Signaling pathways in tobacco smoking-induced cervical carcinogenesis: Beyond HPV-mediated activation

Tobacco smoking is a well-established cofactor for human papillomavirus (HPV) in the development of cervical cancer (CC), but it also contributes to a subset of HPV-negative carcinomas. While the epidemiological link is clear, the molecular signaling pathways through which smoking promotes CC, particularly in the absence of HPV, have not been comprehensively reviewed. This article summarizes current evidence on smoking-triggered signaling mechanisms in both HPV-negative and HPV-positive CC. Our analysis, based on a systematic evaluation of experimental studies, reveals distinct pathways in each context. In HPV‑negative and functionally HPV‑negative cervical cells, smoking activates EGF and VEFG pathways and induces oxidative DNA damage, leading to p53 mutation. In HPV-positive cells, several signaling pathways are activated, encompassing the dysregulated expression of oncogenes governed by the PI3K/AKT axis, such as NF-κB, MMP-2, and p53. Additionally, pathways including Rps27a/Mdm2/p53, AKT/mTOR/4EBP1/eIF4E, EGFR/PI3K/AKT/c-Jun, and α-enolase-mediated glycolysis are also involved, alongside the activation of Ras‑Raf‑Mek1/2‑Erk1/2 signaling pathway. The collective findings indicate that HPV-mediated activation is not a prerequisite for smoking-induced carcinogenic signaling in the cervix. This synthesis underscores the potential for developing targeted interventions against these pathways to prevent or treat smoking-related CC, irrespective of HPV status. However, several questions remain regarding the interplay of smoking with other risk factors, the nuances between HPV-positive and negative contexts, and the need for in vivo validation of these primarily in vitro findings.