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MicroRNAs (miRNAs) have emerged as critical regulators of gene expression in CC, including miR-218-5p, which has been described as a tumor suppressor. In this study, we investigated the impact of HPV-16 oncoproteins E6 and E7 on the regulation of miR-218-5p expression and its target gene PIK3C2A, as well as their functional and clinical relevance in CC. We found that miR-218-5p expression is significantly reduced in HPV-16-positive CC cell lines, while PIK3C2A expression is increased. Silencing the expression of the E6\/E7 oncogenes in Ca Ski cells restored miR-218-5p levels and reduced PIK3C2A expression. Conversely, overexpression of the E6 and E7 oncogenes in C-33 A cells significantly decreased miR-218-5p expression and increased PIK3C2A expression. Functional assays performed on C-33 A cells expressing E6 and E7 revealed that ectopic expression of miR-218-5p suppresses cell proliferation and migration, effects that are partially mediated by PIK3C2A. Bioinformatics analysis showed that low miR-218-5p expression and high PIK3C2A expression are associated with reduced overall survival in patients with cervical cancer. Our findings identify the miR-218-5p\/PIK3C2A axis as a novel regulatory pathway modulated by HPV-16 oncoproteins E6 and E7 that contributes to CC cell proliferation and migration. Furthermore, miR-218-5p and PIK3C2A emerge as potential prognostic biomarkers in CC.<\/jats:p>","DOI":"10.3390\/pathogens15060648","type":"journal-article","created":{"date-parts":[[2026,6,19]],"date-time":"2026-06-19T14:37:42Z","timestamp":1781879862000},"page":"648","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["HPV-16 E6 and E7 Oncoproteins Promote Cell Proliferation and Migration Through the miR-218-5p\/PIK3C2A Axis"],"prefix":"10.3390","volume":"15","author":[{"given":"Brayan","family":"Villazana-Calderon","sequence":"first","affiliation":[{"name":"Subdirecci\u00f3n de Investigaci\u00f3n B\u00e1sica, Instituto Nacional de Cancerolog\u00eda, Mexico City 14080, Mexico"},{"name":"Facultad de Ciencias Qu\u00edmico-Biol\u00f3gicas, Universidad Aut\u00f3noma de Guerrero, Chilpancingo 39090, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hilda","family":"Jim\u00e9nez-Wences","sequence":"additional","affiliation":[{"name":"Facultad de Ciencias Qu\u00edmico-Biol\u00f3gicas, Universidad Aut\u00f3noma de Guerrero, Chilpancingo 39090, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4482-1575","authenticated-orcid":false,"given":"J. No\u00e9","family":"Garc\u00eda-Ch\u00e1vez","sequence":"additional","affiliation":[{"name":"Tecnol\u00f3gico Nacional de M\u00e9xico\/ITS de Irapuato, Irapuato 36821, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Imelda","family":"Mart\u00ednez-Ram\u00edrez","sequence":"additional","affiliation":[{"name":"Subdirecci\u00f3n de Investigaci\u00f3n B\u00e1sica, Instituto Nacional de Cancerolog\u00eda, Mexico City 14080, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7332-3829","authenticated-orcid":false,"given":"Claudia","family":"Gonz\u00e1lez-Espinosa","sequence":"additional","affiliation":[{"name":"Departamento de Farmacobiolog\u00eda, Centro de Investigaci\u00f3n y de Estudios Avanzados, Unidad Sede Sur, Mexico City 14330, Mexico"},{"name":"Centro de Investigaci\u00f3n Sobre el Envejecimiento, Centro de Investigaci\u00f3n y de Estudios Avanzados, Unidad Sede Sur, Mexico City 14330, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3737-2399","authenticated-orcid":false,"given":"Gloria","family":"Fern\u00e1ndez-Tilapa","sequence":"additional","affiliation":[{"name":"Facultad de Ciencias Qu\u00edmico-Biol\u00f3gicas, Universidad Aut\u00f3noma de Guerrero, Chilpancingo 39090, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7553-2541","authenticated-orcid":false,"given":"Marcela","family":"Lizano","sequence":"additional","affiliation":[{"name":"Subdirecci\u00f3n de Investigaci\u00f3n B\u00e1sica, Instituto Nacional de Cancerolog\u00eda, Mexico City 14080, Mexico"},{"name":"Departamento de Medicina Gen\u00f3mica y Toxicolog\u00eda Ambiental, Instituto de Investigaciones Biom\u00e9dicas, Universidad Nacional Aut\u00f3noma de M\u00e9xico, Ciudad Universitaria, Mexico City 04510, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6809-0212","authenticated-orcid":false,"given":"J. 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