Abstract 2933: KLF5 and its association with HIF-1α promotes PTC progression and metastatic potential through AKT activation

Abstract

Abstract Thyroid cancer is the second most common malignancy among females in Saudi Arabia, with Papillary thyroid carcinoma (PTC) accounting for 80-90%. Kruppel-like factor 5 (Klf5) is a transcription factor that plays a critical role in cell transformation, proliferation, and oncogenesis. Immunohistochemical analysis of KLF5 was performed in 1219 PTC cases. KLF5 over-expression was noted in 65.1% (793/1219) of PTCs, and was significantly associated with tall-cell variant (p <0.0001), extrathyroidal extension (p = 0.0003), lymph node metastasis (p < 0.0001) and stage IV tumors (p < 0.0001). A significant association was also noted with HIF-1α over-expression (p = 0.0492). Interestingly, KLF5 over-expressing tumors showed poor disease-free survival (p = 0.0066). Functional studies in PTC cell lines showed that KLF5 co-immunoprecipitated with HIF-1α. Knockdown of KLF5 decreased the expression of HIF-1α while KLF5 was not affected by HIF-1α inhibition, suggesting that KLF5 is a functional upstream of HIF-1α. Down-regulation of KLF5 using a specific inhibitor, ML264 or siRNA inhibited cell migration, invasion, and angiogenesis. Also, the treatment of PTC cell lines with ML264 resulted in inhibition of proliferation and induction of apoptosis in a dose-dependent manner. Furthermore, the silencing of KLF5 significantly decreased the self-renewal ability of spheroids generated from PTC cells. Our findings confer that KLF5 may be a potential therapeutic target for the treatment of papillary thyroid cancer. Citation Format: Pratheeshkumar Poyil, Abdul K Siraj, Divya Padmaja, Sandeep Kumar Parvathareddy, Saravanan Thangavel, Roxanne Melosantos, Ingrid G. Victoria, Rafia Begum, Fouad Al-Dayel, Khawla S. Al-Kuraya. KLF5 and its association with HIF-1α promotes PTC progression and metastatic potential through AKT activation [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2933.