KPNA3 Confers Sorafenib Resistance to Advanced Hepatocellular Carcinoma via TWIST Regulated Epithelial-Mesenchymal Transition
文献类型：期刊论文
| 作者 | Hu, Bo6,7; Cheng, Jian-Wen6,7; Hu, Jin-Wu6,7; Tang, Wei-Guo6,7; Sun, Yun-Fan6,7; Huang, Ao6,7; Zhou, Kai-Qian6,7; Gao, Ping-Ting6,7; Qiu, Shuang-Jian6,7; Zhou, Jian6,7 |
| 刊名 | JOURNAL OF CANCER
 |
| 出版日期 | 2019 |
| 卷号 | 10期号:17页码:3914-3925 |
| 关键词 | hepatocellular carcinoma drug resistance epithelial-mesenchymal transition patient-derived xenograft personalized medicine |
| ISSN号 | 1837-9664 |
| DOI | 10.7150/jca.31448 |
| 文献子类 | Article |
| 英文摘要 | 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. |
| 学科主题 | Oncology |
| WOS关键词 | PATIENT-DERIVED XENOGRAFTS ; INHIBITS TUMOR-GROWTH ; CANCER STATISTICS ; METASTASIS ; EMT |
| 语种 | 英语 |
| WOS记录号 | WOS:000475429200005 |
| 出版者 | IVYSPRING INT PUBL |
| 版本 | 出版稿 |
| 源URL | [http://202.127.25.144/handle/331004/524]  |
| 专题 | 中国科学院上海生命科学研究院营养科学研究所 |
| 作者单位 | 1.Chinese Acad Sci, CAS MPG Partner Inst Comp Biol, Shanghai Inst Biol Sci, Key Lab Computat Biol, Shanghai 200031, Peoples R China; 2.Fudan Univ, Inst Biomed Sci, Key Lab Med Epigenet & Metab, Shanghai 200032, Peoples R China, 3.Minist Educ, Key Lab Carcinogenesis & Canc Invas, Changsha 410078, Hunan, Peoples R China; 4.Cent S Univ, Xiangya Sch Med, Canc Res Inst, Changsha 410078, Hunan, Peoples R China; 5.Fudan Univ, Zhongshan Hosp, Dept Lab Med, Shanghai 200032, Peoples R China; 6.Minist Educ, Key Lab Carcinogenesis & Canc Invas, Shanghai 200032, Peoples R China; 7.Fudan Univ, Zhongshan Hosp, Liver Canc Inst, Dept Liver Surg & Transplantat, Shanghai 200032, Peoples R China; |
| 推荐引用方式 GB/T 7714 | Hu, Bo,Cheng, Jian-Wen,Hu, Jin-Wu,et al. KPNA3 Confers Sorafenib Resistance to Advanced Hepatocellular Carcinoma via TWIST Regulated Epithelial-Mesenchymal Transition[J]. JOURNAL OF CANCER,2019,10(17):3914-3925. |
| APA | Hu, Bo.,Cheng, Jian-Wen.,Hu, Jin-Wu.,Tang, Wei-Guo.,Sun, Yun-Fan.,...&,.(2019).KPNA3 Confers Sorafenib Resistance to Advanced Hepatocellular Carcinoma via TWIST Regulated Epithelial-Mesenchymal Transition.JOURNAL OF CANCER,10(17),3914-3925. |
| MLA | Hu, Bo,et al."KPNA3 Confers Sorafenib Resistance to Advanced Hepatocellular Carcinoma via TWIST Regulated Epithelial-Mesenchymal Transition".JOURNAL OF CANCER 10.17(2019):3914-3925. |
入库方式： OAI收割
来源：上海营养与健康研究所
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