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Oncotarget. 2016 Feb 23;7(8):8850-65. doi: 10.18632/oncotarget.7091.

Nogo-B receptor promotes the chemoresistance of human hepatocellular carcinoma via the ubiquitination of p53 protein.

Author information

1
Division of Hepatobiliary and Pancreatic Surgery, Department of General Surgery, The Second Affiiated Hospital of Dalian Medical University, Dalian, Liaoning, China.
2
Key Laboratory of Separation Science for Analytical Chemistry, National Chromatographic R & A Center, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, China.
3
Division of Pediatric Surgery, Department of Surgery, Children's Research Institute, Medical College of Wisconsin, Milwaukee, WI, USA.
4
Division of Pediatric Pathology, Department of Pathology, Children's Research Institute, Medical College of Wisconsin, Milwaukee, WI, USA.
5
Department of Oncology, The Affiliated Zhongshan Hospital of Dalian University, Dalian, China.
6
Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China.
7
Key Laboratory of Proteomics, Dalian Medical University, Dalian, China.
8
Key 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.

Abstract

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.

KEYWORDS:

HCC; NgBR; chemoresistance

PMID:
26840457
PMCID:
PMC4891009
DOI:
10.18632/oncotarget.7091
[Indexed for MEDLINE]
Free PMC Article

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