한빛사 논문
KAIST
Jae-Kyung Won1, 2, 3, §, Su Jong Yu4, §, Chae Young Hwang1, §, Sung-Hwan Cho1, Sang-Min Park1, Kwangsoo Kim5, Won-Mook Choi4, Hyeki Cho4, Eun Ju Cho4, Jeong-Hoon Lee4, Kyung Bun Lee3, Yoon Jun Kim4, Kyung-Suk Suh6, Ja-June Jang3, Chung Yong Kim4, Jung-Hwan Yoon4, *, Kwang-Hyun Cho1,2, *
1Laboratory for Systems Biology and Bio-inspired Engineering, Department of Bio and Brain Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Korea
2Graduate School of Medical Science and Engineering, KAIST, Daejeon 34141, Korea
3Department of Pathology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul 110-744, Korea
4Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul 110-744, Korea
5Division of Clinical Bioinformatics, Biomedical Research Institute, Seoul National University Hospital, Seoul 110-744, Korea
6Department of Surgery, Seoul National University Hospital, Seoul National University College of Medicine, Seoul 110-744, Korea
§ J.-K. Won, S. J. Yu and C. Y. H. equally contributed to this work.
* J.-H. Yoon and K.-H. Cho equally contributed to this work.
Corresponding author : Prof. Kwang-Hyun Cho
Department of Bio and Brain Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Republic of Korea
Abstract
Sorafenib is the only approved targeted drug for hepatocellular carcinoma (HCC), but its effect on patients' survival gain is limited and varies over a wide range depending on patho-genetic conditions. Thus, enhancing the efficacy of sorafenib and finding a reliable predictive biomarker are crucial to achieve efficient control of HCCs. In this study, we employed a systems approach by combining transcriptome analysis of the mRNA changes in HCC cell lines in response to sorafenib with network analysis to investigate the action and resistance mechanism of sorafenib. Gene list functional enrichment analysis and gene set enrichment analysis (GSEA) revealed that proteotoxic stress and apoptosis modules are activated in the presence of sorafenib. Further analysis of the endoplasmic reticulum (ER) stress network model combined with in vitro experiments showed that introducing an additional stress by treating the orally active protein disulfide isomerase (PDI) inhibitor (PACMA 31) can synergistically increase the efficacy of sorafenib in vitro and in vivo, which was confirmed using a mouse xenograft model. We also found that HCC patients with high PDI expression show resistance to sorafenib and poor clinical outcomes, compared to the low PDI expression group.
Conclusion: These results suggest that PDI is a promising therapeutic target for enhancing the efficacy of sorafenib and can also be a biomarker for predicting sorafenib responsiveness. This article is protected by copyright. All rights reserved.
Keywords: PDI, sorafenib, HCC, ER stress, combination therapy
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