1. Targeting the PI3K/AKT/mTOR pathway offer a promising therapeutic strategy for cholangiocarcinoma patients with high doublecortin-like kinase 1 expression.
- Author
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Liang Z, Ge Y, Li J, Bai Y, Xiao Z, Yan R, An G, and Zhang D
- Subjects
- Humans, Male, Animals, Female, Mice, Epithelial-Mesenchymal Transition, Cell Line, Tumor, Prognosis, Middle Aged, Cell Proliferation, Mice, Nude, Xenograft Model Antitumor Assays, Gene Expression Regulation, Neoplastic, Cholangiocarcinoma pathology, Cholangiocarcinoma metabolism, Cholangiocarcinoma genetics, Cholangiocarcinoma drug therapy, Doublecortin-Like Kinases, TOR Serine-Threonine Kinases metabolism, Proto-Oncogene Proteins c-akt metabolism, Protein Serine-Threonine Kinases metabolism, Protein Serine-Threonine Kinases genetics, Bile Duct Neoplasms pathology, Bile Duct Neoplasms metabolism, Bile Duct Neoplasms genetics, Bile Duct Neoplasms drug therapy, Intracellular Signaling Peptides and Proteins metabolism, Intracellular Signaling Peptides and Proteins genetics, Phosphatidylinositol 3-Kinases metabolism, Signal Transduction
- Abstract
Background: Cholangiocarcinoma (CCA), characterized by high heterogeneity and extreme malignancy, has a poor prognosis. Doublecortin-like kinase 1 (DCLK1) promotes a variety of malignant cancers in their progression. Targeting DCLK1 or its associated regulatory pathways can prevent the generation and deterioration of several malignancies. However, the role of DCLK1 in CCA progression and its molecular mechanisms remain unknown. Therefore, we aimed to investigate whether and how DCLK1 contributes to CCA progression., Methods: The expression of DCLK1 in CCA patients was detected using Immunohistochemistry (IHC). We established DCLK1 knockout and DCLK1 overexpression cell lines for Colony Formation Assay and Transwell experiments to explore the tumor-promoting role of DCLK1. RT-PCR, Western blot and multiple fluorescent staining were used to assess the association between DCLK1 and epithelial-mesenchymal transition (EMT) markers. RNA sequencing and bioinformatics analysis were performed to identify the underlying mechanisms by which DCLK1 regulates CCA progression and the EMT program., Results: DCLK1 was overexpressed in CCA tissues and was associated with poor prognosis. DCLK1 overexpression facilitated CCA cell invasion, migration, and proliferation, whereas DCLK1 knockdown reversed the malignant tendencies of CCA cells, which had been confirmed both in vivo and in vitro. Furthermore, we demonstrated that DCLK1 was substantially linked to the advancement of the EMT program, which included the overexpression of mesenchymal markers and the downregulation of epithelial markers. For the underlying mechanism, we proposed that the PI3K/AKT/mTOR pathway is the key process for the role of DCLK1 in tumor progression and the occurrence of the EMT program. When administered with LY294002, an inhibitor of the PI3K/AKT/mTOR pathway, the tumor's ability to proliferate, migrate, and invade was greatly suppressed, and the EMT process was generally reversed., Conclusions: DCLK1 facilitates the malignant biological behavior of CCA cells through the PI3K/AKT/mTOR pathway. In individuals with cholangiocarcinoma who express DCLK1 at high levels, inhibitors of the PI3K/AKT/mTOR signaling pathway may be an effective therapeutic approach., (© 2024. The Author(s).)
- Published
- 2024
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