Exploration of vitamin D metabolic activity-related biological effects and corresponding therapeutic targets in prostate cancer
Abstract Background Previous studies have unequivocally demonstrated that the vitamin D (VD) metabolism pathway significantly influences prognosis and sensitivity to hormone therapy in prostate cancer (PCa). However, the precise underlying mechanism remains unclear. Methods We performed molecular pr...
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| Format: | Article |
| Language: | English |
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BMC
2024-04-01
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| Series: | Nutrition & Metabolism |
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| Online Access: | https://doi.org/10.1186/s12986-024-00791-2 |
| _version_ | 1797219987591528448 |
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| author | Lei Ding Yong Wang Zhentao Tang Chenbo Ni Qian Zhang Qidi Zhai Chao Liang Jie Li |
| author_facet | Lei Ding Yong Wang Zhentao Tang Chenbo Ni Qian Zhang Qidi Zhai Chao Liang Jie Li |
| author_sort | Lei Ding |
| collection | DOAJ |
| description | Abstract Background Previous studies have unequivocally demonstrated that the vitamin D (VD) metabolism pathway significantly influences prognosis and sensitivity to hormone therapy in prostate cancer (PCa). However, the precise underlying mechanism remains unclear. Methods We performed molecular profiling of 1045 PCa patients, leveraging genes linked to VD synthesis and VD receptors. We then identified highly variable gene modules with substantial associations with patient stratification. Subsequently, we intersected these modules with differentially expressed genes between PCa and adjacent paracancerous tissues. Following a meticulous process involving single-factor regression and LASSO regression to eliminate extraneous variables and construct a prognostic model. Within the high-risk subgroup defined by the calculated risk score, we analyzed their differences in cell infiltration, immune status, mutation landscape, and drug sensitivity. Finally, we selected Apolipoprotein E (APOE), which featured prominently in this model for further experimental exploration to evaluate its potential as a therapeutic target. Results The prognostic model established in this study had commendable predictive efficacy. We observed diminished infiltration of various T-cell subtypes and reduced expression of co-stimulatory signals from antigen-presenting cells. Mutation analysis revealed that the high-risk cohort harbored a higher frequency of mutations in the TP53 and FOXA genes. Notably, drug sensitivity analysis suggested the heightened responsiveness of high-risk patients to molecular inhibitors targeting the Bcl-2 and MAPK pathways. Finally, our investigation also confirmed that APOE upregulates the proliferative and invasive capacity of PCa cells and concurrently enhances resistance to androgen receptor antagonist therapy. Conclusion This comprehensive study elucidated the potential mechanisms through which this metabolic pathway orchestrates the biological behavior of PCa and findings hold promise in advancing the development of combination therapies in PCa. |
| first_indexed | 2024-04-24T12:42:23Z |
| format | Article |
| id | doaj.art-3289b402691d44a3b8cd0b699d06d2ec |
| institution | Directory Open Access Journal |
| issn | 1743-7075 |
| language | English |
| last_indexed | 2024-04-24T12:42:23Z |
| publishDate | 2024-04-01 |
| publisher | BMC |
| record_format | Article |
| series | Nutrition & Metabolism |
| spelling | doaj.art-3289b402691d44a3b8cd0b699d06d2ec2024-04-07T11:10:47ZengBMCNutrition & Metabolism1743-70752024-04-0121111710.1186/s12986-024-00791-2Exploration of vitamin D metabolic activity-related biological effects and corresponding therapeutic targets in prostate cancerLei Ding0Yong Wang1Zhentao Tang2Chenbo Ni3Qian Zhang4Qidi Zhai5Chao Liang6Jie Li7Department of Urology, The First Affiliated Hospital of Nanjing Medical UniversityDepartment of Urology, The Affiliated Wuxi People’s Hospital of Nanjing Medical UniversityDepartment of Urology, The First Affiliated Hospital of Nanjing Medical UniversityDepartment of Urology, The First Affiliated Hospital of Nanjing Medical UniversityDepartment of Urology, The First Affiliated Hospital of Nanjing Medical UniversityDepartment of Urology, The First Affiliated Hospital of Nanjing Medical UniversityDepartment of Urology, The First Affiliated Hospital of Nanjing Medical UniversityDepartment of Urology, The First Affiliated Hospital of Nanjing Medical UniversityAbstract Background Previous studies have unequivocally demonstrated that the vitamin D (VD) metabolism pathway significantly influences prognosis and sensitivity to hormone therapy in prostate cancer (PCa). However, the precise underlying mechanism remains unclear. Methods We performed molecular profiling of 1045 PCa patients, leveraging genes linked to VD synthesis and VD receptors. We then identified highly variable gene modules with substantial associations with patient stratification. Subsequently, we intersected these modules with differentially expressed genes between PCa and adjacent paracancerous tissues. Following a meticulous process involving single-factor regression and LASSO regression to eliminate extraneous variables and construct a prognostic model. Within the high-risk subgroup defined by the calculated risk score, we analyzed their differences in cell infiltration, immune status, mutation landscape, and drug sensitivity. Finally, we selected Apolipoprotein E (APOE), which featured prominently in this model for further experimental exploration to evaluate its potential as a therapeutic target. Results The prognostic model established in this study had commendable predictive efficacy. We observed diminished infiltration of various T-cell subtypes and reduced expression of co-stimulatory signals from antigen-presenting cells. Mutation analysis revealed that the high-risk cohort harbored a higher frequency of mutations in the TP53 and FOXA genes. Notably, drug sensitivity analysis suggested the heightened responsiveness of high-risk patients to molecular inhibitors targeting the Bcl-2 and MAPK pathways. Finally, our investigation also confirmed that APOE upregulates the proliferative and invasive capacity of PCa cells and concurrently enhances resistance to androgen receptor antagonist therapy. Conclusion This comprehensive study elucidated the potential mechanisms through which this metabolic pathway orchestrates the biological behavior of PCa and findings hold promise in advancing the development of combination therapies in PCa.https://doi.org/10.1186/s12986-024-00791-2Vitamin DProstate cancerPrognostic modelApolipoprotein E |
| spellingShingle | Lei Ding Yong Wang Zhentao Tang Chenbo Ni Qian Zhang Qidi Zhai Chao Liang Jie Li Exploration of vitamin D metabolic activity-related biological effects and corresponding therapeutic targets in prostate cancer Nutrition & Metabolism Vitamin D Prostate cancer Prognostic model Apolipoprotein E |
| title | Exploration of vitamin D metabolic activity-related biological effects and corresponding therapeutic targets in prostate cancer |
| title_full | Exploration of vitamin D metabolic activity-related biological effects and corresponding therapeutic targets in prostate cancer |
| title_fullStr | Exploration of vitamin D metabolic activity-related biological effects and corresponding therapeutic targets in prostate cancer |
| title_full_unstemmed | Exploration of vitamin D metabolic activity-related biological effects and corresponding therapeutic targets in prostate cancer |
| title_short | Exploration of vitamin D metabolic activity-related biological effects and corresponding therapeutic targets in prostate cancer |
| title_sort | exploration of vitamin d metabolic activity related biological effects and corresponding therapeutic targets in prostate cancer |
| topic | Vitamin D Prostate cancer Prognostic model Apolipoprotein E |
| url | https://doi.org/10.1186/s12986-024-00791-2 |
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