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C1QBP forms a positive feedback loop with the PAICS/FAK/c-Myc axis to promote cholangiocarcinoma proliferation

ABSTRACT: Cholangiocarcinoma (CCA) is a highly lethal malignancy with increasing incidence and mortality rates worldwide. To investigate the mechanisms underlying CCA tumorigenesis, we conducted bioinformatics analysis, which revealed that C1QBP is the most upregulated membrane protein in CCA and is involved in energy metabolism, nucleotide repair, and resistance to platinum-based chemotherapeutic agents in CCA. Our findings revealed that C1QBP is significantly overexpressed in CCA and is strongly associated with increased proliferation and poor prognosis. Mechanistic studies further demonstrated that c-MYC can upregulate C1QBP expression at the transcriptional level, subsequently influencing PAICS/FAK expression and promoting CCA growth. Interestingly, C1QBP also regulates c-MYC expression by increasing FAK phosphorylation, establishing a positive feedback loop that drives tumor progression. Additionally, we developed a novel siRNA delivery system, si@LH, by encapsulating siC1QBP within hyaluronic acid-dopamine hydrogel-coated liposomes. Ex vivo experiments confirmed that this system enables prolonged and stable C1QBP inhibition. In conclusion, our study suggests that C1QBP may serve as a valuable biomarker for cholangiocarcinoma prognosis and that silencing C1QBP with si@LH, either alone or in combination with other targeted or immunotherapies, holds promise as a therapeutic strategy for cholangiocarcinoma.

ORGANISM(S): Homo sapiens

PROVIDER: GSE308768 | GEO | 2025/09/26

REPOSITORIES: GEO

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Project description:Cholangiocarcinoma (CCA) is a hepatobiliary malignancy with dismal prognosis. Currently available models fail to recapitulate the full complexity of CCA, particularly the desmoplastic environment and the interplay between cancer cells and the extracellular matrix (ECM). We aimed to study the role of epithelial tumor cells in ECM deposition and desmoplasia by designing a model encompassing primary epithelial CCA organoids (CCAOs) and native liver and tumor scaffolds obtained by decellularization Background & Aims: Cholangiocarcinoma (CCA) is a hepatobiliary malignancy with dismal prognosis. Currently available models fail to recapitulate the full complexity of CCA, particularly the desmoplastic environment and the interplay between cancer cells and the extracellular matrix (ECM). We aimed to study the role of epithelial tumor cells in ECM deposition and desmoplasia by designing a model encompassing primary epithelial CCA organoids (CCAOs) and native liver and tumor scaffolds obtained by decellularization. Results: Decellularization resulted in effective removal of cells while preserving ECM structure and retaining important characteristics of the tissue origin. When culturing CCAOs in CCA-M, compared to TFL-M and BME, the genome-wide gene expression profile much more resembled the transcriptome of primary CCA tumor tissue in vivo, with an accompanying increase in chemoresistance. CCAOs in decellularized matrix, both CCA-M and TFL-M, exhibited the formation of complex morphological structures, and revealed environment-dependent proliferation and migration dynamics, driven by the occurrence of epithelial-mesenchymal transition (EMT). CCA-M induced specific extracellular matrix protein production in CCAOs, such as fibronectin 1 (FN1), which is related to desmoplasia and patient survival. In TFL-M, lacking the desmoplastic environment, CCAOs were able to initiate a desmoplastic reaction directly through increased production of multiple collagen types. Conclusions: This improved model of cholangiocarcinoma, combining organoids and native extracellular matrix, recapitulates key components of CCA tumor biology, including transcriptome profiles, migration patterns, EMT, and ECM protein production. The increased production of extracellular matrix proteins suggests that epithelial tumor cells can contribute to their own desmoplastic environment.

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C1QBP forms a positive feedback loop with the PAICS/FAK/c-Myc axis to promote cholangiocarcinoma proliferation

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