Tumour Virus Research最新文献

The global incidence of Head and Neck (HN) cancer has dramatically increased over the past few decades, primarily due to an increasing incidence of HPV infection. HPV infection desensitizes cells to apoptosis through the E6-enabled accelerated degradation of several pro-apoptotic molecules, including p53 and procaspase 8. To block this activity, we used 30-hydroxygambogic acid, GA-OH, a small molecule that binds to HPV16 E6 and inhibits the interactions of E6 with its cellular partners. We found that treatment with GA-OH affects the viability of both HPV(+) and HPV(-) oral cancer cells. Further analysis of gene expression patterns of these cell lines showed that GA-OH induces cell death through both independent and overlapping apoptotic pathways by altering gene expression in both HPV(+) and HPV(-) cancer cells.

The E6 oncoprotein encoded by the cancer-causing human papillomavirus (HPV) is vital for maintaining the ability of the virus to promote cell proliferation and cancer progression. This study identified that cyclin-dependent kinase 5 (CDK5) is a previously unidentified host target of E6 encoded by cancer-causing HPV genotypes. Although E6 may not be a phosphorylation substrate of CDK5, interaction with CDK5 nonetheless increases the steady-state level of E6. To further elucidate the significance of CDK5-E6 interaction, we adopted pharmacological inhibition and silencing approaches. Leveraging the computer-aided molecular docking and in vitro screening approaches, we identified CP681301, a potent CDK5 inhibitor, which can inhibit CDK5-E6 complex formation. More intriguingly, this study underlines that CP681301 can inhibit the E6-E6AP-p53 axis, conferring inhibition on cancer phenotypes of HPV-positive cancer cells, including the ability of cells to proliferate, transform, migrate and invade through Matrigel. Our study highlights that CDK5-E6 is a promising drug target for the design of next-generation targeted therapeutics for HPV-associated diseases.

Cervical cancer is the fourth most common cancer among women globally, with a woman dying every 2 min. Despite the need to understand the tumor microenvironment (TME) transcriptome of cervical squamous cell carcinoma (CSCC) and cervical intraepithelial neoplasia grade 3 (CIN 3), studies remain limited. This study compares the TME transcriptome of HPV-positive CSCC and CIN 3, analyzing 168 genes involved in tumor cell interactions with inflammatory and immune mediators, transcription, signal transduction, oncogenesis, tumor suppression, angiogenesis, and apoptosis. Co-expressed genes identified in HPV + CSCC and CIN 3 were analyzed using computational biology. Gene Ontology and KEGG enrichment identified relevant biological pathways and cancer hallmarks. Fifty-five co-expressed genes were linked to cancer pathways, inflammatory responses, cell migration, and development. KEGG enrichment highlighted viral protein interactions involving cytokines, IL-17 signaling, and chemokine receptor interactions. These genes were associated with cancer hallmark pathways, including angiogenesis, inflammation, proliferation, genomic instability, invasion, and metastasis. Their similar expression in CSCC and CIN 3 suggests a potential prognostic value and that CIN 3 progression may involve changes in gene expression. We propose the term "CSCC-like carcinoma," indicating CIN 3's increased invasive potential at the molecular level.

Since early and late transcription are both regulated from the same central regulatory region in SV40 chromatin, the location of nucleosomes carrying histone modifications may contribute to controlling the direction of transcription from the regulatory region. This could occur through the generation of active chromatin in the direction of transcription and repressive chromatin in the opposite direction. In order to test this hypothesis, we have characterized the products of SV40 transcription and location of nucleosomes carrying histone modifications in SV40 chromatin following treatment of infected cells with inhibitors of histone methylation metabolism. The inhibitors used included GSK-LSD1 to inhibit demethylation of H3K4me1 and H3K9me1, A366 to inhibit the introduction of H3K9me1, and UNC1999 to inhibit the introduction of H3K27me3. The results are consistent with a regulatory model in which nucleosomes carrying H3K9me1 and H3K27me3 located at the ends of the SV40 regulatory region act to regulate transcription.