Network pharmacological analysis of corosolic acid reveals P4HA2 inhibits hepatocellular carcinoma progression
Abstract Background Corosolic acid is a pentacyclic triterpene acid with hypoglycemic, anti-inflammatory, and anti-cancer effects. However, its potential targets in hepatocellular carcinoma (HCC) are unknown, hindering clinical utilization. Methods Differentially expressed proteins of the Bel-7404 c...
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| Language: | English |
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BMC
2023-05-01
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| Series: | BMC Complementary Medicine and Therapies |
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| Online Access: | https://doi.org/10.1186/s12906-023-04008-6 |
| _version_ | 1797811948487704576 |
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| author | Fei-Feng Tang Long Liu Xiao-Ting Tian Ning Li Ying-Xiu Peng Chun-Mei Qian Ting-Ting Jia Jing-Jin Liu Wen-Hui Gao Yan-Feng Xu |
| author_facet | Fei-Feng Tang Long Liu Xiao-Ting Tian Ning Li Ying-Xiu Peng Chun-Mei Qian Ting-Ting Jia Jing-Jin Liu Wen-Hui Gao Yan-Feng Xu |
| author_sort | Fei-Feng Tang |
| collection | DOAJ |
| description | Abstract Background Corosolic acid is a pentacyclic triterpene acid with hypoglycemic, anti-inflammatory, and anti-cancer effects. However, its potential targets in hepatocellular carcinoma (HCC) are unknown, hindering clinical utilization. Methods Differentially expressed proteins of the Bel-7404 cell line were identified with tandem mass tag analysis and differentially expressed genes (DEGs) of an HCC TCGA dataset using bioinformatics. Gene functions and pathways were inferred using the DAVID database. Online databases were used to establish P4HA2 expression in HCC (GEPIA2) and its relationship with patient survival (UALCAN and The Human Protein Atlas), the association between P4HA2 expression and immune cell infiltration (TIMER2), and DNA methylation of the P4HA2 gene (MethSurv). Cell proliferation, cell cycle, and cell death were assessed with PI and SYTOX-Green staining, CCK-8, and colony formation assays. Protein expression levels were detected by Western blotting. Results A total of 44 differentially expressed proteins and 4498 DEGs were identified. Four genes whose proteins were also found in the differential protein profile but with opposing expressions were selected as candidate targets. The candidate gene prolyl 4-hydroxylase subunit alpha 2 (P4HA2) was recognized as the only potential target due to its high expression in public datasets, association with poor patient survival, and relation to immune cell infiltration in HCC tissues. Moreover, the DNA methylation status in 4 CpG islands of the P4HA2 gene correlated with a poor prognosis. Furthermore, corosolic acid treatment inhibited the proliferation of HCC cell lines Bel-7404 and HepG2 in a dose-dependent manner, caused G2/M phase cell cycle arrest, and promoted cell death. In addition, the treatment reduced P4HA2 protein levels. Conclusion Our results indicate that P4HA2 is a potential target of corosolic acid. Thus, they contribute to understanding molecular changes in HCC after corosolic acid treatment and facilitate finding new treatment regimens. |
| first_indexed | 2024-03-13T07:30:17Z |
| format | Article |
| id | doaj.art-33b19299c1aa493c87226f2ea330cbe3 |
| institution | Directory Open Access Journal |
| issn | 2662-7671 |
| language | English |
| last_indexed | 2024-03-13T07:30:17Z |
| publishDate | 2023-05-01 |
| publisher | BMC |
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| series | BMC Complementary Medicine and Therapies |
