PAX1/JAM3双基因联合甲基化检测在宫颈病变管理中的研究进展

doi:10.12280/gjfckx.20251474

摘要/Abstract

摘要：

表观遗传学标志物在宫颈癌精准筛查中的应用价值日益凸显。其中配对盒基因1（paired box gene 1，PAX1）和连接黏附分子3（junctional adhesion molecule 3，JAM3）的异常甲基化作为宿主细胞癌变过程中的关键表观遗传事件，能够客观反映宫颈上皮细胞的异常转化状态，成为宫颈癌早期诊断的生物标志物。PAX1通过抑制Wnt/β-联蛋白（β-catenin）等多条致癌通路发挥抑癌作用，其甲基化是癌变早期敏感指标；JAM3与上皮屏障功能及肿瘤侵袭转移密切相关，甲基化水平随病变进展显著升高。二者联合甲基化检测具有较高的敏感度和特异度，显著优于传统细胞学方法，不仅能实现早期精准识别，还可有效分流人乳头瘤病毒初筛阳性者，减少不必要的阴道镜转诊，且该检测适用于“自采样”模式，有利于提升基层及资源有限地区的筛查可及性。此外，PAX1/JAM3联合甲基化检测还能预测宫颈锥切术后病理升级风险，指导个体化治疗决策。未来需通过多中心、大样本临床研究进一步确立PAX1/JAM3甲基化的标准化界值（cut-off值），该联合检测有望作为核心技术整合入宫颈癌筛查指南，推动宫颈癌筛查由“群体普查”向“个体化精准防控”模式重大转变。

关键词: 配对盒基因1, 连接黏附分子3, 甲基化, 宫颈肿瘤, 癌, 癌症早期检测

Abstract:

The application value of epigenetic biomarkers in the precision screening of cervical cancer is becoming increasingly prominent. Among these, the aberrant methylation of paired box gene 1 (PAX1) and junctional adhesion molecule 3 (JAM3) serves as a key epigenetic event during the malignant transformation of host cells. It can objectively reflect the abnormal transformation state of cervical epithelial cells, establishing itself as a biomarker for the early diagnosis of cervical cancer. PAX1 exerts tumor-suppressive role by inhibiting multiple carcinogenic pathways such as Wnt/β-catenin, and its methylation is a sensitive indicator in the early stages of carcinogenesis. JAM3 is closely related to epithelial barrier function and tumor invasion and metastasis, with its methylation level significantly increasing with disease progression. The combined methylation testing of these two genes exhibits high sensitivity and specificity, significantly outperforming traditional cytological methods. It not only enables precise and early identification but also effectively triages individuals who test positive in primary HPV screening, reducing unnecessary referrals for colposcopy. Furthermore, this test is applicable to the "self-sampling" mode, which helps improve screening accessibility in primary care and resource-limited settings. Additionally, combined PAX1/JAM3 methylation testing can predict the risk of pathological upgrading after cervical conization, guiding individualized therapeutic decisions. In the future, multi-center, large-sample clinical studies are needed to further establish standardized cut-off values for PAX1/JAM3 methylation. This combined testing is expected to be integrated as a core technology into cervical cancer screening guidelines, promoting a major shift in cervical cancer screening from "population-based screening" to a model of "individualized precision prevention and control."

Key words: Paired box gene 1, Junctional adhesion molecule 3, Methylation, Uterine cervical neoplasms, Carcinoma, Early detection of cancer

何倩楠, 黄子杰, 王一帆, 安雨声, 冯淑娴. PAX1/JAM3双基因联合甲基化检测在宫颈病变管理中的研究进展[J]. 国际妇产科学杂志, 2026, 53(3): 278-284.

HE Qian-nan, HUANG Zi-jie, WANG Yi-fan, AN Yu-sheng, FENG Shu-xian. Research Progress on Dual-Gene Methylation Testing of PAX1/JAM3 in Management of Cervical Lesion[J]. Journal of International Obstetrics and Gynecology, 2026, 53(3): 278-284.

