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.
Highlights
Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related death and the fifth most common malignancy worldwide [1,2,3]
And 1C, both the Nogo-B receptor (NgBR) mRNA and protein levels were increased in the Bel/5FU cell lines. These results indicate that higher NgBR expression is associated with chemoresistance in human hepatocellular carcinoma (HCC) cell lines
CCK-8 assay results revealed knockdown of NgBR decreases the cell survival rate of Bel/5FU cells at all 5-FU treatment time points (Figure 2B). These results indicate that NgBR knockdown decreases the chemoresistance of Bel/5FU cells
Summary
Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related death and the fifth most common malignancy worldwide [1,2,3]. Curative interventions such as transplantation, resection, and thermal ablation are applicable for the 30% of patients whose tumors or liver function meet defined criteria [4]. Patients with advanced HCC or liver disease are not suitable for these curative interventions and require systemic chemotherapy [5] These patients frequently develop drug resistance causing their treatments to fail [6, 7]. A comprehensive understanding of mechanisms of chemoresistance in HCC could present opportunities to improve the response to cytotoxic agents and improve clinical outcomes
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