The SP1-12LOX axis promotes chemoresistance and metastasis of ovarian cancer
Abstract Background Ovarian cancer is the most lethal gynecologic cancer. Chemoresistance, especially platinum-resistance, is closely related to metastasis of ovarian cancer, however, the molecular basis by which links chemoresistance and metastasis remains vague. Disordered arachidonic acid (AA) me...
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| Format: | Article |
| Language: | English |
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BMC
2020-05-01
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| Series: | Molecular Medicine |
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| Online Access: | http://link.springer.com/article/10.1186/s10020-020-00174-2 |
| _version_ | 1818042128141385728 |
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| author | Qi Zhang Guifang Yan Juan Lei Yu Chen Ting Wang Juan Gong Yong Zhou Huakan Zhao Hao Chen Yu Zhou Lei Wu Jiangang Zhang Xiao Zhang Jingchun Wang Yongsheng Li |
| author_facet | Qi Zhang Guifang Yan Juan Lei Yu Chen Ting Wang Juan Gong Yong Zhou Huakan Zhao Hao Chen Yu Zhou Lei Wu Jiangang Zhang Xiao Zhang Jingchun Wang Yongsheng Li |
| author_sort | Qi Zhang |
| collection | DOAJ |
| description | Abstract Background Ovarian cancer is the most lethal gynecologic cancer. Chemoresistance, especially platinum-resistance, is closely related to metastasis of ovarian cancer, however, the molecular basis by which links chemoresistance and metastasis remains vague. Disordered arachidonic acid (AA) metabolism has been shown to play an important role in the advanced ovarian cancer. This study aimed to explore the underlying mechanism involving eicosanoid metabolism that controlling chemoresistance and metastasis of ovarian cancer. Methods Cisplatin (DDP)-resistant SKOV3 (SKOV3-R) cells were constantly induced. Ultra-high-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) was performed to determine the AA metabolism in SKOV3 and SKOV3-R cells. Half maximal inhibitory concentration (IC50) and percentage of cell viability were tested using cell counting kit 8 (CCK-8). Realtime quantitative PCR (qPCR) and immunohistochemistry (IHC) were used to evaluate indicated genes and proteins respectively. Bioinformatic analysis and chromatin immunoprecipitation (ChIP) were performed to predict and identify the co-transcription factor of interest genes. Tumor growth and metastasis in the liver were assessed with nude mice by subcutaneously injection of SKOV3-R cells. Results SKOV3-R cells expressed higher multidrug resistance-associated proteins (MRPs) MRP1 and MRP4. They showed enhanced metastatic ability and produced increased AA-derived eicosanoids. Mechanistically, MRPs, epithelial mesenchymal transition (EMT) markers Snail and Slug, as well as key enzymes involved in AA-metabolism including 12-lipoxygenase (12LOX) were transcribed by the mutual transcription factor SP1 which was consistently upregulated in SKOV3-R cells. Inhibition of SP1 or 12LOX sensitized SKOV3-R cells to DDP and impaired metastasis in vitro and in vivo. Conclusion Our results reveal that SP1-12LOX axis signaling plays a key role in DDP-resistance and metastasis, which provide a new therapeutic target for ovarian cancer. |
| first_indexed | 2024-12-10T08:41:23Z |
| format | Article |
| id | doaj.art-373b915609e9468aad33078df4fded2c |
| institution | Directory Open Access Journal |
| issn | 1076-1551 1528-3658 |
| language | English |
| last_indexed | 2024-12-10T08:41:23Z |
| publishDate | 2020-05-01 |
| publisher | BMC |
| record_format | Article |
| series | Molecular Medicine |
