Barx2 Drives Tumor-specific MHC-Ⅱ Signaling to Induce CD4+T/CD8+T Cell Activation in Oral Squamous Cell Carcinoma

doi:10.13701/j.cnki.kqyxyj.2023.08.005

Abstract

Abstract: Objective: To explore the mechanism of BarH-like homeobox 2 (Barx2) killing tumor cells by promoting MHC Class Ⅱ molecules. Methods: The expression levels of CⅡTA/MHC-Ⅱ related molecules in Barx2 overexpressed OSCC cell lines were analyzed by high-throughput sequencing, qPCR, and Western Blot. The combination of Barx2 and CⅡTA pⅢ promoter was verified by double luciferase assay. Human peripheral blood mononuclear cells (PBMC) were extracted and co-cultured with tumor cells in the control group and Barx2 overexpression group, and the number of tumor cells was detected by crystal violet staining. The proliferation activity of CD4⁺T cells and CD8⁺T cells in PBMC was analyzed by flow cytometry after labeling PBMC with CFSE. Results: High-throughput transcriptome sequencing results combined with GSEA gene set enrichment analysis and KEGG signaling pathway analysis showed that overexpression of Barx2 enhanced the up-regulation of factors related to antigen processing and presentation pathway and MHC-Ⅱ signaling molecules. In Barx2 overexpressed cell lines, qPCR and Western blot further confirmed the significant upregulation of the above genes. Barx2 could directly bind upstream to CⅡTA pⅢ promoter. After co-culture with PBMC, the number of tumor cells overexpressing Barx2 was significantly less than that in the control group. Overexpression of Barx2 tumor cells promoted the proliferation of CD4⁺T and CD8⁺T cells. Conclusion: Barx2 can drive the activation of CⅡTA/MHC-Ⅱ signal axis, induce the expression of HLA-DR-dominated MHC-Ⅱ class molecules in tumor cells, and further activate CD4⁺T and CD8⁺T cells to play a role in killing tumor cells.

Key words: BarH-like homeobox 2, MHC-Ⅱ, oral squamous cell carcinoma, immunity to tumors

LI Yiwei, SUN Yanan, PAN Junchen, HU Yaying, ZHANG Yuying, MA Jiyuan, ZHANG Jiali. Barx2 Drives Tumor-specific MHC-Ⅱ Signaling to Induce CD4⁺T/CD8⁺T Cell Activation in Oral Squamous Cell Carcinoma[J]. Journal of Oral Science Research, 2023, 39(8): 684-689.

References

[1] Axelrod ML, Cook RS, Johnson DB, et al. Biological consequences of MHC-Ⅱ expression by tumor cells in cancer [J]. Clin Cancer Res, 2019, 25(8): 2392-2402.
[2] Sander G, Bawden CS, Hynd PI, et al. Expression of the homeobox gene, Barx2, in wool follicle development [J]. J Invest Dermatol, 2000, 115(4): 753-756.
[3] Jones FS, Kioussi C, Copertino DW, et al. Barx2, a new homeobox gene of the Bar class, is expressed in neural and craniofacial structures during development [J]. Proc Natl Acad Sci U S A, 1997, 94(6): 2632-2637.
[4] Makarenkova HP, Meech R. Barx homeobox family in muscle development and regeneration [J]. Int Rev Cell Mol Biol, 2012, 297: 117-173.
[5] Zhang J, Zhang T, Tang B, et al. The miR-187 induced bone reconstruction and healing in a mouse model of osteoporosis, and accelerated osteoblastic differentiation of human multipotent stromal cells by targeting BARX2 [J]. Pathol Res Pract, 2021, 219: 153340.
[6] Ma J, Xia LL, Yao XQ, et al. BARX2 expression is downregulated by CpG island hypermethylation and is associated with suppressed cell proliferation and invasion of gastric cancer cells [J]. Oncol Rep, 2020, 43(6): 1805-1818.
[7] Yang F, Shao C, Wei K, et al. miR-942 promotes tumor migration, invasion, and angiogenesis by regulating EMT via BARX2 in non-small-cell lung cancer [J]. J Cell Physiol, 2019, 234(12): 23596-23607.
[8] Liu Y, Hu Y, Zhao C, et al. CircRNA B cell linker regulates cisplatin sensitivity in nonsmall cell lung cancer via micro RNA-25-3p/BarH-like homeobox 2 axis [J]. Anticancer Drugs, 2023, 34(5):640-651.
[9] Lu Z, Peng H, Li R, et al. BarH-like homeobox 2 represses the transcription of keratin 16 and affects Ras signaling pathway to suppress nasopharyngeal carcinoma progression [J]. Bioengineered, 2022, 13(2): 3122-3136.
[10] Leibundgut-Landmann S, Waldburger JM, Krawczyk M, et al. Mini-review: Specificity and expression of CⅡTA, the master regulator of MHC class Ⅱ genes [J]. Eur J Immunol, 2004, 34(6): 1513-1525.
[11] Bou Nasser Eddine F, Forlani G, Lombardo L, et al. CⅡTA-driven MHC class Ⅱ expressing tumor cells can efficiently prime naive CD4(+) TH cells in vivo and vaccinate the host against parental MHC-Ⅱ-negative tumor cells [J]. Oncoimmunology, 2017, 6(1): e1261777.
[12] Nakano N, Nishiyama C, Yagita H, et al. Notch1-mediated signaling induces MHC class Ⅱ expression through activation of class Ⅱ transactivator promoter Ⅲ in mast cells [J]. J Biol Chem, 2011, 286(14): 12042-12048.
[13] Mccaw TR, Li M, Starenki D, et al. The expression of MHC class Ⅱ molecules on murine breast tumors delays T-cell exhaustion, expands the T-cell repertoire, and slows tumor growth [J]. Cancer Immunol Immunother, 2019, 68(2): 175-188.
[14] Johnson DB, Estrada MV, Salgado R, et al. Melanoma-specific MHC-Ⅱ expression represents a tumour-autonomous phenotype and predicts response to anti-PD-1/PD-L1 therapy [J]. Nat Commun, 2016, 7: 10582.
[15] Oh DY, Kwek SS, Raju SS, et al. Intratumoral CD4(+) T cells mediate anti-tumor cytotoxicity in human bladder cancer [J]. Cell, 2020, 181(7): 1612-1625.

