IGFBP3-mediated effects of an effective combination therapy on HCC
Abstract As all known, hepatocellular carcinoma (HCC) accounts for the majority of cases of liver cancer, which is the third leading cause of cancer mortality globally. Moreover, HCC is always accompanied with HBV infection. Here, we used CMAP, a systematic approach for the discovery of functional c...
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Nature Portfolio
2025-08-01
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| Online Access: | https://doi.org/10.1038/s41598-025-06148-w |
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| author | Lin Chen Lei Zhao Guozhi Wu Tiantian Zhang Zhiwu Liu David Fisher Nguten Thi Thu Hien Erkin Musabaev |
| author_facet | Lin Chen Lei Zhao Guozhi Wu Tiantian Zhang Zhiwu Liu David Fisher Nguten Thi Thu Hien Erkin Musabaev |
| author_sort | Lin Chen |
| collection | DOAJ |
| description | Abstract As all known, hepatocellular carcinoma (HCC) accounts for the majority of cases of liver cancer, which is the third leading cause of cancer mortality globally. Moreover, HCC is always accompanied with HBV infection. Here, we used CMAP, a systematic approach for the discovery of functional connections among diseases and drug actions, to identify quercetin as an effective compound to potentially treat HCC. Furthermore, we proved the inhibitory effects of quercetin on HCC cells, shown as decreased cell viability in HCCLM3 and HepG2 cells. In addition, quercetin disturbed the migration of HCC cells in a dose-dependent manner. Furthermore, quercetin treatments effectively elevated the activities of caspase-3 as well as caspase-9 and increased the Bax expression in HCC cells accompanied with decreased levels of p53 and BCL-2, indicating an enhancement of apoptosis induced by quercetin. Notably, quercetin depressed the activities of antioxidant enzymes, including SOD, GST, GPx and CAT, leading to an increase of ROS accumulation. Additionally, quercetin also exhibited an obvious inhibition of tumor growth of HCC in vivo. Through RNA-seq, results showed that genes related to regulation of cell proliferations were enriched, in which IGFBP3 played a critical role in mediating the effects of quercetin on HCC cells by reducing PI3K-mTOR activation. After silencing IGFBP3 in HCCLM3 cells, quercetin exhibited weaken effects on cell proliferation and apoptosis. Notably, IGFBP3 promotor strengthened the suppressed effects induced by single quercetin administration, indicating a potential drug combination for treatments of HCC. Collectively, this study clarified a novel mechanism underlying the inhibitory effects of quercetin on HCC, providing a potential approach for HCC treatment in clinic. |
| format | Article |
| id | doaj-art-0bc0f9406eb647a9b14201fbb8fa966f |
| institution | Kabale University |
| issn | 2045-2322 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj-art-0bc0f9406eb647a9b14201fbb8fa966f2025-08-24T11:30:37ZengNature PortfolioScientific Reports2045-23222025-08-0115111210.1038/s41598-025-06148-wIGFBP3-mediated effects of an effective combination therapy on HCCLin Chen0Lei Zhao1Guozhi Wu2Tiantian Zhang3Zhiwu Liu4David Fisher5Nguten Thi Thu Hien6Erkin Musabaev7Department of Infectious Diseases, Tsinghua University Affiliated Chuiyangliu HospitalDepartment of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and TechnologyThe First Clinical Medical College, Lanzhou UniversityThe First Clinical Medical College, Lanzhou UniversityDepartment of Clinical Medical Laboratory, the First Hospital of Lanzhou UniversityDepartment of Medical Biosciences, Faculty of Natural Sciences, University of The Western CapeHai Phong University of Medicine and PharmacyThe Research Institute of Virology, Ministry of HealthAbstract As all known, hepatocellular carcinoma (HCC) accounts for the majority of cases of liver cancer, which is the third leading cause of cancer mortality globally. Moreover, HCC is always accompanied with HBV infection. Here, we used CMAP, a systematic approach for the discovery of functional connections among diseases and drug actions, to identify quercetin as an effective compound to potentially treat HCC. Furthermore, we proved the inhibitory effects of quercetin on HCC cells, shown as decreased cell viability in HCCLM3 and HepG2 cells. In addition, quercetin disturbed the migration of HCC cells in a dose-dependent manner. Furthermore, quercetin treatments effectively elevated the activities of caspase-3 as well as caspase-9 and increased the Bax expression in HCC cells accompanied with decreased levels of p53 and BCL-2, indicating an enhancement of apoptosis induced by quercetin. Notably, quercetin depressed the activities of antioxidant enzymes, including SOD, GST, GPx and CAT, leading to an increase of ROS accumulation. Additionally, quercetin also exhibited an obvious inhibition of tumor growth of HCC in vivo. Through RNA-seq, results showed that genes related to regulation of cell proliferations were enriched, in which IGFBP3 played a critical role in mediating the effects of quercetin on HCC cells by reducing PI3K-mTOR activation. After silencing IGFBP3 in HCCLM3 cells, quercetin exhibited weaken effects on cell proliferation and apoptosis. Notably, IGFBP3 promotor strengthened the suppressed effects induced by single quercetin administration, indicating a potential drug combination for treatments of HCC. Collectively, this study clarified a novel mechanism underlying the inhibitory effects of quercetin on HCC, providing a potential approach for HCC treatment in clinic.https://doi.org/10.1038/s41598-025-06148-wHCCQuercetinIGFBP3ResveratrolCombination therapy |
| spellingShingle | Lin Chen Lei Zhao Guozhi Wu Tiantian Zhang Zhiwu Liu David Fisher Nguten Thi Thu Hien Erkin Musabaev IGFBP3-mediated effects of an effective combination therapy on HCC Scientific Reports HCC Quercetin IGFBP3 Resveratrol Combination therapy |
| title | IGFBP3-mediated effects of an effective combination therapy on HCC |
| title_full | IGFBP3-mediated effects of an effective combination therapy on HCC |
| title_fullStr | IGFBP3-mediated effects of an effective combination therapy on HCC |
| title_full_unstemmed | IGFBP3-mediated effects of an effective combination therapy on HCC |
| title_short | IGFBP3-mediated effects of an effective combination therapy on HCC |
| title_sort | igfbp3 mediated effects of an effective combination therapy on hcc |
| topic | HCC Quercetin IGFBP3 Resveratrol Combination therapy |
| url | https://doi.org/10.1038/s41598-025-06148-w |
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