Abstract 5570: Laminin-5 gamma-2 (LAMC2) is highly expressed in anaplastic thyroid carcinoma and is associated with tumor progression, migration and invasion by modulating signaling of EGFR

Context: Anaplastic thyroid carcinoma (ATC) is an aggressive malignancy having no effective treatment. Laminin subunit gamma-2 (LAMC2) is an epithelial basement membrane protein involved in cell migration and tumour invasion and might represent an ideal target for the development of novel therapeutic approaches for ATC. Objective: Study the role of LAMC2 in ATC tumorigenesis. Design: LAMC2 expression was evaluated by RT-PCR, western blotting and immunohistochemistry in tumor specimens, adjacent non-cancerous tissues and cell lines. shRNA approach was used to investigate the effect of LAMC2 knockdown on tumorigenesis of ATC. Results: LAMC2 was highly expressed in ATC samples and cell lines compared to normal thyroid tissues. Silencing LAMC2 by shRNA in ATC cells moderately inhibited cell growth in liquid culture and dramatically decreased growth in soft agar and in xenografts growing in immunodeficient mice. Silencing LAMC2 caused cell cycle arrest and significantly suppressed migration, invasion and wound healing of ATC cells. Rescue experiments by overexpressing LAMC2 in LAMC2 knockdown cells, reversed the inhibitory effects as shown by increased cell proliferation and colony formation. Microarray data demonstrated that LAMC2 shRNA significantly altered expression of genes associated with migration, invasion, proliferation and survival. Immunoprecipitation and co-localization experiments showed that LAMC2 bound to EGFR in ATC cells. Silencing LAMC2 partially blocked EGF-mediated activation of EGFR and its downstream pathway. Interestingly, cetuximab (EGFR blocking antibody) or EGFR siRNA additively enhanced the anti-proliferative activity of the LAMC2 knockdown ATC cells compared to control cells. Conclusions: To our knowledge, this is the first report investigating the effect of LAMC2 on cell growth, cell cycle, migration, invasion and EGFR signaling in ATC cells, suggesting that LAMC2 may be a potential therapeutic target for treatment of ATC. Citation Format: Manoj Garg, Deepika Kanojia, Ryoko Okamoto, Vikas Madan, Wenwen Chien, Abhishek Sampath, Ling-Wen Ding, Meng Xuan, Jonathan W Said, Ngan Doan, Li-Zhen Liu, Henry Yang, Sigal Gery, Gleen D Braunstein, H.Phillip Koeffler. Laminin-5 gamma-2 (LAMC2) is highly expressed in anaplastic thyroid carcinoma and is associated with tumor progression, migration and invasion by modulating signaling of EGFR. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5570. doi:10.1158/1538-7445.AM2014-5570