Nogo-B receptor promotes the chemoresistance of human hepatocellular carcinoma via the ubiquitination of p53 protein.
Nogo-B receptor promotes the chemoresistance of human hepatocellular carcinoma via the ubiquitination of p53 protein.
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Nogo-B受体通过p53蛋白泛素化促进人肝细胞癌化疗耐药
DOI：
10.18632/oncotarget.7091
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发表时间：
2016-02-23
期刊：
影响因子：
--
通讯作者：
Wang L
中科院分区：
文献类型：
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作者：
Dong C;Zhao B;Long F;Liu Y;Liu Z;Li S;Yang X;Sun D;Wang H;Liu Q;Liang R;Li Y;Gao Z;Shao S;Miao QR;Wang L
Nogo-B受体(NGBR)是一种I型单一跨膜区受体，是Nogo-B的特异性受体。我们以前的工作表明，NGBR在乳腺癌细胞中高表达，促进上皮间充质转化(EMT)，这是转移的重要步骤。在此，我们发现，在体外和体内，NGBR表达的增加都有助于增加Bel7402/5FU细胞的化疗耐药性，Bel7402/5FU细胞是一种稳定的5-FU(5-Fu)耐药相关细胞系Bel7402。NGBR基因敲除后，Bel7402/5FU细胞中的S期阻滞被取消，这与G1/S期检查点蛋白p53和p21的减少有关。此外，NGBR通过激活PI3K/Akt/MDM2途径抑制P53蛋白水平，而PI3K/Akt/MDM2途径通过泛素蛋白酶体途径促进P53降解，从而增加人肝癌细胞对5-FU的耐药性。此外，我们还发现NGBR的表达与人肝细胞癌患者的预后不良有关。这些结果表明，靶向NGBR联合化疗药物，如5-FU，可以提高当前抗癌治疗的疗效。
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.