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

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

doi:10.18632/oncotarget.2682

Abstract

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.

Highlights

Hepatocellular carcinoma (HCC) is the fifth most common cancer around the world with approximately 564,000 new cases diagnosed every year, and over 40 percent of all cases of HCC occur in China, which has an annual incidence of 137,000 cases [1]
In a multivariate Cox model that included gender, age, Alchohol intake, liver function, AFP, TNM stage, lymph node metastasis, edmondson grade and Aurora-A protein immunostaining, we found that positive Aurora-A protein expression independently indicated poor prognosis for both 5-year recurrence-free survival (RFS) (HR: 2.055; 95% CI: 1.735-3.455; P=0.012) and 5-year overall survival (OS) (HR: 1.554; 95% CI: 1.232-2.598; P=0.005) in HCC patients (Supporting Table 4)
The correlations of Aurora-A overexpression with poor prognosis of patients are reported in other human cancers, including epithelial ovarian cancer, laryngeal squamous cell carcinoma, and breast cancer, etc [20,21,22]

Summary

Introduction

HCC is the fifth most common cancer around the world with approximately 564,000 new cases diagnosed every year, and over 40 percent of all cases of HCC occur in China, which has an annual incidence of 137,000 cases [1]. Our results indicated that positive Aurora-A protein expression in HCC tissues was significantly correlated with poorer RFS and OS of patients, and Aurora-A promotes in vitro and in vivo chemoresistance of HCC cells by reducing chemotherapyinduced apoptosis via activation of NF-κB/miR-21/ PTEN signaling pathway.

Results

Conclusion