Downregulation of PAX1 in OSCC enhances stemness and immunosuppression via IFIT1 and PD-L1 pathways. A systematic review.
DOI:
https://doi.org/10.51168/sjhrafrica.v6i12.2199Keywords:
Paired box gene 1, oral squamous cell carcinoma, interferon-induced protein with tetratricopeptide repeats 1, programmed death-ligand 1, stemness, immunosuppressionAbstract
Background:
Oral squamous cell carcinoma (OSCC) remains a leading cause of cancer-related morbidity and mortality worldwide. Epigenetic alterations, particularly the hypermethylation-mediated downregulation of paired box gene 1 (PAX1), have been implicated in OSCC progression. Recent evidence suggests that PAX1 silencing may enhance stemness and immunosuppression through the interferon-induced protein with tetratricopeptide repeats 1 (IFIT1) and programmed death-ligand 1 (PD-L1) pathways, thereby promoting tumor aggressiveness and immune evasion.
Aim:
To systematically review and synthesize the available evidence on the downregulation of PAX1 in OSCC, with a focus on its role in enhancing stemness and immunosuppression via IFIT1 and PD-L1 pathways.
Materials and Methods:
A comprehensive search of PubMed, Scopus, Web of Science, and Google Scholar was conducted for studies published up to 15 May 2025. Inclusion criteria comprised original research studies on human OSCC samples or relevant experimental models, evaluating PAX1 expression or methylation status in relation to stemness, immunosuppression, IFIT1, or PD-L1 signaling. Exclusion criteria included reviews, editorials, conference abstracts without full data, studies on non-OSCC malignancies (unless OSCC-specific data were provided), and studies lacking direct assessment of PAX1 status.
Results:
Seven studies met the inclusion criteria. PAX1 hypermethylation was consistently associated with transcriptional downregulation in OSCC tissues, correlating with advanced tumor stage, lymph node metastasis, and poor prognosis. Mechanistic studies revealed that PAX1 silencing activated IFIT1-driven signaling and upregulated PD-L1 expression, leading to enhanced cancer stem cell properties and suppression of anti-tumor immunity.
Conclusion:
Downregulation of PAX1 through promoter hypermethylation plays a critical role in OSCC progression by enhancing stemness and immunosuppressive mechanisms via IFIT1 and PD-L1 pathways. These findings highlight PAX1 as a promising biomarker for risk stratification and as a potential therapeutic target to counteract tumor aggressiveness and immune evasion.
References
Tan Y, Wang Z, Xu M, Li B, Huang Z, Qin S, Nice EC, Tang J, Huang C. Oral squamous cell carcinomas: state of the field and emerging directions. Int J Oral Sci. 2023 Sep 22;15(1):44. doi: 10.1038/s41368-023-00249-w. PMID: 37736748; PMCID: PMC10517027. https://doi.org/10.1038/s41368-023-00249-w
Wang B, Zhang S, Yue K, Wang XD. The recurrence and survival of oral squamous cell carcinoma: a report of 275 cases. Chin J Cancer. 2013 Nov;32(11):614-8. doi: 10.5732/cjc 012.10219. Epub 2013 Apr 19. PMID: 23601241; PMCID: PMC3845544. https://doi.org/10.5732/cjc.012.10219
Choi S, Myers JN. Molecular pathogenesis of oral squamous cell carcinoma: implications for therapy. J Dent Res. 2008 Jan;87(1):14-32. Doi: 10.1177/154405910808700104. Erratum in: J Dent Res. 2008 Feb;87(2):191. PMID: 18096889. https://doi.org/10.1177/154405910808700104
Wu W, Kong X, Jia Y, Jia Y, Ou W, Dai C, Li G, Gao R. An overview of PAX1: Expression, function and regulation in development and diseases. Front Cell Dev Biol. 2022 Oct 28;10:1051102. Doi: 10.3389/fcell.. 2022.1051102. PMID: 36393845; PMCID: PMC9649799. https://doi.org/10.3389/fcell.2022.1051102
Huang, Tien-Hung & Lai, Hung-Cheng & Liu, Hwan-Wun & Lin, Cuei & Wang, Kai-Hung & Ding, Dah-Ching & Chu, Tang. (2010). Quantitative Analysis of Methylation Status of the PAX1 Gene for Detection of Cervical Cancer. International journal of gynecological cancer: official journal of the International Gynecological Cancer Society. 20. 513-9. 10.1111/IGC.0b013e3181c7fe6e. https://doi.org/10.1111/IGC.0b013e3181c7fe6e
Fang C, Wang SY, Liou YL, Chen MH, Ouyang W, Duan KM. The promising role of PAX1 (aliases: HUP48, OFC2) gene methylation in cancer screening. Mol Genet Genomic Med. 2019 Mar;7(3):e506. Doi: 10.1002/mgg3.506. Epub 2019 Jan 12. PMID: 30636379; PMCID: PMC6418350. https://doi.org/10.1002/mgg3.506
Xue Y, Zhao C, Liu T. Interferon-induced protein with tetratricopeptide repeats 1 (IFIT1) accelerates osteoclast formation by regulating signal transducer and activator of transcription 3 (STAT3) signalling. Bioengineered. 2022 Feb;13(2):2285-2295. doi: 10.1080/21655979.2021.2024333. PMID: 35034537; PMCID: PMC8973581. https://doi.org/10.1080/21655979.2021.2024333
Han Y, Liu D, Li L. PD-1/PD-L1 pathway: current cancer research. Am J Cancer Res. 2020 Mar 1;10(3):727-742. PMID: 32266087; PMCID: PMC7136921.
Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, Shamseer L, Tetzlaff JM, Akl EA, Brennan SE, Chou R, Glanville J, Grimshaw JM, Hróbjartsson A, Lalu MM, Li T, Loder EW, Mayo-Wilson E, McDonald S, McGuinness LA, Stewart LA, Thomas J, Tricco AC, Welch VA, Whiting P, Moher D. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ. 2021 Mar 29;372:n71. Doi: 10.1136/bmj.n71. PMID: 33782057; PMCID: PMC8005924. https://doi.org/10.1136/bmj.n71
Ko HH, Peng HH, Chou HE, Hou HH, Liu WW, Kuo MY, Lee AY, Kao HF, Lin HY, Chang YC, Kuo WT, Cheng SJ. Downregulation of PAX1 in OSCC Enhances Stemness and Immunosuppression via IFIT1 and PD-L1 Pathways. Oral Dis. 2025 Jul;31(7):2071-2083. Doi: 10.1111/odi 15225. Epub 2025 Jan 2. PMID: 39748231. https://doi.org/10.1111/odi.15225
Mao YQ, Sun R, Liu S, Zhang WB, Yu Y, Jia LF, Yu GY, Peng X. Distribution of PAX1 and ZNF582 Hypermethylation in the Oral Exfoliated Cells of Oral Squamous Cell Carcinoma. Clin Med Insights Oncol. 2025 May 16;19:11795549251335172. Doi: 10.1177/11795549251335172. PMID: 40386310; PMCID: PMC12084697. https://doi.org/10.1177/11795549251335172
Liu P, Kong X, Yi S, Chen Y, Luo W. IFIT3 accelerates the progression of head and neck squamous cell carcinoma by targeting PD-L1 to activate PI3K/AKT signaling pathway. World J Surg Oncol. 2024 Jan 25;22(1):34. doi: 10.1186/s12957-023-03274-5. PMID: 38273364; PMCID: PMC10809513. https://doi.org/10.1186/s12957-023-03274-5
Weber M, Lutz R, Olmos M, Glajzer J, Baran C, Nobis CP, Möst T, Eckstein M, Kesting M, Ries J. Beyond PD-L1-Identification of Further Potential Therapeutic Targets in Oral Cancer. Cancers (Basel). 2022 Apr 2;14(7):1812. doi: 10.3390/cancers14071812. PMID: 35406584; PMCID: PMC8997752. https://doi.org/10.3390/cancers14071812
Sun R, Juan YC, Su YF, Zhang WB, Yu Y, Yang HY, Yu GY, Peng X. Hypermethylated PAX1 and ZNF582 genes in the tissue sample are associated with aggressive progression of oral squamous cell carcinoma. J Oral Pathol Med. 2020 Sep;49(8):751-760. doi: 10.1111/jop.13035. Epub 2020 Jun 3. PMID: 32428271. https://doi.org/10.1111/jop.13035
Cheng SJ, Chang CF, Ko HH, Liu YC, Peng HH, Wang HJ, Lin HS, Chiang CP. Hypermethylated ZNF582 and PAX1 genes in oral scrapings collected from cancer-adjacent normal oral mucosal sites are associated with aggressive progression and poor prognosis of oral cancer. Oral Oncol. 2017 Dec;75:169-177. doi: 10.1016/j.oraloncology.2017.11.013. Epub 2017 Nov 17. PMID: 29224816. https://doi.org/10.1016/j.oraloncology.2017.11.013
Huang, Y. K., Peng, B. Y., Wu, C. Y., Su, C. T., Wang, H. C., & Lai, H. C. (2014). DNA methylation of PAX1 as a biomarker for oral squamous cell carcinoma. Clinical Oral Investigations, 18(3), 801-808. https://doi.org/10.1007/s00784-013-1048-6
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Copyright (c) 2025 Dr. Dorai Aruna Raj, Dr. A.Selvam, Dr. P. Perumal, Dr. Evangeline Cynthia Dhinakaran, Dr.Karthik Shunmugavelu
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