SKIL Promotes Pancreatic Cancer Metastasis by Inhibiting TSPYL2 to Activate the TGF‐β Pathway
ABSTRACT Background Pancreatic adenocarcinoma (PAAD) represents a highly fatal form of cancer. The 5‐year survival rate for patients with this disease is only around 10%. A significant hurdle in its management is the absence of characteristic early‐stage symptoms. As a result, a large majority of pa...
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| Format: | Article |
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Wiley
2025-06-01
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| Series: | Cancer Innovation |
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| Online Access: | https://doi.org/10.1002/cai2.70011 |
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| author | Chenxi Wang Weiwei Song Yixuan Zhang Hongming Deng Zixiang Zhou Jing Zhu Xiaobing Wang |
| author_facet | Chenxi Wang Weiwei Song Yixuan Zhang Hongming Deng Zixiang Zhou Jing Zhu Xiaobing Wang |
| author_sort | Chenxi Wang |
| collection | DOAJ |
| description | ABSTRACT Background Pancreatic adenocarcinoma (PAAD) represents a highly fatal form of cancer. The 5‐year survival rate for patients with this disease is only around 10%. A significant hurdle in its management is the absence of characteristic early‐stage symptoms. As a result, a large majority of pancreatic cancer patients are diagnosed when the disease has reached an advanced stage or has metastasized. Consequently, taking measures to suppress the occurrence of metastasis in pancreatic cancer can bring about a substantial improvement in patients' survival rates and overall prognosis. SKIL, known to promote cancer progression, is implicated in cell proliferation, epithelial–mesenchymal transition (EMT), and metastasis, but its specific function in pancreatic cancer remains unclear. Methods We investigated the effects of SKIL on the proliferation, apoptosis, and metastasis of pancreatic cancer cells. Through ChIP‐seq, we identified the SKIL downstream target gene and further explored the mechanism by which SKIL regulates the metastasis of pancreatic cancer cells through functional experiments and Western blot. Results A high level of SKIL expression is associated with an unfavorable prognosis in PAAD; it promotes cell migration and EMT. Through ChIP‐seq analysis, we identified that SKIL inhibits TSPYL2, a nuclear protein regulating the TGF‐β pathway by binding to the TGFB1 promoter. Further studies carried out by us confirmed that SKIL modulates the TGF‐β pathway via TSPYL2, facilitating EMT and metastasis in pancreatic cancer cells, independent of Smad4. Conclusions These findings reveal a novel regulatory mechanism involving SKIL, TSPYL2, and the TGF‐β pathway, offering new therapeutic targets for PAAD. |
| format | Article |
| id | doaj-art-f653c5e85d2945e38ee7c945d2d27c99 |
| institution | OA Journals |
| issn | 2770-9191 2770-9183 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | Wiley |
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| series | Cancer Innovation |
| spelling | doaj-art-f653c5e85d2945e38ee7c945d2d27c992025-08-20T02:26:04ZengWileyCancer Innovation2770-91912770-91832025-06-0143n/an/a10.1002/cai2.70011SKIL Promotes Pancreatic Cancer Metastasis by Inhibiting TSPYL2 to Activate the TGF‐β PathwayChenxi Wang0Weiwei Song1Yixuan Zhang2Hongming Deng3Zixiang Zhou4Jing Zhu5Xiaobing Wang6State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital Chinese Academy of Medical Sciences and Peking Union Medical College Beijing ChinaState Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital Chinese Academy of Medical Sciences and Peking Union Medical College Beijing ChinaNMPA Key Laboratory for Monitoring and Evaluation of Cosmetics, Shanghai Innovation R&D Testing and Evaluation Technical Service Platform of Cosmetics(22DZ2292100) Shanghai ChinaState Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital Chinese Academy of Medical Sciences and Peking Union Medical College Beijing ChinaDepartment of Molecular Biology Princeton University Princeton New Jersey USACollege of Nursing and Health Innovation The University of Texas Arlington Arlington Texas USAState Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital Chinese Academy of Medical Sciences and Peking Union Medical College Beijing ChinaABSTRACT Background Pancreatic adenocarcinoma (PAAD) represents a highly fatal form of cancer. The 5‐year survival rate for patients with this disease is only around 10%. A significant hurdle in its management is the absence of characteristic early‐stage symptoms. As a result, a large majority of pancreatic cancer patients are diagnosed when the disease has reached an advanced stage or has metastasized. Consequently, taking measures to suppress the occurrence of metastasis in pancreatic cancer can bring about a substantial improvement in patients' survival rates and overall prognosis. SKIL, known to promote cancer progression, is implicated in cell proliferation, epithelial–mesenchymal transition (EMT), and metastasis, but its specific function in pancreatic cancer remains unclear. Methods We investigated the effects of SKIL on the proliferation, apoptosis, and metastasis of pancreatic cancer cells. Through ChIP‐seq, we identified the SKIL downstream target gene and further explored the mechanism by which SKIL regulates the metastasis of pancreatic cancer cells through functional experiments and Western blot. Results A high level of SKIL expression is associated with an unfavorable prognosis in PAAD; it promotes cell migration and EMT. Through ChIP‐seq analysis, we identified that SKIL inhibits TSPYL2, a nuclear protein regulating the TGF‐β pathway by binding to the TGFB1 promoter. Further studies carried out by us confirmed that SKIL modulates the TGF‐β pathway via TSPYL2, facilitating EMT and metastasis in pancreatic cancer cells, independent of Smad4. Conclusions These findings reveal a novel regulatory mechanism involving SKIL, TSPYL2, and the TGF‐β pathway, offering new therapeutic targets for PAAD.https://doi.org/10.1002/cai2.70011epithelial–mesenchymal transitionpancreatic adenocarcinomaSKILTGF‐β pathwayTSPYL2 |
| spellingShingle | Chenxi Wang Weiwei Song Yixuan Zhang Hongming Deng Zixiang Zhou Jing Zhu Xiaobing Wang SKIL Promotes Pancreatic Cancer Metastasis by Inhibiting TSPYL2 to Activate the TGF‐β Pathway Cancer Innovation epithelial–mesenchymal transition pancreatic adenocarcinoma SKIL TGF‐β pathway TSPYL2 |
| title | SKIL Promotes Pancreatic Cancer Metastasis by Inhibiting TSPYL2 to Activate the TGF‐β Pathway |
| title_full | SKIL Promotes Pancreatic Cancer Metastasis by Inhibiting TSPYL2 to Activate the TGF‐β Pathway |
| title_fullStr | SKIL Promotes Pancreatic Cancer Metastasis by Inhibiting TSPYL2 to Activate the TGF‐β Pathway |
| title_full_unstemmed | SKIL Promotes Pancreatic Cancer Metastasis by Inhibiting TSPYL2 to Activate the TGF‐β Pathway |
| title_short | SKIL Promotes Pancreatic Cancer Metastasis by Inhibiting TSPYL2 to Activate the TGF‐β Pathway |
| title_sort | skil promotes pancreatic cancer metastasis by inhibiting tspyl2 to activate the tgf β pathway |
| topic | epithelial–mesenchymal transition pancreatic adenocarcinoma SKIL TGF‐β pathway TSPYL2 |
| url | https://doi.org/10.1002/cai2.70011 |
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