参考文献 37

[1]	张希, 杨雷, 刘硕, 等. 2022年全球恶性肿瘤统计报告解读[J]. 中华肿瘤杂志, 2024, 46(7):710-721. doi: 10.3760/cma.j.cn112152-20240416-00152.
[2]	Li Z, Liu P, Yin A, et al. Global landscape of cervical cancer incidence and mortality in 2022 and predictions to 2030: The urgent need to address inequalities in cervical cancer[J]. Int J Cancer, 2025, 157(2):288-297. doi: 10.1002/ijc.35369. pmid: 40026066
[3]	Zhang J, Yang T, Wang K, et al. Multi-omics analysis reveals the panoramic picture of TOP2A in pan-cancer[J]. Sci Rep, 2025, 15(1):6046. doi: 10.1038/s41598-025-85929-9.
[4]	商晓, 孔令华, 肖晓萍, 等. 子宫颈细胞学PAX1/JAM3双基因甲基化检测用于子宫颈癌筛查的多中心研究[J]. 中华医学杂志, 2024, 104(20):1852-1859. doi: 10.3760/cma.j.cn12137-20231004-00630.
[5]	Zhang Y, Qiu K, Ren J, et al. Roles of human papillomavirus in cancers: oncogenic mechanisms and clinical use[J]. Signal Transduct Target Ther, 2025, 10(1):44. doi: 10.1038/s41392-024-02083-w.
[6]	Pavelescu LA, Mititelu-Zafiu NL, Mindru DE, et al. Molecular Insights into HPV-Driven Cervical Cancer: Oncoproteins, Immune Evasion, and Epigenetic Modifications[J]. Microorganisms, 2025, 13(5):1000. doi: 10.3390/microorganisms13051000.
[7]	Sen P, Ganguly P, Ganguly N. Modulation of DNA methylation by human papillomavirus E6 and E7 oncoproteins in cervical cancer[J]. Oncol Lett, 2018, 15(1):11-22. doi: 10.3892/ol.2017.7292. pmid: 29285184
[8]	Soto D, Song C, McLaughlin-Drubin ME. Epigenetic Alterations in Human Papillomavirus-Associated Cancers[J]. Viruses, 2017, 9(9):248. doi: 10.3390/v9090248.
[9]	Obanya DI, Wootton LM, Morgan EL. Advances in understanding the mechanisms of the human papillomavirus oncoproteins[J]. Biochem Soc Trans, 2025, 53(3):565-577. doi: 10.1042/BST20253041.
[10]	Rusan M, Li YY, Hammerman PS. Genomic landscape of human papillomavirus-associated cancers[J]. Clin Cancer Res, 2015, 21(9):2009-2019. doi: 10.1158/1078-0432.CCR-14-1101. pmid: 25779941
[11]	Yakici N, Kreins AY, Catak MC, et al. Expanding the clinical and immunological phenotypes of PAX1-deficient SCID and CID patients[J]. Clin Immunol, 2023, 255:109757. doi: 10.1016/j.clim.2023.109757.
[12]	Zhang W, Wang H, Chen S, et al. Reactivation of methylation-silenced PAX1 inhibits cervical cancer proliferation and migration via the WNT/TIMELESS pathway[J]. Mol Carcinog, 2024, 63(7):1349-1361. doi: 10.1002/mc.23728.
[13]	Su PH, Lai HC, Huang RL, et al. Paired Box-1 (PAX1) Activates Multiple Phosphatases and Inhibits Kinase Cascades in Cervical Cancer[J]. Sci Rep, 2019, 9(1):9195. doi: 10.1038/s41598-019-45477-5.
[14]	Anisimova M, Jain M, Shcherbakova L, et al. Detection of CADM1, MAL, and PAX1 Methylation by ddPCR for Triage of HPV-Positive Cervical Lesions[J]. Biomedicines, 2025, 13(6):1450. doi: 10.3390/biomedicines13061450.
[15]	Zhou XY, Chen MM, Yu JM, et al. Interaction of MTHFR polymorphism with PAX1 methylation in cervical cancer[J]. Open Life Sci, 2025, 20(1):20221052. doi: 10.1515/biol-2022-1052.
[16]	Lauko A, Mu Z, Gutmann DH, et al. Junctional Adhesion Molecules in Cancer: A Paradigm for the Diverse Functions of Cell-Cell Interactions in Tumor Progression[J]. Cancer Res, 2020, 80(22):4878-4885. doi: 10.1158/0008-5472.CAN-20-1829. pmid: 32816855
[17]	Peng J, Chen Y, Yin A. JAM3 promotes cervical cancer metastasis by activating the HIF-1α/VEGFA pathway[J]. BMC Womens Health, 2024, 24(1):293. doi: 10.1186/s12905-024-03127-7. pmid: 38760803
[18]	Yin A, Zhang Q, Kong X, et al. JAM3 methylation status as a biomarker for diagnosis of preneoplastic and neoplastic lesions of the cervix[J]. Oncotarget, 2015, 6(42):44373-44387. doi: 10.18632/oncotarget.6250. pmid: 26517242
[19]	Mersakova S, Nachajova M, Szepe P, et al. DNA methylation and detection of cervical cancer and precancerous lesions using molecular methods[J]. Tumour Biol, 2016, 37(1):23-27. doi: 10.1007/s13277-015-4197-1.
[20]	Li X, Zhou X, Zeng M, et al. Methylation of PAX1 gene promoter in the prediction of concurrent chemo-radiotherapy efficacy in cervical cancer[J]. J Cancer, 2021, 12(17):5136-5143. doi: 10.7150/jca.57460.
