BAP1 acts as a tumor suppressor in intrahepatic cholangiocarcinoma by modulating the ERK1/2 and JNK/c-Jun pathways.
BAP1 acts as a tumor suppressor in intrahepatic cholangiocarcinoma by modulating the ERK1/2 and JNK/c-Jun pathways.
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BAP1 通过调节 ERK1/2 和 JNK/c-Jun 通路在肝内胆管癌中充当肿瘤抑制因子。
DOI：
10.1038/s41419-018-1087-7
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发表时间：
2018-10-10
影响因子：
9
通讯作者：
Yang XR
中科院分区：
文献类型：
--
作者：
Chen XX;Yin Y;Cheng JW;Huang A;Hu B;Zhang X;Sun YF;Wang J;Wang YP;Ji Y;Qiu SJ;Fan J;Zhou J;Yang XR
目前对肝内胆管细胞癌(ICC)的治疗选择非常有限，这在很大程度上是由于对ICC的分子发病机制缺乏了解。乳腺癌1型易感蛋白相关蛋白-1(BAP1)在多种肿瘤类型中具有广谱抑瘤作用，但其在ICC中的作用尚不清楚。本研究的目的是探讨BAP1在ICC中的临床意义和生物学功能。我们的结果表明，与配对的非肿瘤组织相比，ICC组织中BAP1的信使RNA和蛋白水平显著下调。野生型而非突变型BAP1的过表达显著抑制了ICC细胞的增殖、细胞周期进展和体外侵袭，以及体内的肿瘤进展。相反，BAP1的敲除产生了相反的效果。机制上，BAP1通过抑制细胞外信号调节激酶1/2和c-jun氨基末端激酶/c-jun通路在ICC中发挥肿瘤抑制作用，这一功能可通过失活突变来取消。临床上，BAP1的低表达与肿瘤的侵袭性特征呈正相关，如肿瘤体积较大、有无淋巴转移、肿瘤转移分期较晚。生存分析显示，BAP1的低表达与根治性手术后总体生存率和无复发生存率显著相关。综上所述，BAP1是ICC的一种潜在的肿瘤抑制因子，可能是一种有价值的预后生物标志物和潜在的治疗靶点。
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.
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DOI：
10.1038/nrd.2017.152
发表时间：
2018-01
期刊：
Nature reviews. Drug discovery
影响因子：
--
作者：
Harrigan JA;Jacq X;Martin NM;Jackson SP
通讯作者：
Jackson SP
影响因子：
11.2
作者：
Kadariya Y;Cheung M;Xu J;Pei J;Sementino E;Menges CW;Cai KQ;Rauscher FJ;Klein-Szanto AJ;Testa JR
通讯作者：
Testa JR
DOI：
10.1126/science.1194472
发表时间：
2010-12-03
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Harbour JW;Onken MD;Roberson ED;Duan S;Cao L;Worley LA;Council ML;Matatall KA;Helms C;Bowcock AM
通讯作者：
Bowcock AM
影响因子：
8
作者：
Jensen, DE;Proctor, M;Rauscher, FJ
通讯作者：
Rauscher, FJ
影响因子：
6.2
作者：
Farges, Olivier;Fuks, David;Regimbeau, Jean Marc
通讯作者：
Regimbeau, Jean Marc