This study explores how the integration of HPV18, a virus linked to cervical cancer, into specific parts of the genome affects cell behavior. Using a special gene editing technique, researchers created a model to observe how HPV18 changes the structure of DNA and increases the activity of genes related to cancer. They found that HPV18 reprograms the metabolism of cells, increasing sugars and fats, which leads to the release of a signaling molecule that activates pathways involved in cell growth and cancer progression. Blocking this signaling pathway reduced cancer-related changes and limited the growth of HPV-infected cells. These results help us understand how HPV contributes to cervical cancer and suggest new treatment options.
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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-ÎșB 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.
