Biomolecules & Therapeutics

  • 제29권5호
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  • Pages.551-561
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  • 2021
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  • 1976-9148(pISSN)
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  • 2005-4483(eISSN)
한국응용약물학회 (The Korean Society of Applied Pharmacology)
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Platelet-Derived Growth Factor Receptor-α Subunit Targeting Suppresses Metastasis in Advanced Thyroid Cancer In Vitro and In Vivo

  • Lin, Ching-Ling (Department of Internal Medicine, Cathay General Hospital) ;
  • Tsai, Ming-Lin (Department of General Surgery, Cathay General Hospital) ;
  • Chen, Yu-hsin (Department of Internal Medicine, Cathay General Hospital) ;
  • Liu, Wei-Ni (School of Medical Laboratory Science and Biotechnology, College of Medical Science and Technology, Taipei Medical University) ;
  • Lin, Chun-Yu (Institute of Bioinformatics and Systems Biology, National Yang Ming Chiao Tung University) ;
  • Hsu, Kai-Wen (Institute of New Drug Development, China Medical University) ;
  • Huang, Chien-Yu (Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University) ;
  • Chang, Yu-Jia (Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University) ;
  • Wei, Po-Li (Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University) ;
  • Chen, Shu-Huey (Department of Pediatrics, School of Medicine, College of Medicine, Taipei Medical University) ;
  • Huang, Li-Chi (Department of Internal Medicine, Cathay General Hospital) ;
  • Lee, Chia-Hwa (School of Medical Laboratory Science and Biotechnology, College of Medical Science and Technology, Taipei Medical University)
  • 투고 : 2020.11.12
  • 심사 : 2021.04.23
  • 발행 : 2021.09.01
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초록

Thyroid cancer is the most common endocrine malignancy. Patients with well-differentiated thyroid cancers, such as papillary and follicular cancers, have a favorable prognosis. However, poorly differentiated thyroid cancers, such as medullary, squamous and anaplastic advanced thyroid cancers, are very aggressive and insensitive to radioiodine treatment. Thus, novel therapies that attenuate metastasis are urgently needed. We found that both PDGFC and PDGFRA are predominantly expressed in thyroid cancers and that the survival rate is significantly lower in patients with high PDGFRA expression. This finding indicates the important role of PDGF/PDGFR signaling in thyroid cancer development. Next, we established a SW579 squamous thyroid cancer cell line with 95.6% PDGFRA gene insertion and deletions (indels) through CRISPR/Cas9. Protein and invasion analysis showed a dramatic loss in EMT marker expression and metastatic ability. Furthermore, xenograft tumors derived from PDGFRA geneedited SW579 cells exhibited a minor decrease in tumor growth. However, distant lung metastasis was completely abolished upon PDGFRA gene editing, implying that PDGFRA could be an effective target to inhibit distant metastasis in advanced thyroid cancers. To translate this finding to the clinic, we used the most relevant multikinase inhibitor, imatinib, to inhibit PDGFRA signaling. The results showed that imatinib significantly suppressed cell growth, induced cell cycle arrest and cell death in SW579 cells. Our developed noninvasive apoptosis detection sensor (NIADS) indicated that imatinib induced cell apoptosis through caspase-3 activation. In conclusion, we believe that developing a specific and selective targeted therapy for PDGFRA would effectively suppress PDGFRA-mediated cancer aggressiveness in advanced thyroid cancers.

키워드

과제정보

We would like to acknowledge the following for their kind services: Facility Center of Taipei Medical University; Instrument Center and the Laboratory Animal Center at the National Defense Medical Center. This study was also partially supported by "TMU Research Center of Cancer Translational Medicine", "the Center for Intelligent Drug Systems and Smart Bio-devices (IDS2B)" and "Drug Development Center, China Medical University" from The Featured Areas Research Center Program with in the frame work of the Higher Education Sprout Project by the Ministry of Education (MOE) in Taiwan. This study was supported by the Ministry of Science and Technology, grant Most-109-2628-B-038-014 for Dr. Lee, grant MOST-109-2314-B-281-007 for Dr. Lin, Cathay General Hospital, by the grant 108-CGH-TMU-04 for both Dr. Lin and Dr. Lee. This work was also financially supported from the Young Scholar Fellowship Program by the Ministry of Science and Technology (MOST) in Taiwan, Grant MOST 109-2636-B-009-007. None of the funding bodies were involved in the design of the study, the collection, analysis, and interpretation of the data, or the writing of the manuscript.

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