Aurora-A promotes chemoresistance in hepatocelluar carcinoma by targeting NF-kappaB/microRNA-21/PTEN signaling pathway

作者：Zhang, Kai; Chen, Jing; Chen, Dongqin; Huang, Jiayuan; Feng, Bing; Han, Siqi; Chen, Yitian; Song, Haizhu; De, Wei; Zhu, Ziman; Wang, Rui^*; Chen, Longbang

来源：Oncotarget, 2014, 5(24): 12916-12935.

DOI：10.18632/oncotarget.2682

• Hepatocellular carcinoma
• Aurora-A
• NF-kappaB
• MicroRNA-21
• PTEN
• Chemoresistance
• Apoptosis

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 Ikappa beta-alpha (I kappa beta alpha ) protein and enhances NF-kappa B (NF-kappa B) activity, thus promotes the transcription of miR-21. This study first reported the involvement of Aurora-A/NF-kappa B/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.

• 出版日期2014-12-30
• 单位中国人民解放军总医院; 南京医科大学; 南京大学