Nogo-B receptor promotes the chemoresistance of human hepatocellular carcinoma via the ubiquitination of p53 protein
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Chengyong Dong1,*, Baofeng Zhao2,6,7,*, Fei Long1, Ying Liu3,4, Zhenzhen Liu1, Song Li1, Xuejun Yang1, Deguang Sun1, Haibo Wang1, Qinlong Liu1, Rui Liang1, Yan Li4, Zhenming Gao1, Shujuan Shao5, Qing Robert Miao6,7,8, Liming Wang1
1Division of Hepatobiliary and Pancreatic Surgery, Department of General Surgery, The Second Affiiated Hospital of Dalian Medical University, Dalian, Liaoning, China
2Key Laboratory of Separation Science for Analytical Chemistry, National Chromatographic R & A Center, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, China
3Department of Oncology, The Affiliated Zhongshan Hospital of Dalian University, Dalian, China
4Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China
5Key Laboratory of Proteomics, Dalian Medical University, Dalian, China
6Division of Pediatric Surgery, Department of Surgery, Children’s Research Institute, Medical College of Wisconsin, Milwaukee, WI, USA
7Division of Pediatric Pathology, Department of Pathology, Children’s Research Institute, Medical College of Wisconsin, Milwaukee, WI, USA
8Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, National Center for Nanoscience and Technology of China and Institute of High Energy Physics, Chinese Academy of Sciences (CAS), Beijing, China
*These authors have contributed equally to this work
Liming Wang, e-mail: email@example.com
Qing Robert Miao, e-mail: firstname.lastname@example.org
Keywords: NgBR, chemoresistance, HCC
Received: August 17, 2015 Accepted: January 17, 2016 Published: January 31, 2016
Nogo-B receptor (NgBR), a type I single transmembrane domain receptor is the specific receptor for Nogo-B. Our previous work demonstrated that NgBR is highly expressed in breast cancer cells, where it promotes epithelial mesenchymal transition (EMT), an important step in metastasis. Here, we show that both in vitro and in vivo increased expression of NgBR contributes to the increased chemoresistance of Bel7402/5FU cells, a stable 5-FU (5-Fluorouracil) resistant cell line related Bel7402 cells. NgBR knockdown abrogates S-phase arrest in Bel7402/5FU cells, which correlates with a reduction in G1/S phase checkpoint proteins p53 and p21. In addition, NgBR suppresses p53 protein levels through activation of the PI3K/Akt/MDM2 pathway, which promotes p53 degradation via the ubiquitin proteasome pathway and thus increases the resistance of human hepatocellular cancer cells to 5-FU. Furthermore, we found that NgBR expression is associated with a poor prognosis of human hepatocellular carcinoma (HCC) patients. These results suggest that targeting NgBR in combination with chemotherapeutic drugs, such as 5-FU, could improve the efficacy of current anticancer treatments.
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