BAP1 dependent expression of long non-coding RNA NEAT-1 contributes to sensitivity to gemcitabine in cholangiocarcinoma

Molecular Cancer

Research

Yan Asmann¹  Xue Wang¹  Sayantan Maji²  Irene K. Yan²  Tushar Patel²  Catherine Foye²  Mansi Parasramka²  Akiko Matsuda²  Phuong Nguyen² 

[1] Department of Health Sciences Research, Mayo Clinic, Jacksonville, FL, USA;Department of Transplantation and Department of Cancer Biology, Mayo Clinic, 4500 San Pablo Road, 32224, Jacksonville, Florida, USA;

关键词: Cholangiocarcinoma;    LncRNA;    BAP1;    NEAT-1;    Gemcitabine;    Cisplatin;    Combination therapy;   

DOI  :  10.1186/s12943-017-0587-x

 received in 2016-11-09, accepted in 2017-01-13,  发布年份 2017

来源: Springer

【 摘 要 】

BackgroundGenetic alterations in chromatin modulators such as BRCA-1 associated protein-1 (BAP1) are the most frequent genetic alteration in intrahepatic cholangiocarcinomas (CCA). We evaluated the contribution of BAP1 expression on tumor cell behavior and therapeutic sensitivity to identify rationale therapeutic strategies.MethodsThe impact of BAP1 expression on sensitivity to therapeutic agents was evaluated in CCA cells with a 7-fold difference in BAP1 expression (KMBC-low, HuCCT1-high) and genetically engineered haplo-insufficient BAP1 knockout cells. We also identified long non-coding RNA genes associated with loss of BAP1 and their role in therapeutic sensitivity.ResultsSensitivity to gemcitabine was greater in low BAP1 expressing or BAP1 knockout cells compared with the high BAP1 expressing cells or control haplo-insufficient cells respectively. Similar results were observed with TSA, olaparib, b-AP15 but not with GSK126. A differential synergistic effect was observed in combinations of gemcitabine with olaparib or GSK126 in KMBC cells and TSA or bAP15 in HuCCT1 cells, indicating BAP1 dependent target-specific synergism and sensitivity to gemcitabine. A BAP1 dependent alteration in expression of lncRNA NEAT-1 was identified by RT-PCR based lncRNA expression profiling, and an inverse relationship between this lncRNA and BAP1 was observed in analysis of the Tumor Cancer Genome Atlas cholangiocarcinoma dataset. Exogenous modulation of NEAT-1 and/or BAP1 expression altered tumor cell phenotype and modulated sensitivity to gemcitabine.ConclusionsNEAT-1 is a downstream effector of gemcitabine sensitivity in CCA. The expression of BAP1 is a determinant of sensitivity to therapeutic drugs that can be exploited to enhance responses through combination strategies.

【 授权许可】

CC BY   
© The Author(s). 2017