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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Apoptosis
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Blotting, Western
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Carcinoma, Hepatocellular / drug therapy*
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Carcinoma, Hepatocellular / metabolism
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Carcinoma, Hepatocellular / pathology
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Cell Cycle
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Cell Proliferation
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Drug Resistance, Neoplasm*
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Female
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Fluorouracil / pharmacology*
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Follow-Up Studies
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Humans
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Immunoenzyme Techniques
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Liver Neoplasms / drug therapy*
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Liver Neoplasms / metabolism
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Liver Neoplasms / pathology
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Male
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Mice
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Mice, Nude
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Middle Aged
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Neoplasm Staging
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Phosphatidylinositol 3-Kinases / genetics
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Phosphatidylinositol 3-Kinases / metabolism
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Phosphorylation
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Prognosis
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Proto-Oncogene Proteins c-akt / genetics
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Proto-Oncogene Proteins c-akt / metabolism
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Proto-Oncogene Proteins c-mdm2 / genetics
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Proto-Oncogene Proteins c-mdm2 / metabolism
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RNA, Messenger / genetics
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Real-Time Polymerase Chain Reaction
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Receptors, Cell Surface / genetics
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Receptors, Cell Surface / metabolism*
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Reverse Transcriptase Polymerase Chain Reaction
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Survival Rate
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Tumor Cells, Cultured
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Tumor Suppressor Protein p53 / genetics
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Tumor Suppressor Protein p53 / metabolism*
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Ubiquitin / metabolism*
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Ubiquitination
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Xenograft Model Antitumor Assays
Substances
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NUS1 protein, human
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RNA, Messenger
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Receptors, Cell Surface
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TP53 protein, human
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Tumor Suppressor Protein p53
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Ubiquitin
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MDM2 protein, human
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Proto-Oncogene Proteins c-mdm2
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Phosphatidylinositol 3-Kinases
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Proto-Oncogene Proteins c-akt
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Fluorouracil