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Hepatology, First published: 09 October 2018 | https://doi.org/10.1002/hep.30307
PI3Kδ is a new therapeutic target in hepatocellular carcinoma
Eunkyong Ko1, Hyun-Wook Seo1, Eun Sun Jung2, Soomi Ju1,3, Baek-hui Kim4, Hyeki Cho5, Yoon Jun Kim5, Young Min Park6, Jong-Seo Kim1,3, Guhung Jung1,*
1Department of Biological Sciences, College of Natural Sciences, Seoul National University, 599 Gwanak-ro, Gwanak-gu, Seoul, 151-747, South Korea.
1Department of Biological Sciences, College of Natural Sciences, Seoul National University, 599 Gwanak-ro, Gwanak-gu, Seoul, 151-747, South Korea.
2Department of Pathology, Seoul St. Mary's Hospital, The Catholic University of Korea, 505 Banpo-dong, Seocho-Gu, Seoul, 133-782, South Korea.
3Center for RNA Research, Institute of Basic Science (IBS), Seoul, 151-747, South Korea.
4Department of Pathology, Korea University Guro Hospital, Korea University College of Medicine, 152-703, Seoul, South Korea.
5Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, 110-744, Seoul, South Korea.
6Hepatology Center and Laboratory of Hepatocarcinogenesis, Bundang Jesaeng General Hospital, 463-774, Kyungkido, South Korea.
*Contact Information
Guhung Jung, Ph.D., Department of Biological Sciences, College of Natural Sciences, Seoul National University, 599 Gwanak-ro, Gwanak-gu, Seoul, 08826, Republic of Korea
*Contact Information
Guhung Jung, Ph.D., Department of Biological Sciences, College of Natural Sciences, Seoul National University, 599 Gwanak-ro, Gwanak-gu, Seoul, 08826, Republic of Korea
Abstract
Class I phosphoinositide 3-kinase (PI3K) signaling is a major pathway in human cancer development and progression. Amongst the four PI3K isoforms, PI3Kα and PI3Kβ are ubiquitously expressed while PI3Kγ and PI3Kδ are mainly found in leukocytes. Until now, PI3K targeting in solid tumors has focused on inhibiting PI3Kα- and PI3Kβ-mediated cancer-cell-intrinsic PI3K activity. The role of PI3Kδ in solid tumors is unknown. Here, we evaluated the effects of PI3Kδ using established hepatocellular carcinoma (HCC) cells, malignant hepatocytes derived from patients with advanced HCC, murine models, and HCC tissues using RNA-sequencing, quantitative PCR, immunoblotting, immunofluorescence, microarray, LC/MS-MS, and kinase assay. We established a chemical carcinogenesis model of liver malignancy, which reflects the malignant phenotype and the in vivo environment of advanced HCC. In this in vivo advanced HCC-mimic system using HCC-cells treated with H2O2, we showed that H2O2 selectively increases PI3Kδ activity while decreasing that of other class I PI3Ks. Blocking PI3Kδ activity with a PI3Kδ inhibitor or siRNA-mediated PI3Kδ gene silencing inhibited HCC-cell proliferation and dampened key features of malignant HCC, including the upregulation of telomerase reverse transcriptase (TERT). Mechanistically, H2O2 induced oxidative modification of the serpin peptidase inhibitor, SERPINA3, blocking its ubiquitin-dependent degradation and enhancing its activity as a transcriptional activator of PI3Kδ and TERT. High PI3Kδ levels in HCC were found to correlate with poor survival rates, with human advanced HCC showing positive correlations between the protein levels of oxidized-SERPINA3, PI3Kδ, and TERT. Thus, PI3Kδ plays significant roles in malignant liver tumors.
Conclusion
Our data identify PI3Kδ inhibition, recently approved for the treatment of human B-cell malignancies, as a potential new treatment for HCC.
Keywords: PI3Kδ, SERPINA3, TERT, ROS, human liver cancer
Keywords: PI3Kδ, SERPINA3, TERT, ROS, human liver cancer
논문정보
- Research article
- 2018년 10월 (BRIC 등록일 2018-10-26)
- 국내 연구진
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