Biomolecules & Therapeutics  https://doi.org/10.4062/biomolther.2020.205
Platelet-Derived Growth Factor Receptor-α Subunit Targeting Suppresses Metastasis in Advanced Thyroid Cancer In Vitro and In Vivo
Ching-Ling Lin1,2,3, Ming-Lin Tsai4, Yu-hsin Chen1,2,5, Wei-Ni Liu6, Chun-Yu Lin7,8, Kai-Wen Hsu9,10, Chien-Yu Huang11,12, Yu-Jia Chang13,14, Po-Li Wei11,14,15,16, Shu-Huey Chen17,18, Li-Chi Huang1,2,* and Chia-Hwa Lee6,14,19,*
1Department of Internal Medicine, Cathay General Hospital, Taipei 10630,
2Department of Endocrinology and Metabolism, Cathay General Hospital, Taipei 10630,
3Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031,
4Department of General Surgery, Cathay General Hospital, Taipei 10630,
5Department of Cytology, Cathay General Hospital, Taipei 10630,
6School of Medical Laboratory Science and Biotechnology, College of Medical Science and Technology, Taipei Medical University, Taipei 11031,
7Institute of Bioinformatics and Systems Biology, National Yang Ming Chiao Tung University, Hsinchu 30010,
8Center for Intelligent Drug Systems and Smart Bio-Devices, National Yang Ming Chiao Tung University, Hsinchu 30010,
9Institute of New Drug Development, China Medical University, Taichung 40402,
10Research Center for Cancer Biology, China Medical University, Taichung 40402,
11Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031,
12Division of General Surgery, Department of Surgery, Shuang Ho Hospital, Taipei Medical University, Taipei 11031,
13Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei 11031,
14TMU Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei 11031,
15Division of Colorectal Surgery, Department of Surgery, Taipei Medical University Hospital, Taipei Medical University, Taipei 11031,
16Graduate Institute of Cancer Biology and Drug Discovery, Taipei Medical University, Taipei 11031,
17Department of Pediatrics, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031,
18Department of Pediatrics, Shuang Ho Hospital, Taipei Medical University, New Taipei City 23561,
19Ph. D. Program in Medical Biotechnology, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan
*E-mail: chlee@tmu.edu.tw (Lee CH), likih@seed.net.tw (Huang LC)
Tel: +886-2-27361661 (Lee CH), +886-2-27082121 (Huang LC)
Fax: +886-2-27395133 (Lee CH), +886-2-27016818 (Huang LC)
Received: November 12, 2020; Revised: April 22, 2021; Accepted: April 23, 2021; Published online: May 25, 2021.
© The Korean Society of Applied Pharmacology. All rights reserved.

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Abstract
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.
Keywords: Advanced thyroid cancer, PDGFRA, CRISPR/Cas9, Lung distant metastasis, Imatinib


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