# Synergistic impact of dysglycemia and HPV on cervical cancer risk: a potential mediating role of Ki-67

## TL;DR

This study finds that high blood sugar and HPV infection together increase cervical cancer risk, possibly through the protein Ki-67.

## Contribution

The study identifies a synergistic effect of dysglycemia and HPV on cervical cancer risk, mediated in part by Ki-67 expression.

## Key findings

- Dysglycemia and HPV together increase cervical cancer risk by over three-fold compared to HPV alone.
- Ki-67 expression mediates about 40% of the combined effect of dysglycemia and HPV on cervical cancer.
- The interaction between dysglycemia and HPV has a significant indirect effect on Ki-67 levels.

## Abstract

Cervical cancer, linked to HPV and dysglycemia, lacks clarity on their combined impact. This study explores Ki-67’s role in mediating HPV and dysglycemia effects on cervical cancer risk.

This study enrolled patients with abnormal cervical cancer screening results, undergoing colposcopy and conization at Fujian Maternity and Child Health Hospital’s Cervical Disease Center from June 2018 to June 2023. Statistical analyses compared baseline characteristics across cervical lesion categories. Multinomial logistic regression examined HPV and dysglycemia associations with LSIL (low-grade squamous intraepithelial lesions), HSIL(high-grade squamous intraepithelial lesions), and cervical cancer, highlighting interaction and mediation analyses involving Ki-67.

A total of 4,115 participants were included: 573 with hyperglycemia, 1,479 with HPV only, and 548 with both HPV and hyperglycemia. Prediabetes and diabetes significantly increased cancer risk (OR: 2.47, 95% CI: 1.75-3.47 and OR: 3.67, 95% CI: 2.41-5.6, respectively). Coexisting hyperglycemia further elevated cervical cancer risk by over three-fold (OR: 3.12, 95% CI: 2.34-4.16) compared to HPV-positive normoglycemics. A significant interaction between hyperglycemia and HPV infection was observed (AP (attributable proportion): 0.69, 95% CI: 0.61-0.77, p<0.001; SI (synergy index): 3.27, 95% CI: 2.5-4.27, p<0.001). Ki-67+ expression accounted for 39.84%, 37.35%, and 55.18% of the total effect of hyperglycemia, HPV, and their combined impact, respectively. Additionally, the combination of dysglycemia and HPV had a significant indirect effect on Ki-67 levels (estimate: 0.08, 95% CI: 0.06- 0.09, p<0.001).

Dysglycemia and HPV infection synergistically elevate cervical cancer risk, possibly influenced by Ki-67. Effective screening and management for both are vital in prevention. Further research is required to validate findings and elucidate molecular mechanisms.