| spelling | doaj.art-373b915609e9468aad33078df4fded2c2022-12-22T01:55:51ZengBMCMolecular Medicine1076-15511528-36582020-05-012611910.1186/s10020-020-00174-2The SP1-12LOX axis promotes chemoresistance and metastasis of ovarian cancerQi Zhang0Guifang Yan1Juan Lei2Yu Chen3Ting Wang4Juan Gong5Yong Zhou6Huakan Zhao7Hao Chen8Yu Zhou9Lei Wu10Jiangang Zhang11Xiao Zhang12Jingchun Wang13Yongsheng Li14Clinical Medicine Research Center, Xinqiao Hospital, Army Medical UniversityClinical Medicine Research Center, Xinqiao Hospital, Army Medical UniversityClinical Medicine Research Center, Xinqiao Hospital, Army Medical UniversityClinical Medicine Research Center, Xinqiao Hospital, Army Medical UniversityInstitute of Cancer, Xinqiao Hospital, Army Medical UniversityInstitute of Cancer, Xinqiao Hospital, Army Medical UniversityChongqing Weisiteng Biotech Translational Research InstituteClinical Medicine Research Center, Xinqiao Hospital, Army Medical UniversityDepartment of Medical Administration, Xinqiao Hospital, Army Medical UniversityClinical Medicine Research Center, Xinqiao Hospital, Army Medical UniversityClinical Medicine Research Center, Xinqiao Hospital, Army Medical UniversityClinical Medicine Research Center, Xinqiao Hospital, Army Medical UniversityClinical Medicine Research Center, Xinqiao Hospital, Army Medical UniversityClinical Medicine Research Center, Xinqiao Hospital, Army Medical UniversityClinical Medicine Research Center, Xinqiao Hospital, Army Medical UniversityAbstract Background Ovarian cancer is the most lethal gynecologic cancer. Chemoresistance, especially platinum-resistance, is closely related to metastasis of ovarian cancer, however, the molecular basis by which links chemoresistance and metastasis remains vague. Disordered arachidonic acid (AA) metabolism has been shown to play an important role in the advanced ovarian cancer. This study aimed to explore the underlying mechanism involving eicosanoid metabolism that controlling chemoresistance and metastasis of ovarian cancer. Methods Cisplatin (DDP)-resistant SKOV3 (SKOV3-R) cells were constantly induced. Ultra-high-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) was performed to determine the AA metabolism in SKOV3 and SKOV3-R cells. Half maximal inhibitory concentration (IC50) and percentage of cell viability were tested using cell counting kit 8 (CCK-8). Realtime quantitative PCR (qPCR) and immunohistochemistry (IHC) were used to evaluate indicated genes and proteins respectively. Bioinformatic analysis and chromatin immunoprecipitation (ChIP) were performed to predict and identify the co-transcription factor of interest genes. Tumor growth and metastasis in the liver were assessed with nude mice by subcutaneously injection of SKOV3-R cells. Results SKOV3-R cells expressed higher multidrug resistance-associated proteins (MRPs) MRP1 and MRP4. They showed enhanced metastatic ability and produced increased AA-derived eicosanoids. Mechanistically, MRPs, epithelial mesenchymal transition (EMT) markers Snail and Slug, as well as key enzymes involved in AA-metabolism including 12-lipoxygenase (12LOX) were transcribed by the mutual transcription factor SP1 which was consistently upregulated in SKOV3-R cells. Inhibition of SP1 or 12LOX sensitized SKOV3-R cells to DDP and impaired metastasis in vitro and in vivo. Conclusion Our results reveal that SP1-12LOX axis signaling plays a key role in DDP-resistance and metastasis, which provide a new therapeutic target for ovarian cancer.http://link.springer.com/article/10.1186/s10020-020-00174-2SP1LipoxygenaseChemoresistanceMetastasisOvarian cancer |
| spellingShingle | Qi Zhang Guifang Yan Juan Lei Yu Chen Ting Wang Juan Gong Yong Zhou Huakan Zhao Hao Chen Yu Zhou Lei Wu Jiangang Zhang Xiao Zhang Jingchun Wang Yongsheng Li The SP1-12LOX axis promotes chemoresistance and metastasis of ovarian cancer Molecular Medicine SP1 Lipoxygenase Chemoresistance Metastasis Ovarian cancer |
| title | The SP1-12LOX axis promotes chemoresistance and metastasis of ovarian cancer |
| title_full | The SP1-12LOX axis promotes chemoresistance and metastasis of ovarian cancer |
| title_fullStr | The SP1-12LOX axis promotes chemoresistance and metastasis of ovarian cancer |
| title_full_unstemmed | The SP1-12LOX axis promotes chemoresistance and metastasis of ovarian cancer |
| title_short | The SP1-12LOX axis promotes chemoresistance and metastasis of ovarian cancer |
| title_sort | sp1 12lox axis promotes chemoresistance and metastasis of ovarian cancer |
| topic | SP1 Lipoxygenase Chemoresistance Metastasis Ovarian cancer |
| url | http://link.springer.com/article/10.1186/s10020-020-00174-2 |
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