遗传变异可以通过改变 N6-甲基腺苷 (m6A) 修饰的水平来影响基因表达。更好地了解这些遗传变异与宫颈癌 (CC) 易感性的关联可以促进疾病筛查和治疗的进步。使用 TCGA 和 JENGER 数据库，结合 RNA-seq 和 MeRIP-seq 的数据，对 CC 的 m6A 相关功能 SNP 进行全基因组鉴定。筛选出的风险相关SNP rs1059288（A>G）位于TAPBP的3'UTR，在一项涉及921例病例和1077例对照的病例对照研究中得到进一步验证。结果显示 rs1059288 与 CC 风险之间存在显着相关性（OR 1.48，95% CI 1.13-1.92）。从机制上讲，与 A 等位基因相比，rs1059288 的风险 G 等位基因的存在与 TAPBP 的 m6A 修饰增加相关。 m6A 甲基转移酶 METTL14 和阅读蛋白 YTHDF2 促进了这种修饰。含有 61 个 CC 和 45 个正常组织的组织微阵列的免疫组织化学染色显示 CC 中 TAPBP 过度表达。此外，TAPBP的上调促进CC细胞的生长和迁移以及成瘤能力，抑制细胞凋亡，并增加对博莱霉素、顺铂和阿霉素等常用化疗药物的耐药性。 TAPBP 的敲低抑制了 CC 细胞中的 JAK/STAT/MICB 信号通路，并上调了某些免疫基因，包括 ISG15、IRF3、PTPN6 和 HLA-A。这些发现为 TAPBP 的遗传变异参与 CC 的发展和进展提供了见解。© 2024。作者获得 Springer-Verlag GmbH 德国（Springer Nature 旗下公司）的独家许可。

Genetic variants can affect gene expression by altering the level of N6-methyladenosine (m6A) modifications. A better understanding of the association of these genetic variants with susceptibility to cervical cancer (CC) can promote advances in disease screening and treatment. Genome-wide identification of m6A-associated functional SNPs for CC was performed using the TCGA and JENGER databases, incorporating the data from RNA-seq and MeRIP-seq. The screened risk-associated SNP rs1059288 (A>G), which is located in the 3' UTR of TAPBP, was further validated in a case-control study involving 921 cases and 1077 controls. The results revealed a significant association between rs1059288 and the risk of CC (OR 1.48, 95% CI 1.13-1.92). Mechanistically, the presence of the risk G allele of rs1059288 was associated with increased m6A modification of TAPBP compared with the A allele. This modification was facilitated by the m6A methyltransferase METTL14 and the reading protein YTHDF2. Immunohistochemical staining of tissue microarrays containing 61 CC and 45 normal tissues showed an overexpression of TAPBP in CC. Furthermore, the upregulation of TAPBP promoted the growth and migration of CC cells as well as tumor-forming ability, inhibited apoptosis, and conferred increased resistance to commonly used chemotherapeutic drugs such as bleomycin, cisplatin, and doxorubicin. Knockdown of TAPBP inhibited the JAK/STAT/MICB signaling pathway in CC cells and upregulated certain immune genes including ISG15, IRF3, PTPN6, and HLA-A. These findings offer insights into the involvement of genetic variations in TAPBP in the development and progression of CC.© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.