Aurora-A promotes chemoresistance in hepatocelluar carcinoma by targeting NF-kappaB/microRNA-21/PTEN signaling pathway
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Kai Zhang1,*, Jing Chen1,*, Dongqin Chen1, Jiayuan Huang1, Bing Feng1, Siqi Han1, Yitian Chen1, Haizhu Song1, Wei De2, Ziman Zhu3, Rui Wang1 and Longbang Chen1
1 Department of Medical Oncology, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, Jiangsu, China
2 Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing, Jiangsu, China
3 Department of Hepatobiliary Surgery, First Hospital Affiliated to the Chinese PLA General Hospital, Fucheng, Haidian District, Beijing, China
* They authors contributed equally to this work.work
Rui Wang, email:
Long-Bang Chen, email:
Keywords: Hepatocellular carcinoma; Aurora-A; NF-kappaB; MicroRNA-21; PTEN; Chemoresistance; Apoptosis
Received: August 27, 2014 Accepted: November 04, 2014 Published: November 04, 2014
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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