Aurora-a confers radioresistance in human hepatocellular carcinoma by activating NF-\u03baB signaling pathway

Ze-Tian Shen,Long-Bang Chen,Ying Chen,Xi-Xu Zhu,Gui-Chun Huang,Rui Wang

doi:10.1186/s12885-019-6312-y

Ze-Tian Shen, Long-Bang Chen + Show 4 more

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https://doi.org/10.1186/s12885-019-6312-y

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Abstract

BackgroundRadiotherapy failure is a significant clinical challenge due to the development of resistance in the course of treatment. Therefore, it is necessary to further study the radiation resistance mechanism of HCC. In our early study, we have showed that the expression of Aurora-A mRNA was upregulated in HCC tissue samples or cells, and Aurora-A promoted the malignant phenotype of HCC cells. However, the effect of Aurora-A on the development of HCC radioresistance is not well known.MethodsIn this study, colony formation assay, MTT assays, flow cytometry assays, RT-PCR assays, Western blot, and tumor xenografts experiments were used to identify Aurora-A promotes the radioresistance of HCC cells by decreasing IR-induced apoptosis in vitro and in vivo. Dual-luciferase reporter assay, MTT assays, flow cytometry assays, and Western blot assay were performed to show the interactions of Aurora-A and NF-κB.ResultsWe established radioresistance HCC cell lines (HepG2-R) and found that Aurora-A was significantly upregulated in those radioresistant HCC cells in comparison with their parental HCC cells. Knockdown of Aurora-A increased radiosensitivity of radioresistant HCC cells both in vivo and in vitro by enhancing irradiation-induced apoptosis, while upregulation of Aurora-A decreased radiosensitivity by reducing irradiation-induced apoptosis of parental cells. In addition, we have showed that Aurora-A could promote the expression of nuclear IkappaB-alpha (IκBα) protein while enhancing the activity of NF-kappaB (κB), thereby promoted expression of NF-κB pathway downstream effectors, including proteins (Mcl-1, Bcl-2, PARP, and caspase-3), all of which are associated with apoptosis.ConclusionsAurora-A reduces radiotherapy-induced apoptosis by activating NF-κB signaling, thereby contributing to HCC radioresistance. Our results provided the first evidence that Aurora-A was essential for radioresistance in HCC and targeting this molecular would be a potential strategy for radiosensitization in HCC.

Highlights

Radiotherapy failure is a significant clinical challenge due to the development of resistance in the course of treatment
HepG2-R cells showed more antiapoptotic ability induced by IR, compared to parental HepG2 cells. These results indicated that HepG2-R cells had acquired radioresistance
Aurora-a reduces the in vitro radiosensitivity of Hepatocellular carcinoma (HCC) cells by decreasing irradiation-induced apoptosis Previously, we have reported that overexpression of Aurora-A correlates with poor prognosis of HCC patients and its downregulation could induce growth inhibition and apoptosis enhancement in HCC cells [9, 10]

Summary

Introduction

Radiotherapy failure is a significant clinical challenge due to the development of resistance in the course of treatment. Our previous study confirmed that clinical stage and lymphatic metastasis of HCC patients could effectively affect the expression level of Aurora-A, and its inhibition could significantly reverse malignant phenotypes of HCC cells [9, 10]. Under the action of ionizing radiation, NF-κB is overactivated, thereby upregulating certain inhibitor of apoptosis protein such as BCL-XL [15] These anti-apoptotic proteins inhibit cell release of pigment C and inhibit caspase 9 activation, eventually leading to radiotherapy resistance. Since Aurora-A could cause abnormal activation of NF-κB and further activate the NF-κB signaling pathway [16], we hypothesized that Aurora-A might play an important role in inhibiting cell apoptosis via regulating NF-κB to contribute to radioresistance in HCC cells

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