcinoma cell lines.
[1] Sangro B，Sarobe P，Hervás-Stubbs S，et al. Advances in immunotherapy for hepatocellular carcinoma [J]. Nat Rev Gastroenterol Hepatol，2021，18（8）：525-543.
[2] Ma W，Pham B，Li T. Cancer neoantigens as potential targets for immunotherapy [J]. Clin Exp Metastasis，2021，5：1-10.
[3] Yang P，Meng M，Zhou Q. Oncogenic cancer/testis antigens are a hallmarker of cancer and a sensible target for cancer immunotherapy [J]. Biochim Biophys Acta Rev Cancer，2021， 1876（1）：188558.
[4] Schietinger A，Philip M，Krisnawan V，et al. Tumor-specific T cells dysfuction is a dynamic antgens-driven differentiation program initiated early during tumourigenesis [J]. Immunity，2016，45（2）：389-401.
[5] Xiao WH，Sanren GW，Zhu JH，et al. Effect of 5-Aza-2’- deoxycytidine on immune-associated proteins in exosomes from hepatoma [J]. World J Gastroentero，2010，16（19）：2371-2377.
[6] Yamamoto TN，Kishton RJ，Restifo NP. Developing neoantigen-targeted T cell-based treatments for solid tumors [J]. Nat Med，2019，25（10）：1488-1499.
[7] Meng X，Sun X，Liu Z，et al. A novel era of cancer/testis antigen in cancer immunotherapy [J]. Int Immunopharmacol，2021，98：107889.
[8] Bagchi S，Yuan R，Engleman EG. Immune Checkpoint Inhibitors for the Treatment of Cancer：Clinical Impact and Mechanisms of Response and Resistance [J]. Annu Rev Pathol，2021，16：223-249.
[9] Jerby-Arnon L，Shah P，Cuoco MS，et al. A Cancer Cell Program Promotes T Cell Exclusion and Resistance to Checkpoint Blockade [J]. Cell，2018，175（4）：984-997.
[10] 肖文华，刘丽华.5-脱氧杂氮胞苷抑制肝癌细胞DNA甲基转移酶转录[J].肿瘤防治研究，2001，29（4）：294-295.
[11] Li Z，Guo P，Guo PY，et al. 5-aza-2’-deoxycytidine （DAC） treatment induces the MAGE-A10 expression and improves the cytotoxicity of MAGE-A10-specific CTLs in lung cancer cells [J]. Trans Cancer Res，2020，9（2）：1235-1245.
[12] Bull C，Mayrhofer G，Fenech M. Exposure to hypomethylating 5-aza-2’-dexoycytidine （decitabine） causes rapid，severe DNA damage，telomere elongation and mistotic dysfuction in human WIL2-NS cells [J]. Mut Res Gene Toxicol Environ Mutagen，2021，868-869：503385.
[13] Tsai HC，Li H，Neste LV，et al. Transient low doses of DNA demethylating agents exert durable anti-tumor effects on hemaotlogical and epithlial tumor cells [J]. Cancer Cell，2012，21（3）：430-446.
[14] Hill B，Jagadeesh D，Pohlman B，et al. A pilot clinical trial of oral tetrahydrouridine/decitabine for noncytotoxic epigenetic therapy of chemoresistant lymphoid malignancies [J]. Semin Hematol，2021，58（1）：35-44.
[15] Chi P，Wang X. Reactivation of oncogenes involved in G1/S transcription and apoptosis pathway by low dose decitabine promotes HT29 human colon cancer cell growth in vitro [J]. Am J Transl Res，2020，12（12）：7938-7952.
[16] Ge YY，Zhang QM，Liu C，et al. Combined treatment with epigenetic agents enhances anti-tumor activity of T cell by upregulating the ACRBP expression in hepatocellur carcinoma [J]. Am J Trans Res，2021，13（7）：7591-7609.
[17] Klasic M，Kristic J，Korac P，et al. DNA hypomethylation upregulate expression of the MGAT3 gene in HepG2 cells and leads to changes in N-glycosylation of secreted glycoproteins [J]. Sci Rep，2016，6：24363.
[18] Wu Y，Zhang X，Liu Y，et al. Decreased expression of BNC1 and BNC2 is associated with genetic or epgenetic regulation in hepatocellular carcinoma [J]. Int J Mol Sci，2016，17（2）：153.
[19] Karpf AR，Lasek AW，Ririe TO，et al. Limited gene activating in tumour and normal epithelial cells treated with the DNA methylatransferase inhibitor 5-aza-2’-doxycytidine [J]. Mol Pharmacol，2004，65：18-27.
[20] Jansen YTL，Verset G，Schats K，et al. Phase I clinical trial of decitabine （5-aza-2’-deoxycytidine）administered by hepatic arterial infusion in patients with unsectable liver-predominant metastases [J]. ESMO Open，2019，4（2）：e000464.
[21] Zhu H，Yang B，Liu J，et al. A novel treatment regimen of granulocyte colony-stimulating factor combined with ultra-low-dose decitabine and low-dose cytarabine in older patients with acute myeloid leukemia and myelodysplastic syndromes [J]. Ther Adv Hematol，2021，12：1-10.
[22] Li H，Wang L，Wu Y，et al. Very-low-dose decitabine is effective in treating intermediate or high-risk myelodysplastic syndrome [J]. Acta Hematol，2017，138（3）：168-174.
[23] Wyli B，Chee J，Forbes CA，et al. Acquired resistance during adoptive cell therapy by transcriptional silencing of immunogenic antigens [J]. Oncoimmunology，2019，8（8）：1609874.
[24] Chen M，Nie J，Liu Y，et al. Phse Ⅰb/Ⅱ study of safety and efficacy of low-dose decitabine-primed chemoimmunotherapy in patients with drug-resistant relapsed/refractory alimentary tract cancer [J]. Int J Cancer，2018，143（6）：1530- 1540.
[25] Liu Y，Wang C，Li X，et al. Improved clinical outcome in a radomized phase Ⅱ study of anti-PD-1 Camrelizumab plus decitabine in relapsed/refractory Hodgkin lymphoma [J]. J Immunother Cancer，2021，9（4）：e002347.
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