Molecular profiling reveals potential targets in cholangiocarcinoma

Dan Liu; Yang Shi; Hongze Chen; Muhammad Azhar Nisar; Nicholas Jabara; Noah Langwinski; Sophia Mattson; Katsuya Nagaoka; Xuewei Bai; Shaolei Lu; Chiung-Kuei Huang

doi:10.3748/wjg.v29.i25.4053

Molecular profiling reveals potential targets in cholangiocarcinoma

World J Gastroenterol. 2023 Jul 7;29(25):4053-4071. doi: 10.3748/wjg.v29.i25.4053.

Authors

Affiliations

¹ Department of Gastroenterology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China.
² Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, LA 70112, United States.
³ Department of Medicine, Rhode Island Hospital and the Alpert Medical School of Brown University, Providence, RI 02903, United States.
⁴ Department of Pathology, Alpert Medical School of Brown University, Providence, RI 02903, United States.
⁵ Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, LA 70112, United States. chuang17@tulane.edu.

Abstract

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 Kras^G12D 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.

Keywords: Bile duct cancer; Cell cycle; Liver cancer; Notch; Therapeutic target.

MeSH terms

Animals
Bile Duct Neoplasms* / pathology
Bile Ducts, Intrahepatic / pathology
Cell Line
Cell Line, Tumor
Cholangiocarcinoma* / genetics
Cholangiocarcinoma* / pathology
Gene Expression Profiling
Humans
Mice