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.
Highlights
Intrahepatic cholangiocarcinoma (ICC), arising from the malignant transformation of intrahepatic cholangiocytes, is the second most common primary hepatic malignancy[1,2,3]
Breast cancer type 1 susceptibility protein-associated protein-1 (BAP1) is downregulated in human ICC and correlates with lymphatic metastasis To explore the potential role of BAP1 in ICC, we first evaluated messenger RNA expression of BAP1 in paired ICC samples and matched adjacent non-tumor liver tissues
The results showed that BAP1 messenger RNA (mRNA) expression was downregulated in 73.3% (44/60) of ICC tissues, relative to the adjacent non-tumor liver tissues (P = 0.039) (Fig. 1a)
Summary
Intrahepatic cholangiocarcinoma (ICC), arising from the malignant transformation of intrahepatic cholangiocytes, is the second most common primary hepatic malignancy[1,2,3]. As one of the most aggressive tumors, the incidence and mortality of ICC have been rapidly increasing worldwide, with geographic variation[4,5]. Surgical resection remains the mainstay of potentially curative therapy for patients with ICC, but the resectability rate is quite low because of the high frequency of metastases[6,7]. No effective chemotherapies or molecular target therapies are available for ICC, which is mainly attributed to poor understanding of the molecular pathogenesis of this malignancy[8,9,10]. A better understanding of the molecular mechanisms associated with ICC progression would benefit the development of new effective treatment modalities. The ubiquitin–proteasome system (UPS) is an essential and highly regulated system in charge of 80–90% protein degradation and turnover, which is central to keeping
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