# Site-specific HPV18 integration facilitates cervical carcinogenesis through metabolic reprogramming-induced dysfunction of the SpHK1/S1P/S1PR1 pathway

## TL;DR

This study shows how HPV18 integration at a specific genomic site promotes cervical cancer through metabolic changes and signaling pathway activation.

## Contribution

The study reveals a novel mechanism linking HPV18 integration to metabolic reprogramming and SpHK1/S1P/S1PR1 pathway dysfunction in cervical carcinogenesis.

## Key findings

- HPV18 integration at 8q24 alters genome structure and up-regulates cancer-related genes like IL-17 and S100A8/A9.
- HPV18 integration reprograms cell metabolism, enhancing glycolysis and lipid synthesis to increase S1P levels.
- Inhibiting the S1P/S1PR1 pathway reduces S100A8/A9 expression and suppresses HPV-KI cell growth and tumor formation.

## Abstract

Integration of high-risk human papillomavirus into specific loci of the genome is a pivotal event in cervical carcinogenesis; however, it’s underlying mechanism remains largely undefined. Here, through establishing an 8q24 site-specific HPV18 gene knock-in cell model by utilizing the CRISPR/Cas9 system, we discover that HPV18 knock-in (HPV-KI) results in a global alteration of the genome’s topologically associating domain structure and an up-regulation of cancer-related genes in HPV- HaCaT cells, among which the significantly up-regulated IL-17 signaling pathway and S100A8/A9 are partitularly prominent. Further mechanistic study demonstrate that HPV-KI reprograms metabolic pathway, especially up-regulates glycolysis and subsequently facilitates glycerolipid synthesis in HaCaT cell, leading to sphingosine-1-phospate (S1P) secretion and enhanced SpHK1/S1P/S1PR1 signaling pathway, thereby activating the the MAPK and NF-κB signaling pathways followed by inducing the expression of S100A8/A9, and hence induces the malignant transformation of cells. Importantly, inhibition of the S1P/S1PR1 signaling pathway down-regulates the expression of S100A8/A9 and suppresses the growth of HPV-KI cells and xenograft derived from cervical cancer patient. These findings provide novel insights into HPV integration-induced cervical carcinogenesis and identify potential therapeutic targets for its treatment.