Toxicological Pathway Alterations Driven by Cervical Micrornas (Mir-21, Mir-155, Mir-9) in Persistent High-Risk Hpv Infection Publisher



Ghadimi K ; Mirnurollahi SM ; Sadat Shandiz SA ; Pourhossein B ; Bagherian M ; Hashemi ZS ; Zarmehri B ; Hajian A ; Fazeli M
Source: International Journal of Medical Toxicology and Forensic Medicine Published:2026

Abstract

Background: Persistent high-risk human papillomavirus (HR-HPV) infection is necessary for cervical carcinogenesis, yet most infections regress. Host microRNAs (miRNAs) that regulate cellular stress responses may help discriminate persistent from transient infection. In this study, we evaluated cervical expression of miR-21, miR-155, and miR-9 in relation to oxidative stress, DNA damage, apoptosis, and inflammatory signaling in HR-HPV persistence. Methods: Cervical samples from 60 women referred to private laboratories in Tehran, the capital of Iran (2023-2024), were classified as persistent HR-HPV (qPCR-positive at baseline and 9 months), transient HR-HPV (positive at baseline and subsequently cleared), or HPV-negative controls with normal cytology. HPV DNA was monitored seasonally by qPCR; E6/E7 mRNA was assessed using the Aptima assay. miR-21, miR-155, and miR-9 were quantified using stem-loop RT-qPCR with normalization to U6 snRNA; relative expression was calculated by △△ C_t. Group comparisons were performed using t-tests/ANOVA with Bonferroni correction (p<0.05). Results: miR-21 and miR-155 were significantly elevated in persistent infection versus transient infection and controls (p<0.01). E6/E7 mRNA was detected in all persistent cases. In the transient group, 13/17 (76.5%) were E6/E7 mRNA-negative, whereas 4/17 (23.5%) were mRNA-positive at any time point. miR-21 and miR-155 correlated with E6/E7 mRNA positivity (r=0.74 and r=0.71; p<0.01). Over 12 months, miR-21 and miR-155 increased progressively in persistent infections (both p < 0.01), whereas they remained largely stable in the transient and control groups. miR-9 showed greater intra-group variability, fluctuating without a consistent trajectory and being lower than controls at multiple time points (p<0.05). Low-grade cytological abnormalities (inflammation/CIN1) were more frequent in persistent infections (p<0.05). Conclusion: HR-HPV persistence is associated with sustained upregulation of miR-21 and miR-155 and a heterogeneous, often reduced miR-9 pattern. This profile is biologically consistent with previously reported HPV-related alterations in apoptotic and inflammatory pathways and may be compatible with increased susceptibility to oxidative DNA damage of persistence and as indicators of stress-pathway remodeling during HPV-driven cervical transformation. Copyright © 2026 The Author(s); This is an open access article distributed under the terms of the Creative Commons Attribution License (CC-By-NC: https://creativecommons.org/licenses/by-nc/4.0/legalcode.en), which permits use, distribution, and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.