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A Three-Dimensional Spheroid Model to Investigate the Tumor-Stromal Interaction in Hepatocellular Carcinoma
Published on: September 30, 2021
Involvement and Targeted Intervention of Mortalin-Regulated Proteome Phosphorylated-Modification in Hepatocellular
1Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China.
Objectives:
To reveal the mechanisms of the effects of mortalin in hepatocellular carcinoma (HCC) and to identify potential novel chemical inhibitors of mortalin.
Materials And Methods:
For the experiments, three HCC cell lines (HepG2 cells, Hep3B cells, and sorafenib-resistant HuH7 cells) and xenografted nude mice were used. For the clinical analysis, cohorts of 126 patients with HCC and 34 patients with advanced recurrent HCC receiving sorafenib therapy were examined.
Results:
Mortalin regulated the phosphorylation-modification of cancer-associated proteins and also regulated angiogenesis-related secretome to cause angiogenesis and sorafenib resistance in HCC cells. Two molecular mechanisms were identified. In one, via phosphatidylinositol 3-kinase (PI3K)/Akt signaling, mortalin regulated nuclear factor (NF)-κB and then activated vascular endothelial growth factor (VEGF)/vascular endothelial growth factor receptor (VEGFR)2 and granulocyte-macrophage colony-stimulating factor (GM-CSF), leading to neovascularization. In the other, mortalin regulated PI3K/Akt/β-catenin and then regulated Bcl-XL and Bcl-2, leading to the antiapoptosis effect of HCC. Treatment of the sorafenib-resistant xenografts with sorafenib in combination with mortalin knockdown facilitated the sorafenib-mediated inhibition of tumor growth and angiogenesis and increased apoptosis. Mortalin was a potential risk factor for HCC, predicting poor prognosis and sorafenib resistance. Finally, we showed that caffeic acid (C9H8O4) could bind to and induce the ubiquitination-mediated degradation of mortalin, which in turn blocked the abovementioned signaling pathways, leading to the inhibition of angiogenesis and the reversal of sorafenib resistance.
Conclusions:
Mortalin, which regulates the phosphorylation of cancer-associated proteins, caused angiogenesis and sorafenib resistance, and was a competitive risk factor for HCC. Caffeic acid can therefore be considered a novel chemical inhibitor that targets the action of mortalin and a potential treatment for HCC.
Insights
Mortalin drives hepatocellular carcinoma (HCC) growth, angiogenesis, and sorafenib resistance by regulating key signaling pathways. Caffeic acid inhibits mortalin, offering a potential new treatment for HCC.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Mortalin (HSP70) is implicated in various cancers, but its specific roles in hepatocellular carcinoma (HCC) and resistance to targeted therapies like sorafenib require elucidation.
- Understanding mortalin's mechanisms in HCC is crucial for developing effective therapeutic strategies against this prevalent liver cancer.
Purpose of the Study:
- To elucidate the molecular mechanisms by which mortalin contributes to hepatocellular carcinoma (HCC) progression, angiogenesis, and sorafenib resistance.
- To identify novel chemical inhibitors targeting mortalin for potential HCC treatment.
Main Methods:
- Utilized HCC cell lines (HepG2, Hep3B, sorafenib-resistant HuH7) and xenografted nude mice models for experimental validation.
- Conducted clinical analysis on patient cohorts with HCC and advanced recurrent HCC undergoing sorafenib therapy.
- Investigated signaling pathways including PI3K/Akt, NF-κB, VEGF/VEGFR2, GM-CSF, and β-catenin, and apoptosis-related proteins (Bcl-XL, Bcl-2).
Main Results:
- Mortalin promotes HCC angiogenesis and sorafenib resistance via PI3K/Akt/NF-κB/VEGF/GM-CSF and PI3K/Akt/β-catenin/Bcl-XL/Bcl-2 pathways.
- Mortalin knockdown combined with sorafenib treatment inhibited tumor growth and angiogenesis while increasing apoptosis in resistant xenografts.
- Mortalin identified as a risk factor for HCC, predicting poor prognosis and sorafenib resistance.
- Caffeic acid demonstrated ability to bind mortalin, inducing its degradation and blocking associated signaling pathways, thereby inhibiting angiogenesis and reversing sorafenib resistance.
Conclusions:
- Mortalin plays a critical role in HCC pathogenesis by regulating protein phosphorylation, promoting angiogenesis, and conferring sorafenib resistance.
- Mortalin acts as a significant risk factor for HCC, correlating with adverse outcomes and treatment resistance.
- Caffeic acid emerges as a promising novel chemical inhibitor targeting mortalin, with potential as a therapeutic agent for HCC.
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