IGFBP3-mediated effects of an effective combination therapy on HCC
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ABSTRACT:
PROVIDER: PRJNA1186675 | ENA |
REPOSITORIES: ENA
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Project description: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.
2025-08-27 | GSE282022 | GEO
Project description: Not available
| S-EPMC12365044 | biostudies-literature
Project description:Human-correlated genetic HCC and HCC-organoid models identify combination therapy for precision medicine
| PRJNA1150922 | ENA
Project description:Hepatocellular carcinoma (HCC), the most common form of primary liver cancer, is a leading cause of cancer related mortality worldwide. HCC occurs typically from a background of chronic liver disease, caused by a spectrum of predisposing conditions. Tumour development is driven by the expansion of clones that accumulated progressive driver mutations, with hepatocytes the most likely cell of origin. However, the landscape of driver mutations in HCC is independent of the underlying aetiologies. Despite an increasing range of systemic treatment options for advanced HCC outcomes remain heterogeneous and typically poor. Emerging data suggest that drug efficacies depend on disease aetiology and genetic alterations. Exploring subtypes in preclinical models with human relevance will therefore be essential to advance precision medicine in HCC. We generated over twenty-five new genetically-driven in vivo and in vitro HCC models. Our models represent multiple features of human HCC, including clonal origin, histopathological appearance, and metastasis to distant organs. We integrated transcriptomic data from the mouse models with human HCC data and identified four common human-mouse subtype clusters. The subtype clusters had distinct transcriptomic characteristics that aligned with histopathology. In a proof-of-principle analysis, we verified response to standard of care treatment and used a linked in vitro-in vivo pipeline to identify a promising therapeutic candidate, cladribine, that has not been linked to HCC treatment before. Cladribine acts in a highly effective subtype-specific manner in combination with standard of care therapy.
2024-12-02 | GSE273806 | GEO
Project description:Human-correlated genetic HCC models identify combination therapy for precision medicine
| PRJNA1143392 | ENA
Project description:Hepatocellular carcinoma (HCC), the most common form of primary liver cancer, is a leading cause of cancer related mortality worldwide. HCC occurs typically from a background of chronic liver disease, caused by a spectrum of predisposing conditions. Tumour development is driven by the expansion of clones that accumulated progressive driver mutations, with hepatocytes the most likely cell of origin. However, the landscape of driver mutations in HCC is independent of the underlying aetiologies. Despite an increasing range of systemic treatment options for advanced HCC outcomes remain heterogeneous and typically poor. Emerging data suggest that drug efficacies depend on disease aetiology and genetic alterations. Exploring subtypes in preclinical models with human relevance will therefore be essential to advance precision medicine in HCC. We generated over twenty-five new genetically-driven in vivo and in vitro HCC models. Our models represent multiple features of human HCC, including clonal origin, histopathological appearance, and metastasis to distant organs. We integrated transcriptomic data from the mouse models with human HCC data and identified four common human-mouse subtype clusters. The subtype clusters had distinct transcriptomic characteristics that aligned with histopathology. In a proof-of-principle analysis, we verified response to standard of care treatment and used a linked in vitro-in vivo pipeline to identify a promising therapeutic candidate, cladribine, that has not been linked to HCC treatment before. Cladribine acts in a highly effective subtype-specific manner in combination with standard of care therapy.
2024-12-02 | GSE275443 | GEO
Project description:Human-correlated genetic HCC organoid models identify combination therapy for precision medicine
| PRJNA1150928 | ENA
Project description:Inhibition of mitochondrial translocase SLC25A5 and histone deacetylation is an effective combination therapy in neuroblastoma
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Project description:Nobelitin and Sorafenib Combination Therapy
| PRJNA1029033 | ENA
Project description:To enhance hepatocellular carcinoma (HCC) treatment, the combination of Nobelitin (NOB) and Sorafenib (SOR) is being explored. Nobelitin is utilized to induce the expression of BMAL1, a circadian rhythm-related protein, with the goal of improving the effectiveness of SOR in treating HCC. This innovative strategy holds promise for optimizing treatment outcomes for HCC patients.
2024-11-16 | GSE245588 | GEO