BAP1 acts as a tumor suppressor in intrahepatic cholangiocarcinoma by modulating the ERK1/2 and JNK/c-Jun pathways

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.

BUB1B promotes extrahepatic cholangiocarcinoma progression via JNK/c-Jun pathways

“…A recent study reported that the activation of JNK/c-Jun signaling played important roles in cholangiocellular proliferation, differentiation, and carcinogenesis 34 . Furthermore, the inhibition of JNK/c-Jun pathway by BAP1 suppressed intrahepatic CAA progression 35 . In this study, the results of the phosphokinase array indicated that JNK/c-Jun activation was positively correlated with the BUB1B expression in our research.…”

Intrahepatic cholangiocarcinoma development in a patient with a novel BAP1 germline mutation and low exposure to asbestos

“…BAP1 somatic inactivating mutations occur with a relatively high frequency in iCCA (16-32%) and have been reported to correlate with poor overall survival and relapse-free survival [15][16][17]. Conversely, the incidence of BAP1 germline mutations and their contribution to cholangiocarcinogenesis still remain to be fully clarified.…”

Discordance in prediction of prognosis among patients with intrahepatic cholangiocarcinoma: A preoperative vs postoperative perspective

“…For example, the poor prognosis may be related to fundamentally more aggressive genetic characteristics of the ICC tumor that are not adequately captured in traditional factors used in preoperative predictive models (eg tumor size, number, CA19‐9/CEA levels, etc). To this point, Chen et al noted that low breast cancer type 1 susceptibility protein‐associated protein‐1 expression in ICC tumors was correlated with a more aggressive tumor phenotype, as well as worse long‐term outcomes including a shorter relapse‐free survival and OS. Several other studies have confirmed that the genetic heterogeneity of ICC correlated with varied clinical outcomes .…”