Molecular profiling reveals potential targets in cholangiocarcinoma
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Published on: September 15, 2023
Dan Liu1, Yang Shi1, Hongze Chen2
1Department of Gastroenterology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China.
Background:
Cholangiocarcinoma (CCA) is a devastating malignancy and has a very poor prognosis if tumors spread outside the liver. Understanding the molecular mechanisms underlying the CCA progression will likely yield therapeutic approaches toward treating this deadly disease.
Aim:
To determine the molecular pathogenesis in CCA progression.
Methods:
In silico analysis, in vitro cell culture, CCA transgenic animals, histological, and molecular assays were adopted to determine the molecular pathogenesis.
Results:
The transcriptomic data of human CCA samples were retrieved from The Cancer Genome Atlas (TGCA, CHOL), European Bioinformatics Institute (EBI, GAD00001001076), and Gene Expression Omnibus (GEO, GSE107943) databases. Using Gene set enrichment analysis, the cell cycle and Notch related pathways were demonstrated to be significantly activated in CCA in TCGA and GEO datasets. We, through differentially expressed genes, found several cell cycle and notch associated genes were significantly up-regulated in cancer tissues when compared with the non-cancerous control samples. The associated genes, via quantitative real-time PCR and western blotting assays, were further examined in normal human cholangiocytes, CCA cell lines, mouse normal bile ducts, and mouse CCA tumors established by specifically depleting P53 and expressing KrasG12D mutation in the liver. Consistently, we validated that the cell cycle and Notch pathways are up-regulated in CCA cell lines and mouse CCA tumors. Interestingly, targeting cell cycle and notch pathways using small molecules also exhibited significant beneficial effects in controlling tumor malignancy. More importantly, we demonstrated that several cell cycle and Notch associated genes are significantly associated with poor overall survival and disease-free survival using the Log-Rank test.
Conclusion:
In summary, our study comprehensively analyzed the gene expression pattern of CCA samples using publicly available datasets and identified the cell cycle and Notch pathways are potential therapeutic targets in this deadly disease.
Insights
Cholangiocarcinoma (CCA) progression involves activated cell cycle and Notch pathways. Targeting these pathways shows promise for treating this deadly liver cancer.
Area of Science:
- Oncology
- Molecular Biology
- Genomics
Background:
- Cholangiocarcinoma (CCA) is a lethal liver cancer with poor outcomes, especially upon metastasis.
- Understanding CCA's molecular drivers is crucial for developing effective treatments.
Purpose of the Study:
- To investigate the molecular pathogenesis of cholangiocarcinoma progression.
- To identify key molecular pathways and genes involved in CCA development and their therapeutic potential.
Main Methods:
- Utilized in silico transcriptomic data analysis from public databases (TCGA, EBI, GEO).
- Employed in vitro cell culture and in vivo CCA transgenic mouse models.
- Conducted histological and molecular assays, including quantitative real-time PCR and western blotting.
Main Results:
- Gene set enrichment analysis revealed significant activation of cell cycle and Notch pathways in CCA.
- Differentially expressed genes confirmed upregulation of cell cycle and Notch-associated genes in cancer tissues and models.
- Targeting these pathways with small molecules demonstrated anti-tumor effects, and associated genes correlated with poor patient survival.
Conclusions:
- The cell cycle and Notch pathways are significantly activated in cholangiocarcinoma.
- These pathways represent promising therapeutic targets for managing CCA.
- Comprehensive analysis of gene expression patterns aids in identifying novel treatment strategies for CCA.
