N6-methyladenosine in cervical carcinogenesis: Mechanistic insights and therapeutic perspectives (Review)

Abstract

Cervical cancer is one of the most common malignant tumors among women worldwide. Its primary etiology is closely associated with human papillomavirus infection, which poses a serious threat to the health of women. N6-methyladenosine (m6A) modifications notably affect the biological characteristics of tumor cells, such as their proliferation, metastasis and chemoresistance, by regulating the stability, translation and degradation of RNA. It also serves an important regulatory role in the pathogenesis of cervical cancer. The present review details the mechanisms underlying m6A modification in cervical cancer and analyzes its impact on tumor progression. Moreover, it explores the potential clinical applications of m6A modification as a biomarker and therapeutic target to provide new insights and evidence regarding the early diagnosis and individualized treatment of patients with cervical cancer.

Keywords: N6-methyladenosine; biomarker; cervical cancer; signaling pathway.

Figure 1.

Dynamic regulatory mechanism of m6A modification. Writers are responsible for adding m6A modifications to mRNA, erasers for removing these modifications, and readers for recognizing and responding to m6A modifications. These collectively regulate gene expression and cellular functions. m6A, N6-methyladenosine. WTAP, Wilms tumor 1-associated protein; KIAA1429/VIRMA, Vir-like m6A methyltransferase associated; RBM15/RBM15B, RNA binding motif protein 15/15B; METTL14, methyltransferase like 14; ZC3H13, zinc finger CCCH-type containing 13; FTO, fat mass and obesity-associated protein; ALKBH5, AlkB homolog 5; YTHDF1, YTH N6-methyladenosine RNA binding protein 1; YTHDC1, YTH domain containing 1; HNRNPC, heterogeneous nuclear ribonucleoprotein C; IGF2BP1, insulin-like growth factor 2 mRNA-binding protein 1.

Figure 2.

In cervical cancer, writers and their interacting readers jointly regulate target mRNA to promote or inhibit the progression of cervical cancer. The readers include (A) METTL3, (B) METTL14, (C) RBM15, (D) WTAP, KIAA1429 and ZC3H13. METTL, methyltransferase; RBM15, RNA binding motif protein 15; WTAP, WT1-associated protein; KIAA1429, Vir-like m6A methyltransferase associated; ZC3H13, zinc finger CCCH-type containing 13; TXNDC5, thioredoxin domain containing 5; PDE3A, phosphodiesterase 3A; CTSL, cathepsin L; DDX6, DEAD-box helicase 6; TAPBP, TAP binding protein; FTH1, ferritin heavy chain 1; EZH2, enhancer of zeste 2 polycomb repressive complex 2 subunit; CENPK, centromere protein K; CKAP2, cytoskeleton associated protein 2; LARP1, La ribonucleoprotein 1.

Figure 3.

Targets and signaling pathways of m6A erasers in CC. The m6A erasers FTO and ALKBH5 dynamically regulate CC progression by modulating distinct molecular targets and signaling networks. m6A, N6-methyladenosine; FTO, fat mass and obesity-associated protein; ALKBH5, AlkB homolog 5, RNA demethylase; CC, cervical cancer. HIF1A, hypoxia-inducible factor 1 subunit alpha; CCDC134, Coiled-coil domain containing 134; GSK3β, Glycogen synthase kinase 3β; E2F1, E2F transcription factor 1; PAK5, P21 (RAC1) activated kinase 5.

Figure 4.

m6A readers and related signaling pathways in the development, metastasis and radioresistance of CC. m6A readers affect tumor development, metastasis and radioresistance via regulating downstream signaling pathways. The Hippo/YAP, Wnt/β-catenin and PI3K/MAPK signaling pathways are all highly activated and serve a role in the tumor cell proliferation, differentiation and metastasis of CC cells. m6A, N6-methyladenosine; CC, cervical cancer; NR4A1, nuclear receptor subfamily 4 group A member 1; AKT1, AKT serine/threonine kinase 1; SYVN, synoviolin; NLRP3, NLR family pyrin domain containing 3; FOXM1, forkhead box M1; MAPK, mitogen-activated protein kinase; FASN, fatty acid synthase.

Figure 5.

Lollipop plot of the immune infiltration profiles of the m6A regulators. A correlation analysis was performed using the ggplot2 package between several m6A regulators in the data and the immune infiltration matrix. m6A, N6-methyladenosine. The immune cell types included T helper cells, Th2 cells, Tcm, NK cells, Tem, eosinophils, mast cells, NK CD56 bright cells, CD8 T cells, Tgd, Tfh, macrophages, Th17 cells, neutrophils, iDC, pDC, T cells, DC, aDC, NK CD56dim cells, B cells, Treg, Th1 cells and cytotoxic cells. Treg, T-regulatory cells; Th2, type 2 T-helper; NK, natural killer; DC, dendritic cells; aDC, activated DC; iDC, interdigitating DC; pDC, plasmacytoid DC; Tcm, central memory T-cells; Tem, effector memory T-cells; Tgd, gamma delta T cells; Tfh, T follicular helper cells. *P<0.05, **P<0.01 and ***P<0.001.