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BAP1 acts as a tumor suppressor in intrahepatic cholangiocarcinoma by modulating the ERK1/2 and JNK/c-Jun pathways
Xu-Xiao Chen1,2, Yue Yin1,2, Jian-Wen Cheng1,2
1Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University, 200032, Shanghai, China.
Abstract:
Current therapeutic options for intrahepatic cholangiocarcinoma (ICC) are very limited, which is largely attributed to poor understanding of molecular pathogenesis of ICC. Breast cancer type 1 susceptibility protein-associated protein-1 (BAP1) has been reported to be a broad-spectrum tumor suppressor in many tumor types, yet its role in ICC remains unknown. The aim of this study was to investigate the clinical implications and biological function of BAP1 in ICC. Our results showed that the messenger RNA and protein levels of BAP1 were significantly downregulated in ICC versus paired non-tumor tissues. Overexpression of wild-type but not mutant BAP1 significantly suppressed ICC cell proliferation, cell cycle progression, and invasion in vitro, as well as tumor progression in vivo. Conversely, knockdown of BAP1 yielded opposing effects. Mechanistically, BAP1 functioned as a tumor suppressor in ICC by inhibiting the extracellular signal-regulated kinase 1/2 and c-Jun N-terminal kinase/c-Jun pathways, and this function was abolished by inactivating mutations. Clinically, low BAP1 expression was positively correlated with aggressive tumor characteristics, such as larger tumor size, presence of lymphatic metastasis, and advanced tumor node metastasis stage. Survival analysis revealed that low BAP1 expression was significantly and independently associated with poor overall survival and relapse-free survival after curative surgery. In conclusion, BAP1 is a putative tumor suppressor of ICC, and may serve as a valuable prognostic biomarker as well as potential therapeutic target for ICC.
Insights
Breast cancer susceptibility protein 1 (BAP1) acts as a tumor suppressor in intrahepatic cholangiocarcinoma (ICC). Low BAP1 expression correlates with aggressive ICC and predicts poor patient survival, suggesting BAP1 as a therapeutic target.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Pathogenesis
Background:
- Intrahepatic cholangiocarcinoma (ICC) has limited therapeutic options due to poor understanding of its molecular drivers.
- Breast cancer type 1 susceptibility protein-associated protein-1 (BAP1) is a known tumor suppressor, but its role in ICC is uncharacterized.
Purpose of the Study:
- To investigate the clinical significance and biological function of BAP1 in intrahepatic cholangiocarcinoma.
- To determine if BAP1 acts as a tumor suppressor in ICC and its potential as a prognostic biomarker.
Main Methods:
- Quantitative analysis of BAP1 mRNA and protein levels in ICC and non-tumor tissues.
- In vitro and in vivo experiments involving BAP1 overexpression and knockdown in ICC cells.
- Analysis of signaling pathways (ERK1/2, JNK/c-Jun) affected by BAP1.
- Correlation of BAP1 expression with clinicopathological features and patient survival outcomes.
Main Results:
- BAP1 mRNA and protein levels were significantly downregulated in ICC tissues compared to non-tumor tissues.
- Overexpression of wild-type BAP1 suppressed ICC cell proliferation, invasion, and tumor growth, while BAP1 knockdown enhanced these processes.
- BAP1 functions as a tumor suppressor by inhibiting ERK1/2 and JNK/c-Jun pathways; this is dependent on functional BAP1.
- Low BAP1 expression correlated with aggressive ICC features (larger size, metastasis, advanced stage) and predicted poor overall and relapse-free survival.
Conclusions:
- BAP1 acts as a tumor suppressor in intrahepatic cholangiocarcinoma.
- Downregulation of BAP1 is linked to aggressive tumor behavior and poorer patient prognosis.
- BAP1 represents a potential prognostic biomarker and therapeutic target for ICC.
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