PIWIL2/PDK1 Axis Promotes the Progression of Cervical Epithelial Lesions via Metabolic Reprogramming to Maintain Tumor‐Initiating Cell Stemness
Abstract When PIWIL2 expression is restored via heterogeneous integration of human papillomavirus, cellular reprogramming is initiated to form tumor‐initiating cells (TICs), which triggers cervical squamous intraepithelial lesions (SIL). TIC stemness is critical for the prognosis of SIL. However, th...
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| Format: | Article |
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Wiley
2024-12-01
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| Series: | Advanced Science |
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| Online Access: | https://doi.org/10.1002/advs.202410756 |
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| author | Yuebo Li Wenhui Wang Dongkui Xu Haiyan Liang Huan Yu Ying Zhou Jing Liang Heming Sun Xiaodie Liu Ming Xue Bin Ling Dingqing Feng |
| author_facet | Yuebo Li Wenhui Wang Dongkui Xu Haiyan Liang Huan Yu Ying Zhou Jing Liang Heming Sun Xiaodie Liu Ming Xue Bin Ling Dingqing Feng |
| author_sort | Yuebo Li |
| collection | DOAJ |
| description | Abstract When PIWIL2 expression is restored via heterogeneous integration of human papillomavirus, cellular reprogramming is initiated to form tumor‐initiating cells (TICs), which triggers cervical squamous intraepithelial lesions (SIL). TIC stemness is critical for the prognosis of SIL. However, the mechanisms underlying TIC stemness maintenance and tumorigenicity remain unclear. Here, it is revealed that aberrant pyruvate dehydrogenase kinase 1 (PDK1) expression is closely related to aerobic glycolysis in SIL and poor survival in patients with cervical cancer. Mechanistically, that PIWIL2, which induced by stable transfection of either PIWIL2 or HPV16 oncogene E6 in human primary cervical basal epithelial cells and keratinocyte cell line HaCaT, upregulates PDK1 expression via the LIN28/let‐7 axis, hence reprogramming metabolism to activate glycolysis and synchronize with TIC formation. It is further demonstrate that PDK1 is critical for TIC stemness maintenance and tumorigenicity via the PI3K/AKT/mTOR pathway both in vitro and in vivo, revealing a previously unclear mechanism for SIL progression, regression or relapse. Therefore, this findings suggest a potential rationale for prognostic predictions and selecting targeted therapy for cervical lesions. |
| format | Article |
| id | doaj-art-3ad9855b6c0a4d3d88f84f6f736fc239 |
| institution | Kabale University |
| issn | 2198-3844 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj-art-3ad9855b6c0a4d3d88f84f6f736fc2392024-12-27T13:00:47ZengWileyAdvanced Science2198-38442024-12-011148n/an/a10.1002/advs.202410756PIWIL2/PDK1 Axis Promotes the Progression of Cervical Epithelial Lesions via Metabolic Reprogramming to Maintain Tumor‐Initiating Cell StemnessYuebo Li0Wenhui Wang1Dongkui Xu2Haiyan Liang3Huan Yu4Ying Zhou5Jing Liang6Heming Sun7Xiaodie Liu8Ming Xue9Bin Ling10Dingqing Feng11Department of Obstetrics and Gynecology China‐Japan Friendship Hospital Beijing 100029 ChinaDepartment of Obstetrics and Gynecology China‐Japan Friendship Hospital Beijing 100029 ChinaVIP Department National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital Chinese Academy of Medical Sciences & Peking Union Medical College Beijing 100021 ChinaDepartment of Obstetrics and Gynecology China‐Japan Friendship Hospital Beijing 100029 ChinaDepartment of Obstetrics and Gynecology China‐Japan Friendship Hospital Beijing 100029 ChinaDepartment of Obstetrics and Gynecology The First Affiliated Hospital of University of Science and Technology of China Hefei 230001 ChinaDepartment of Obstetrics and Gynecology China‐Japan Friendship Hospital Beijing 100029 ChinaInstitute of Clinical Medical Sciences China‐Japan Friendship Hospital Beijing 100029 ChinaDepartment of Obstetrics and Gynecology China‐Japan Friendship Hospital Beijing 100029 ChinaDepartment of Obstetrics and Gynecology China‐Japan Friendship Hospital Beijing 100029 ChinaDepartment of Obstetrics and Gynecology China‐Japan Friendship Hospital Beijing 100029 ChinaDepartment of Obstetrics and Gynecology China‐Japan Friendship Hospital Beijing 100029 ChinaAbstract When PIWIL2 expression is restored via heterogeneous integration of human papillomavirus, cellular reprogramming is initiated to form tumor‐initiating cells (TICs), which triggers cervical squamous intraepithelial lesions (SIL). TIC stemness is critical for the prognosis of SIL. However, the mechanisms underlying TIC stemness maintenance and tumorigenicity remain unclear. Here, it is revealed that aberrant pyruvate dehydrogenase kinase 1 (PDK1) expression is closely related to aerobic glycolysis in SIL and poor survival in patients with cervical cancer. Mechanistically, that PIWIL2, which induced by stable transfection of either PIWIL2 or HPV16 oncogene E6 in human primary cervical basal epithelial cells and keratinocyte cell line HaCaT, upregulates PDK1 expression via the LIN28/let‐7 axis, hence reprogramming metabolism to activate glycolysis and synchronize with TIC formation. It is further demonstrate that PDK1 is critical for TIC stemness maintenance and tumorigenicity via the PI3K/AKT/mTOR pathway both in vitro and in vivo, revealing a previously unclear mechanism for SIL progression, regression or relapse. Therefore, this findings suggest a potential rationale for prognostic predictions and selecting targeted therapy for cervical lesions.https://doi.org/10.1002/advs.202410756cervical lesionpyruvate dehydrogenase kinase 1stemnesstumor‐initiating cells |
| spellingShingle | Yuebo Li Wenhui Wang Dongkui Xu Haiyan Liang Huan Yu Ying Zhou Jing Liang Heming Sun Xiaodie Liu Ming Xue Bin Ling Dingqing Feng PIWIL2/PDK1 Axis Promotes the Progression of Cervical Epithelial Lesions via Metabolic Reprogramming to Maintain Tumor‐Initiating Cell Stemness Advanced Science cervical lesion pyruvate dehydrogenase kinase 1 stemness tumor‐initiating cells |
| title | PIWIL2/PDK1 Axis Promotes the Progression of Cervical Epithelial Lesions via Metabolic Reprogramming to Maintain Tumor‐Initiating Cell Stemness |
| title_full | PIWIL2/PDK1 Axis Promotes the Progression of Cervical Epithelial Lesions via Metabolic Reprogramming to Maintain Tumor‐Initiating Cell Stemness |
| title_fullStr | PIWIL2/PDK1 Axis Promotes the Progression of Cervical Epithelial Lesions via Metabolic Reprogramming to Maintain Tumor‐Initiating Cell Stemness |
| title_full_unstemmed | PIWIL2/PDK1 Axis Promotes the Progression of Cervical Epithelial Lesions via Metabolic Reprogramming to Maintain Tumor‐Initiating Cell Stemness |
| title_short | PIWIL2/PDK1 Axis Promotes the Progression of Cervical Epithelial Lesions via Metabolic Reprogramming to Maintain Tumor‐Initiating Cell Stemness |
| title_sort | piwil2 pdk1 axis promotes the progression of cervical epithelial lesions via metabolic reprogramming to maintain tumor initiating cell stemness |
| topic | cervical lesion pyruvate dehydrogenase kinase 1 stemness tumor‐initiating cells |
| url | https://doi.org/10.1002/advs.202410756 |
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