A genetic variant in the TAPBP gene enhances cervical cancer susceptibility by increasing m6A modification

IF 4.8 2区 医学 Q1 TOXICOLOGY Archives of Toxicology Pub Date : 2024-07-12 DOI:10.1007/s00204-024-03820-4
Jing Hu, Shizhi Wang, Xing Zhang, Wenjing Yan, Haohan Liu, Xue Chen, Yamei Nie, Fengying Liu, Yun Zheng, Yiran Lu, Hua Jin
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Abstract

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.

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TAPBP 基因中的一个遗传变异会通过增加 m6A 修饰来提高宫颈癌的易感性。
基因变异可通过改变 N6-甲基腺苷(m6A)修饰水平来影响基因表达。更好地了解这些基因变异与宫颈癌(CC)易感性的关系,可以促进疾病筛查和治疗的进步。我们利用 TCGA 和 JENGER 数据库,结合 RNA-seq 和 MeRIP-seq 数据,对与宫颈癌相关的 m6A 功能 SNPs 进行了全基因组鉴定。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了进一步验证。结果显示,rs1059288 与 CC 风险之间存在明显关联(OR 1.48,95% CI 1.13-1.92)。从机理上讲,与 A 等位基因相比,rs1059288 的 G 等位基因与 TAPBP 的 m6A 修饰增加有关。这种修饰由 m6A 甲基转移酶 METTL14 和阅读蛋白 YTHDF2 促进。对含有61个CC和45个正常组织的组织芯片进行免疫组化染色显示,TAPBP在CC中过度表达。此外,TAPBP的上调促进了CC细胞的生长和迁移以及肿瘤形成能力,抑制了细胞凋亡,并增强了对博来霉素、顺铂和多柔比星等常用化疗药物的耐药性。敲除 TAPBP 可抑制 CC 细胞中的 JAK/STAT/MICB 信号通路,并上调某些免疫基因,包括 ISG15、IRF3、PTPN6 和 HLA-A。这些发现有助于深入了解TAPBP基因变异对CC发病和进展的影响。
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来源期刊
Archives of Toxicology
Archives of Toxicology 医学-毒理学
CiteScore
11.60
自引率
4.90%
发文量
218
审稿时长
1.5 months
期刊介绍: Archives of Toxicology provides up-to-date information on the latest advances in toxicology. The journal places particular emphasis on studies relating to defined effects of chemicals and mechanisms of toxicity, including toxic activities at the molecular level, in humans and experimental animals. Coverage includes new insights into analysis and toxicokinetics and into forensic toxicology. Review articles of general interest to toxicologists are an additional important feature of the journal.
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