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J Cancer 2019; 10(17):3914-3925. doi:10.7150/jca.31448 This issue Cite

Research Paper

KPNA3 Confers Sorafenib Resistance to Advanced Hepatocellular Carcinoma via TWIST Regulated Epithelial-Mesenchymal Transition

Bo Hu^1*, Jian-Wen Cheng^1*, Jin-Wu Hu^1*, Hong Li², Xiao-Lu Ma³, Wei-Guo Tang¹, Yun-Fan Sun¹, Wei Guo³, Ao Huang¹, Kai-Qian Zhou¹, Ping-Ting Gao¹, Ya Cao⁴, Shuang-Jian Qiu¹, Jian Zhou^1,5, Jia Fan^1,5, Xin-Rong Yang^1✉

1. Department of Liver Surgery and transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai 200032, P.R.China;
2. Key Laboratory for Computational Biology, CAS-MPG Partner Institute for Computing Biology, Shanghai Institute for Biological Sciences, Chinese Academy of Sciences, Shanghai, 200031, China;
3. Department of Laboratory Medicine, Zhongshan Hospital, Fudan University;
4. Cancer Research Institute, Xiangya School of Medicine, Central South University; Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Changsha 410078, China;
5. Key Laboratory of Medical Epigenetics and Metabolism, Institute of Biomedical Sciences, Fudan University, Shanghai 200032, P. R. China
*These authors have contributed equally to this work.

✉ Corresponding author: yang.xinrongsh.cn; Tel.: +86-021-6404-1990

Abstract

Sorafenib, a multikinase inhibitor, is a new standard treatment for patients with advanced hepatocellular carcinoma (HCC). However, resistance to this regimen is frequently observed in clinical practice, and the molecular basis of this resistance remains largely unknown. Herein, the antitumor activity of sorafenib was assessed in 16 patient-derived xenograft (PDX) models of HCC. Gene expression analysis was conducted to identify factors that promote sorafenib resistance. Quantitative RT-PCR and immunoblotting were used to determine gene expression and activation of signaling pathways. Cell proliferation, clone formation, and transwell assays were conducted to evaluate drug-sensitivity, proliferation, and invasiveness, respectively. Kaplan-Meier analysis was used to evaluate the predictive power of biomarkers for sorafenib response. Differential gene expression analysis suggested that sorafenib resistance correlated with high karyopherin subunit alpha 3 (KPNA3) expression. Overexpression of KPNA3 in HCC cells enhanced tumor cell growth and invasiveness. Interestingly, KPNA3 was found to trigger epithelial-mesenchymal transition (EMT), a key process mediating drug resistance. On a mechanistic level, KPNA3 increased phosphorylation of AKT, which then phosphorylated ERK, and ultimately promoted TWIST expression to induce EMT and sorafenib resistance. Moreover, retrospective analysis revealed that HCC patients with low KPNA3 expression had remarkably longer survival after sorafenib treatment. Finally, we have identified a novel KPNA3-AKT-ERK-TWIST signaling cascade that promotes EMT and mediates sorafenib resistance in HCC. These findings suggest that KPNA3 is a promising biomarker for predicting patient responsiveness to sorafenib. Targeting KPNA3 may also contribute to resolving sorafenib resistance in HCC.

Keywords: hepatocellular carcinoma, drug resistance, epithelial-mesenchymal transition, patient-derived xenograft, personalized medicine

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