| spelling | doaj.art-33b19299c1aa493c87226f2ea330cbe32023-06-04T11:06:22ZengBMCBMC Complementary Medicine and Therapies2662-76712023-05-0123111310.1186/s12906-023-04008-6Network pharmacological analysis of corosolic acid reveals P4HA2 inhibits hepatocellular carcinoma progressionFei-Feng Tang0Long Liu1Xiao-Ting Tian2Ning Li3Ying-Xiu Peng4Chun-Mei Qian5Ting-Ting Jia6Jing-Jin Liu7Wen-Hui Gao8Yan-Feng Xu9Department of Pharmacy, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese MedicineDepartment of Traditional Chinese Medicine, Tianyou Hospital of Tongji UniversityShanghai Chest Hospital, Shanghai Institute of Thoracic Oncology, Shanghai Jiao Tong University School of MedicineCentral Laboratory, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese MedicineDepartment of Pharmacy, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese MedicineCentral Laboratory, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese MedicineDepartment of Pharmacy, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese MedicineDepartment of Pharmacy, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese MedicineDepartment of Pharmacy, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese MedicineDepartment of Pharmacy, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese MedicineAbstract Background Corosolic acid is a pentacyclic triterpene acid with hypoglycemic, anti-inflammatory, and anti-cancer effects. However, its potential targets in hepatocellular carcinoma (HCC) are unknown, hindering clinical utilization. Methods Differentially expressed proteins of the Bel-7404 cell line were identified with tandem mass tag analysis and differentially expressed genes (DEGs) of an HCC TCGA dataset using bioinformatics. Gene functions and pathways were inferred using the DAVID database. Online databases were used to establish P4HA2 expression in HCC (GEPIA2) and its relationship with patient survival (UALCAN and The Human Protein Atlas), the association between P4HA2 expression and immune cell infiltration (TIMER2), and DNA methylation of the P4HA2 gene (MethSurv). Cell proliferation, cell cycle, and cell death were assessed with PI and SYTOX-Green staining, CCK-8, and colony formation assays. Protein expression levels were detected by Western blotting. Results A total of 44 differentially expressed proteins and 4498 DEGs were identified. Four genes whose proteins were also found in the differential protein profile but with opposing expressions were selected as candidate targets. The candidate gene prolyl 4-hydroxylase subunit alpha 2 (P4HA2) was recognized as the only potential target due to its high expression in public datasets, association with poor patient survival, and relation to immune cell infiltration in HCC tissues. Moreover, the DNA methylation status in 4 CpG islands of the P4HA2 gene correlated with a poor prognosis. Furthermore, corosolic acid treatment inhibited the proliferation of HCC cell lines Bel-7404 and HepG2 in a dose-dependent manner, caused G2/M phase cell cycle arrest, and promoted cell death. In addition, the treatment reduced P4HA2 protein levels. Conclusion Our results indicate that P4HA2 is a potential target of corosolic acid. Thus, they contribute to understanding molecular changes in HCC after corosolic acid treatment and facilitate finding new treatment regimens.https://doi.org/10.1186/s12906-023-04008-6Corosolic acidHepatocellular carcinomaNetwork pharmacologyProteomicsP4HA2 |
| spellingShingle | Fei-Feng Tang Long Liu Xiao-Ting Tian Ning Li Ying-Xiu Peng Chun-Mei Qian Ting-Ting Jia Jing-Jin Liu Wen-Hui Gao Yan-Feng Xu Network pharmacological analysis of corosolic acid reveals P4HA2 inhibits hepatocellular carcinoma progression BMC Complementary Medicine and Therapies Corosolic acid Hepatocellular carcinoma Network pharmacology Proteomics P4HA2 |
| title | Network pharmacological analysis of corosolic acid reveals P4HA2 inhibits hepatocellular carcinoma progression |
| title_full | Network pharmacological analysis of corosolic acid reveals P4HA2 inhibits hepatocellular carcinoma progression |
| title_fullStr | Network pharmacological analysis of corosolic acid reveals P4HA2 inhibits hepatocellular carcinoma progression |
| title_full_unstemmed | Network pharmacological analysis of corosolic acid reveals P4HA2 inhibits hepatocellular carcinoma progression |
| title_short | Network pharmacological analysis of corosolic acid reveals P4HA2 inhibits hepatocellular carcinoma progression |
| title_sort | network pharmacological analysis of corosolic acid reveals p4ha2 inhibits hepatocellular carcinoma progression |
| topic | Corosolic acid Hepatocellular carcinoma Network pharmacology Proteomics P4HA2 |
| url | https://doi.org/10.1186/s12906-023-04008-6 |
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