한빛사논문
- 조회3,081
Abstract
Doohyung Lee1, Juri Na2,†, Jihye Ryu1,†, Hye-Jin Kim1,†, Seo Hee Nam3,†, Minkyung Kang1,4, Jae Woo Jung3, Mi-Sook Lee1, Haeng Eun Song1, Jungeun Choi3, Gyu-Ho Lee1, Tai Young Kim1, June-Key Chung2,5, Ki Hun Park6, Sung-Hak Kim7, Hyunggee Kim7, Howon Seo8, Pilhan Kim8, Hyewon Youn2,5 and Jung Weon Lee1,3,*
1 Department of Pharmacy, College of Pharmacy, Research Institute of Pharmaceutical Sciences, Seoul National University
2 Department of Nuclear Medicine, Cancer Research Institute, College of Medicine, Seoul National University
3 Interdisciplinary Program in Genetic Engineering, Seoul National University
4 Department of Biomedical Sciences, College of Medicine, Seoul National University, Seoul
5 Cancer Imaging Center, Seoul National University Hospital, Seoul
6 Division of Applied Life Science, Gyeongsang National University, Jinju
7 School of Life Sciences and Biotechnology, Korea University, Seoul, Korea (Republic of)
8 Graduate School of Nanoscience and Technology, Korea Advanced Institute of Science and Technology, Daejeon, Korea (Republic of)
†equally contributed
*Contact information: Jung Weon Lee, Ph.D. Department of Pharmacy, College of Pharmacy, Seoul National University, Seoul 1510742, Korea
Abstract
Tumor metastasis involves circulating and tumor-initiating capacities of metastatic cancer cells. Epithelial-mesenchymal transition is related to self-renewal capacity and circulating tumor cell (CTC) characteristics for tumor metastasis. Although tumor metastasis as a life-threatening complicated process occurs through circulation of tumor cells, mechanistic aspects of self-renewal and circulating capacities have been largely unknown. Hepatic TM4SF5 promotes EMT for malignant growth and migration, so that it was rationalized TM4SF5 as a hepatocellular carcinoma (HCC) biomarker might be important for metastatic potentials throughout metastasis. Here, self-renewal capacity by TM4SF5 was mechanistically explored using hepatocarcinoma cells with or without TM4SF5 expression, and explored whether they became CTCs using mouse liver-orthotopic model systems. We found that TM4SF5-dependent sphere growth correlated with CD24-, ALDH activity, and a physical association between CD44 and TM4SF5. The interaction between TM4SF5 and CD44 was through their extracellular domains with N-glycosylation modifications. The TM4SF5/CD44 interaction activated c-Src/STAT3/Twist1/Bmi1 signaling for spheroid formation, while disturbing the interaction, expression, or activity of any component in this signaling pathway inhibited the spheroid formation. In serial xenografts using 200 ∼ 5000 cells per injection, TM4SF5-positive tumors exhibited subpopulations with locally-increased CD44 expressions, supporting for tumor cell differentiation. TM4SF5-positive, but not TM4SF5- or CD44-knocked-down, cells were identified circulating in blood 4 to 6 weeks after orthotopic liver-injection using an in vivo laser scanning endomicroscopy. Anti-TM4SF5 reagent blocked their metastasis to distal intestinal organs. Conclusion: Altogether, our results evidence that TM4SF5 promotes self-renewal and CTC properties supported by TM4SF5+/CD44+(TM4SF5-bound)/ALDH+/CD24- markers, during HCC metastasis. This article is protected by copyright. All rights reserved.
Keywords: biomarkers; circulating tumor cells; epithelial-mesenchymal transition; hepatic cancer; self-renewal
논문정보
- Research article
- 2015년 01월 (BRIC 등록일 2015-01-30)
- 국내 연구진
- 의약학 > 약학
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