Aurora-A promotes chemoresistance in hepatocelluar carcinoma by targeting NF-kappaB/microRNA-21/PTEN signaling pathway.
Aurora-A promotes chemoresistance in hepatocelluar carcinoma by targeting NF-kappaB/microRNA-21/PTEN signaling pathway.
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Aurora-A 通过靶向 NF-kappaB/microRNA-21/PTEN 信号通路促进肝细胞癌化疗耐药
DOI：
10.18632/oncotarget.2682
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发表时间：
2014-12-30
期刊：
影响因子：
--
通讯作者：
Chen L
中科院分区：
文献类型：
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作者：
Zhang K;Chen J;Chen D;Huang J;Feng B;Han S;Chen Y;Song H;De W;Zhu Z;Wang R;Chen L
肝细胞癌（HCC）对化疗具有高度耐药性。以前，我们已经表明，Aurora-A mRNA在HCC细胞或组织中上调，并且使用小干扰RNA（siRNA）沉默Aurora-A降低HCC细胞的生长并增强其凋亡。然而，Aurora-A蛋白在HCC中表达的临床意义以及Aurora-A表达与HCC化疗耐药性之间的关系尚不清楚。在此，我们发现Aurora-A蛋白在HCC组织中上调，并与患者的无复发和总生存率显著相关，多变量分析表明Aurora-A的免疫染色将是患者的独立预后因素。Aurora-A的沉默显著增加了肝癌细胞在体外和体内的化疗敏感性，而Aurora-A的过表达诱导了相反的效果。此外，Aurora-A的过表达通过促进microRNA-21的表达来减少化疗诱导的细胞凋亡，microRNA-21负性调节PTEN，然后抑制caspase-3介导的细胞凋亡诱导。在机制上，我们证明Aurora-A促进核Ikappaβ-alpha（Iκβα）蛋白的表达并增强NF-κ B（NF-κB）活性，从而促进miR-21的转录。本研究首次报道Aurora-A/NF-κB/miR-21/PTEN/Akt信号通路参与了肝癌细胞的化疗耐药性，提示靶向该信号通路将有助于肝癌化疗耐药性的逆转。
Hepatocellular carcinoma (HCC) is highly resistant to chemotherapy. Previously, we have shown that Aurora-A mRNA is upregulated in HCC cells or tissues and silencing of Aurora-A using small interfering RNA (siRNA) decreases growth and enhances apoptosis in HCC cells. However, the clinical significance of Aurora-A protein expression in HCC and association between Aurora-A expression and HCC chemoresistance is unclear. Here, we showed that Aurora-A protein is upregulated in HCC tissues and significantly correlated with recurrence-free and overall survival of patients and multivariate analysis indicated that immunostaining of Aurora-A will be an independent prognostic factor for patients. Silencing of Aurora-A significantly increased the chemosensitivity of HCC cells both in vitro and in vivo, while overexpression of Aurora-A induced the opposite effects. Furthermore, overexpression of Aurora-A reduces chemotherapy-induced apoptosis by promoting microRNA-21 expression, which negatively regulates PTEN and then inhibits caspase-3-mediated apoptosis induction. Mechanically, we demonstrated that Aurora-A promotes expression of nuclear Ikappaβ-alpha (Iκβα) protein and enhances NF-kappa B (NF-κB) activity, thus promotes the transcription of miR-21. This study first reported the involvement of Aurora-A/NF-κB/miR-21/PTEN/Akt signaling axis in chemoresistance of HCC cells, suggesting that targeting this signaling pathway would be helpful as a therapeutic strategy for the reversal of chemoresistance in HCC.
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影响因子：
2.1
作者：
Dogini DB;Pascoal VD;Avansini SH;Vieira AS;Pereira TC;Lopes-Cendes I
通讯作者：
Lopes-Cendes I
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作者：
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影响因子：
6.4
作者：
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通讯作者：
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影响因子：
8
作者：
通讯作者：
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