Barx2 Drives Tumor-specific MHC-Ⅱ Signaling to Induce CD4⁺T/CD8⁺T Cell Activation in Oral Squamous Cell Carcinoma

PDF (PC)

Knowledge

Abstract

Cite this article

share this article

References

Related Articles 15

Recommended Articles

Metrics

[1]	CHEN Zhuoxuan, CHEN Linlin. Recent Advance on Examination Methods of Invasion Depth of Early Oral Tongue Squamous Cell Carcinoma [J]. Journal of Oral Science Research, 2023, 39(6): 487-490.
[2]	YANG Ke, SUN Yanan, HU Yaying, LV Yinan, ZHEN Xiaofeng, LI Yiwei, ZHANG Jiali. Prediction of Prognosis of HPV-negative Oral and Oropharyngeal Squamous Cell Carcinoma by Deep Learning Identification and Prediction Model of Cyclin D1 Expression Pattern [J]. Journal of Oral Science Research, 2023, 39(4): 308-315.
[3]	JIANG Zhimin, MA Guowu, SUN Bo. Nomograms to Predict the Prognosis in Locally Advanced Oral Squamous Cell Carcinoma after Curative Resection [J]. Journal of Oral Science Research, 2023, 39(1): 56-61.
[4]	PENG Yanshuang, LIU Ying. Review on the Role and Mechanism of Sox Gene in Oral Squamous Cell Carcinoma [J]. Journal of Oral Science Research, 2022, 38(4): 312-315.
[5]	HU Qingang, NI Yanhong, WANG Yuhan. Application of Metabolomics in the Early Diagnosis and Precise Treatment of Oral Squamous Cell Carcinoma [J]. Journal of Oral Science Research, 2022, 38(3): 207-211.
[6]	LI Yang, LI Wen, CHEN Zhuo, LI Shuaize, QIAO Bin. Detection of Epithelial-mesenchymal Transition Status of Circulating Tumor Cells in Patients with Oral Squamous Cell Carcinoma [J]. Journal of Oral Science Research, 2022, 38(1): 34-38.
[7]	LI Lei, CHEN Yanping, YANG Kaicheng, LI You, WANG Xinchen, LUO Fengyu. Analysis of AKR1C3 Expression in Oral Squamous Cell Carcinoma Based on GEO [J]. Journal of Oral Science Research, 2021, 37(6): 514-518.
[8]	ZHANG Xu, LIU Jiawen. Expression and Significance of MMP-9, COX-2, and NF-κB in Oral Squamous Cell Carcinoma [J]. Journal of Oral Science Research, 2021, 37(4): 360-365.
[9]	YIN Fang, LI Jinjie, GONG Ping, ZHOU Tengpeng, LIU Kebin, ZHANG Tiejun. Effect of Two Different General Anesthesia Methods on Immune Function of Oral Squamous Cell Carcinoma Patients: A Randomized Controlled Study [J]. Journal of Oral Science Research, 2021, 37(2): 153-156.
[10]	GAO Antian, LIN Zitong. Advancement of Optical Imaging on Precise Assessment for Surgical Margin of Oral Squamous Cell Carcinoma [J]. Journal of Oral Science Research, 2020, 36(5): 413-415.
[11]	HU Qingang, ZHAO Xingxing. Advancement of Cancer-associated Fibroblasts in Oral Squamous Cell Carcinoma [J]. Journal of Oral Science Research, 2020, 36(4): 309-313.
[12]	GUO Junfeng, ZHANG Gang, TAN Yinghui. Expression of CYP27B1 in Oral Squamous Cell Carcinoma and Its Relationship with Prognosis [J]. Journal of Oral Science Research, 2020, 36(10): 930-933.
[13]	XIE Long, SANG Lei, SONG Zhuoying, JIANG Yanjun. Diagnostic Values of Salivary MicroRNA-375 for OSCC and Its Effects on Biological Function of OSCC Cells [J]. Journal of Oral Science Research, 2019, 35(9): 883-888.
[14]	GAO Xu, ZHOU Yang, LI Chen, XUE Xiao-han, WEI Xiu-feng. Expression and Significance of Eya4 in Oral Squamous Cell Carcinoma [J]. Journal of Oral Science Research, 2019, 35(6): 555-558.
[15]	ZHOU Tong, ZHANG Tong-fei, ZHANG Ze-bing, QUAN Hai-ying. Influence of MSA on Proliferation, Migration, Apoptosis, and Cell Cycle of Oral Squamous Cell Carcinoma Tca8113 and KB Cells [J]. Journal of Oral Science Research, 2019, 35(6): 568-572.