1. Department of Ultrasound, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110004, China.
2. Department of Anesthesiology, Cancer Hospital of China Medical University, Liaoning Cancer Hospital &Institute, Shenyang, Liaoning 110122, China.
3. Department of Gastroenterology, Tianjin Medical University Cancer Hospital, City Key Laboratory of Tianjin Cancer Center and National Clinical Research Center for Cancer, Tianjin, China.
Papillary thyroid cancer (PTC) is the most common endocrine system tumor. FOXK2 is involved in the development of different types of cancers, however, its function has not been investigated in papillary thyroid cancer. In the present study, we demonstrated that FOXK2 expression was up-regulated in papillary thyroid carcinoma tissues compared with matched normal tissues. Importantly, we found that FOXK2 expression was significantly associated with the tumor size, T stage, and TNM stage. Furthermore, stable knockdown of FOXK2 markedly inhibited PTC cell proliferation, significantly increased the ratio of LC3-II/LC3-I, and reduced p62 expression, whereas overexpression of FOXK2 showed opposite effects. In FOXK2 knockdown cell lines, mCherry-GFP-LC3 immunofluorescence demonstrated increased punctate aggregates of mCherry-GFP-LC3, and transmission electron microscopy revealed increased numbers of autophagosomes. Autophagy-related protein ULK1, VPS34, and FOXO3 were markedly up-regulated by FOXK2 knockdown and down-regulated by FOXK2 overexpression. Finally, autophagy inhibitor 3-MA attenuated autophagy activation and rescued the inhibition of cell proliferation caused by FOXK2 knockdown, suggesting that FOXK2 silencing inhibits cell proliferation through up-regulating autophagy. These findings revealed an important role of FOXK2 in PTC progression and suggested that FOXK2 might be a potential new target for the diagnosis and treatment of PTC.
Keywords: FOXK2, proliferation, autophagy, papillary thyroid cancer