[21]	Gu Y, Chu C, Yuan B, et al. Expression and hypermethylation of JAM and EPB41L3 in cervical squamous cell carcinoma: Clinical significance and applications[J]. Histol Histopathol, 2024, 39(8):1043-1051. doi: 10.14670/HH-18-697.
[22]	陈飞, 王华庆, 赵方辉. 中国子宫颈癌三级规范化防治蓝皮书[M]. 北京: 人民卫生出版社, 2023.
[23]	余芙蓉, 马洁稚, 周希, 等. 女性阴道自采样本检测PAX1/JAM3双基因甲基化标志物作为子宫颈癌筛查的可行性评估[J]. 中华检验医学杂志, 2024, 47(4):419-427. doi: 10.3760/cma.j.cn114452-20240109-00016.
[24]	de Waard J, Bhattacharya A, de Boer MT, et al. Methylation Analysis to Detect CIN3+ in High-Risk Human Papillomavirus-Positive Self-Samples From the Population-Based Cervical Cancer Screening Program[J]. Mod Pathol, 2024, 37(8):100528. doi: 10.1016/j.modpat.2024.100528.
[25]	Verhoef L, Bleeker M, Polman N, et al. Evaluation of DNA methylation biomarkers ASCL1 and LHX8 on HPV-positive self-collected samples from primary HPV-based screening[J]. Br J Cancer, 2023, 129(1):104-111. doi: 10.1038/s41416-023-02277-z.
[26]	Chen S, Dai H, Hu S, et al. Novel triple-target panels utilizing methylation-sensitive restriction enzyme-based quantitative PCR for detecting advanced cervical precancers and cancers among high-risk HPV-positive women[J]. J Transl Med, 2025, 23(1):857. doi: 10.1186/s12967-025-06822-7. pmid: 40750892
[27]	中国中西医结合学会检验医学专业委员会, 中华医学会检验医学分会, 中国医师协会检验医师分会, 等. 子宫颈癌PAX1联合JAM3双基因甲基化检测流程、报告及临床应用专家共识[J]. 中华检验医学杂志, 2025, 48(2):192-200. doi: 10.3760/cma.j.cn114452-20241017-00566.
[28]	Sun D, Shu C, Zeng F, et al. The performance of JAM3/PAX1 methylation in the diagnosis of high-grade squamous intraepithelial lesions for women with high-risk HPV infection[J]. BMC Cancer, 2024, 24(1):1514. doi: 10.1186/s12885-024-13299-y. pmid: 39696066
[29]	De Strooper L, Berkhof J, Steenbergen R, et al. Cervical cancer risk in HPV-positive women after a negative FAM19A4/mir124-2 methylation test: A post hoc analysis in the POBASCAM trial with 14 year follow-up[J]. Int J Cancer, 2018, 143(6):1541-1548. doi: 10.1002/ijc.31539. pmid: 29663363
[30]	Fei J, Zhai L, Wang J, et al. Evaluating PAX1/JAM3 methylation for triage in HPV 16/18-infected women[J]. Clin Epigenetics, 2024, 16(1):190. doi: 10.1186/s13148-024-01804-w. pmid: 39726021
[31]	中华预防医学会肿瘤预防与控制专业委员会, 中国医师协会妇产科医师分会阴道镜与宫颈病变专业委员会, 中国优生科学协会阴道镜和子宫颈病理学分会, 等. 人乳头状瘤病毒核酸检测用于宫颈癌筛查中国专家共识(2022)[J]. 中华医学杂志, 2023, 103:1184-1195. doi: 10.3760/cma.j.cn112137-20230117-00096.
[32]	Dick S, Kremer WW, De Strooper L, et al. Long-term CIN3+ risk of HPV positive women after triage with FAM19A4/miR124-2 methylation analysis[J]. Gynecol Oncol, 2019, 154(2):368-373. doi: 10.1016/j.ygyno.2019.06.002. pmid: 31182225
[33]	Chen X, Jiang H, Xu H, et al. Cervical cancer screening: efficacy of PAX1 and JAM3 methylation assay in the triage of atypical squamous cell of undetermined significance (ASC-US)[J]. BMC Cancer, 2024, 24(1):1385. doi: 10.1186/s12885-024-13082-z. pmid: 39528979
[34]	Shang X, Kong L, You Y, et al. Cytologic DNA methylation for managing minimally abnormal cervical cancer screening results[J]. Int J Gynaecol Obstet, 2025, 171(1):405-414. doi: 10.1002/ijgo.70167. pmid: 40238123
[35]	Chen X, Xu H, Zhao L, et al. The role of PAX1 and JAM3 methylation in predicting the pathological upgrading of cervical intraepithelial neoplasia before conization[J]. Sci Rep, 2025, 15(1):17684. doi: 10.1038/s41598-025-01422-3.
[36]	Ebisch R, Rutten D, IntHout J, et al. Long-Lasting Increased Risk of Human Papillomavirus-Related Carcinomas and Premalignancies After Cervical Intraepithelial Neoplasia Grade 3: A Population-Based Cohort Study[J]. J Clin Oncol, 2017, 35(22):2542-2550. doi: 10.1200/JCO.2016.71.4543. pmid: 28541790
[37]	Dick S, Heideman D, Mom CH, et al. Methylation testing for the detection of recurrent cervical intraepithelial neoplasia[J]. Int J Cancer, 2023, 153(12):2011-2018. doi: 10.1002/ijc.34678. pmid: 37539971