Dataset Information

Treachery of hepatic protector triggers Notch signaling to promote hepatocyte-originated cholangiocarcinoma

ABSTRACT: Here, we found mesencephalic astrocyte-derived neurotrophic factor (MANF), a hepatic protector, was upregulated in human ICC tissues and sleeping beauty transposon (SBT) or thioacetamide (TAA)-induced mice ICC tissues. We verified the oncogenic role of MANF in ICC using cell lines overexpressing/knocked down MANF and mice specifically knocked in/out MANF in hepatocytes. Lineage tracing revealed that MANF promoted mature hepatocytes transformation into ICC. Mechanistically, we found a complex composed of MANF, CK19, and Notch2 intracellular domain (NICD2). MANF interacted with CK19 at Ser35 to suppress CK19 phosphorylation and membrane recruitment. Cytosolic CK19 bound to AR domain of NICD2 to stabilize NICD2 protein level and trigger Notch signaling, which contributed to hepatocytes transformation to ICC. We uncover a novel role of MANF and the original mechanism，which shed light on ICC intervention and treatment.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Epithelial Cell, Cell Culture

DISEASE(S): Cholangiocarcinoma

SUBMITTER: Qiong Mei

LAB HEAD: Yuxian Shen

PROVIDER: PXD048451 | Pride | 2025-08-25

REPOSITORIES: Pride

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Publications

Hepatic factor MANF drives hepatocytes reprogramming by detaining cytosolic CK19 in intrahepatic cholangiocarcinoma.

Mei Qiong Q Zhang Yu Y Li Hong H Ma Wei W Huang Wenkai W Wu Zhengsheng Z Huang Yongli Y Liang Yanyan Y Wei Chuansheng C Wang Jinfeng J Ruan Yuefeng Y Yang Lin L Huang Yan Y Shen Yujun Y Liu Jun J Feng Lijie L Shen Yuxian Y

Cell death and differentiation 20250219 8

Intrahepatic cholangiocarcinoma (ICC) is characterized by poor prognosis and limited treatment. Hepatocytes have been considered as one of the origins of ICC, however, the underlying mechanisms remain unclear. Here, we found mesencephalic astrocyte-derived neurotrophic factor (MANF), a hepatoprotective factor, was exceptionally upregulated in human ICC tissues and experimental mouse ICC models induced by sleeping beauty transposon (SBT) or thioacetamide (TAA) challenge. We identified MANF as a b ...[more]

PMID: 39972058

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Project description:Intrahepatic cholangiocarcinoma (ICC) is the second most common type of primary cancer in the liver. ICC is an aggressive cancer with poor prognosis and limited therapeutic strategies. The identification of new drug targets and prognostic biomarkers is an important clinical challenge for ICC. The presence of an abundant stroma is a histological hallmark of ICC. Given the well established role of the stromal compartment in the progression of cancer diseases, we hypothesized that relevant biomarkers could be identified by analyzing the stroma of ICC. By combining laser capture microdissection and gene expression profiling we demonstrated that ICC stromal cells exhibit dramatic genomic changes. We identified a signature of 1,073 non-redundant genes that significantly discriminate the tumor stroma from non tumor fibrous tissue. Functional analysis of differentially expressed genes demonstrated that up-regulated genes in the stroma of ICC were related to cell cycle, extracellular matrix and Transforming Growth Factor beta (TGFM-NM-2) pathways. Tissue microarray analysis using an independent cohort of 40 ICC patients validated at a protein level the increase expression of Collagen 4, Laminin, Osteopontin/SPP1, KIAA0101 and TGFM-NM-22 genes in the stroma of ICC. Statistical analysis of clinical and pathological features demonstrated that the expression of Osteopontin, TGFM-NM-22 and Laminin in the stroma of ICC was significantly correlated with patient overall survival. More importantly, multivariate analysis demonstrated that the stromal expression of Osteopontin was an independent prognostic marker for overall and disease-free survival. Conclusion: The study identifies clinically relevant genomic alterations in the stroma of ICC, including candidates biomarkers for prognosis, supporting the idea that tumor stroma is an important factor for ICC onset and progression. 20 RNA samples were analyzed, from 10 patients with ICC. For each patient, RNA were isolated from laser capture microdissected (LCM) stroma from tumor and non tumor areas.

			Action	DRS
	1.param	Other
	F017257.dat	Other
	F017257.noredundant	Other
	F017257.noredundant.fasta	Fasta
	F017257.optimal	Other