Cervical cancer is the second leading cause of cancer-related death in Mexico, primarily due to persistent infection with high-risk Alpha-papillomavirus genotypes, such as HPV16 and 18. Next-generation sequencing (NGS) has revealed a high prevalence of Beta- and Gamma-HPVs, mainly Beta-2 types 38b, 80, 107, and 122, in cervical cancer samples from Mexico. Our group previously reported that HPVs 38b, 107, and 122 possess transforming properties in primary fibroblasts; however, the oncogenic potential of E6/E7-HPV80 has not yet been elucidated. For this purpose, primary human fibroblasts were transduced with E6/E7-HPV80 (FB-E6/E7-HPV80), and functional assays were conducted to evaluate changes in proliferation, metabolic activity, and cell migration. RNA-seq analysis identified differentially expressed genes (DEGs) and enriched pathways. Fibroblasts transduced with E6/E7-HPV16 (FB-E6/E7-HPV16) or empty vector (FB-pLVX) served as controls. FB-E6/E7-HPV80 extended their lifespan and exhibited increased proliferation, metabolic activity, and migration capacity. RNA-seq analysis identified 196 upregulated DEGs (such as GPAT2, MST1R, ACAN, SLCO4A1, and CHRNA3) and 887 downregulated DEGs (such as KLHDC7B, TRIM58, CST1, FBLL1, INHBE, and TMEM132D) shared between FB-E6/E7-HPV80 and FB-E6/E7-HPV16. Enriched pathways included p53, TNF, IL-17, apoptosis, cell cycle, etc. These findings suggest that E6/E7-HPV80 exhibits transforming capabilities that could play an important role in cervical carcinogenesis.

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Background: Cervical cancer (CC) remains a major cause of cancer-related mortality among women worldwide, primarily driven by persistent infection with high-risk human papillomavirus (HPV) types. Given that natural products with selective antitumour properties offer potential for novel therapies, we evaluated the cytotoxic, antiproliferative, and molecular effects of cinnamon essential oil (CEO) on HPV-positive cervical cancer cell lines (HeLa and SiHa) and nontumorigenic keratinocytes (HaCaT). Methods: Cells were exposed to a range of dilutions of CEO. Cell viability was determined by WST-1 and sulforhodamine B assays. Apoptosis was assessed using Annexin V/PI staining, caspase-3/8/9 activation, and mitochondrial membrane potential (Δψm) loss by flow cytometry. Proliferation was measured using EdU incorporation, and senescence was measured by β-galactosidase activity. Genome-wide transcriptional changes and HPV E6/E7 oncogene expression were analysed by RNA-Seq and validated with qPCR. Results: CEO induced dose-dependent cytotoxicity and inhibited proliferation in cervical cancer cells, while HaCaT cells were significantly more resistant. Apoptosis was evidenced by Annexin V/PI positivity, activation of caspases -8, -9, and -3, and significant loss of mitochondrial membrane potential. No significant senescence induction was observed. Additionally, CEO also significantly downregulated HPV E6 / E7 oncogene expression in HeLa and SiHa cells. Transcriptomic analysis revealed broad differential gene expression, including upregulation of stress and apoptosis-related genes and downregulation of proliferation, oxidative phosphorylation, and viral-related pathways. Conclusion: CEO exerts selective cytotoxic and antiproliferative effects on cervical cancer cells by triggering mitochondria-mediated apoptosis and suppressing HPV oncogenes. These findings support CEO as a potential source of bioactive compounds for complementary strategies against HPV-related malignancies.