{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,6]],"date-time":"2026-06-06T19:20:40Z","timestamp":1780773640417,"version":"3.54.1"},"reference-count":48,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2025,12,3]],"date-time":"2025-12-03T00:00:00Z","timestamp":1764720000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2025,12,3]],"date-time":"2025-12-03T00:00:00Z","timestamp":1764720000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82160625"],"award-info":[{"award-number":["82160625"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["analyticalsciencejournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J of Applied Toxicology"],"published-print":{"date-parts":[[2026,6]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Nicotine exerts a substantial influence on cervical carcinogenesis by affecting the malignant progression of human papillomavirus (HPV)\u201318 positive and HPV\u2010negative cervical cancer cells, as well as HPV\u2010immortalized cervical epithelial cells. Further research is needed to fully elucidate the impact of nicotine on HPV\u201016 positive cervical cancer. This study investigated the molecular mechanisms of nicotine in HPV\u201016\u2010positive cervical (SiHa) cells. First, we conducted cell counting kit\u20108, flow cytometry, wound healing, transwell assays to evaluate cellular proliferation, migration, and invasion capabilities. The data illustrated that nicotine\u2010treated SiHa cells displayed stronger malignant transformation capability compared to the control (\n                    <jats:italic>p<\/jats:italic>\n                    \u2009&lt;\u20090.05). Furthermore, western blot analysis was used to evaluate the expression changes of cellular proteins in SiHa cells. The results revealed that nicotine induces a significant upregulation of PI3K, AKT, phosphorylated AKT (Ser473) (p\u2010AKT), the p\u2010AKT\/AKT ratio, and matrix metalloproteinase\u20102 (MMP\u20102), along with a marked increase in its secretion. Also, it was accompanied by the suppression of tumor suppressor p53 and decreased levels of p21 and Caspase\u20103, as well as the active form of Caspase\u20103 (cleaved Caspase\u20103), indicating suppression of apoptosis. Critically, the use of a PI3K inhibitor (LY294002) demonstrated that the nicotine\u2010induced downregulation of p53 and upregulation of MMP\u20102, as well as the enhancement of cellular invasion are dependent on PI3K\/AKT pathway activation. These findings conclusively demonstrate that nicotine promotes the malignant transformation of HPV\u201016 positive cervical cancer cells by altering the expressions of MMP\u20102, p53, Caspase\u20103, and p21 via the activation of the PI3K\/AKT pathway. This highlights the therapeutic potential of targeting this pathway in cervical cancer treatment.\n                  <\/jats:p>","DOI":"10.1002\/jat.70019","type":"journal-article","created":{"date-parts":[[2025,12,3]],"date-time":"2025-12-03T23:31:08Z","timestamp":1764804668000},"page":"2077-2089","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Nicotine Activates PI3K\/AKT Pathway to Induce Cellular Proliferation, Invasion, and Migration in HPV\u201016 Positive Cervical Cancer SiHa Cells"],"prefix":"10.1002","volume":"46","author":[{"given":"Juan","family":"Wang","sequence":"first","affiliation":[{"name":"School of Public Health, Jiangxi Medical College Nanchang University  Nanchang Jiangxi China"},{"name":"Jiangxi Provincial Key Laboratory of Disease Prevention and Public Health Nanchang University  Nanchang Jiangxi China"},{"name":"Chongqing Research Institute Nanchang University  Chongqing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuxin","family":"Hu","sequence":"additional","affiliation":[{"name":"School of Public Health, Jiangxi Medical College Nanchang University  Nanchang Jiangxi China"},{"name":"Jiangxi Provincial Key Laboratory of Disease Prevention and Public Health Nanchang University  Nanchang Jiangxi China"},{"name":"Chongqing Research Institute Nanchang University  Chongqing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jin","family":"Gong","sequence":"additional","affiliation":[{"name":"Nanchang University Library  Nanchang Jiangxi China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Chen","sequence":"additional","affiliation":[{"name":"Hubei Provincial Center for Disease Control and Prevention  Wuhan Hubei China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Zhang","sequence":"additional","affiliation":[{"name":"Hubei Province Xianning Center for Disease Control and Prevention  Xianning Hubei China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-7918-3138","authenticated-orcid":false,"given":"Huai","family":"Wang","sequence":"additional","affiliation":[{"name":"School of Public Health, Jiangxi Medical College Nanchang University  Nanchang Jiangxi China"},{"name":"Jiangxi Provincial Key Laboratory of Disease Prevention and Public Health Nanchang University  Nanchang Jiangxi China"},{"name":"Chongqing Research Institute Nanchang University  Chongqing China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,12,3]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrc2657"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.semcancer.2019.07.009"},{"key":"e_1_2_11_4_1","unstructured":"American Cancer Society.2020. \u201cCervical Cancer Survival Rates|Cancer 5 Year Survival Rates [WWW Document].\u201dhttps:\/\/www.cancer.org\/cancer\/types\/cervical\u2010cancer\/detection\u2010diagnosis\u2010staging\/survival.html."},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.3322\/caac.21834"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12885-022-09386-7"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1093\/toxsci\/kfy246"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tox.2019.02.017"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-22-0332"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ab.2019.113473"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-20-2833"},{"issue":"4","key":"e_1_2_11_12_1","first-page":"57","article-title":"Multifactorial Etiology of Cervical Cancer: A Hypothesis","volume":"7","author":"Haverkos H. 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