SOX4 is a pivotal regulator of tumorigenesis in differentiated thyroid cancer.

The SOX family consists of about 20 transcription factors involved in embryonic development, reprogramming, and cell fate determination. In this study, we demonstrated that SOX4 was significantly upregulated in differentiated thyroid cancer. Immunohistochemical analysis revealed that high SOX4 expression was associated with papillary histology, extrathyroidal extension, lymph node metastasis, and advanced disease stage. Patients whose tumors exhibited high SOX4 expression had a shorter recurrence-free survival, though significance was lost in multivariate Cox regression analysis. SOX4 silencing in thyroid cancer cells slowed cell growth, attenuated clonogenicity, and suppressed anoikis resistance. Additionally, SOX4 knockdown impeded xenograft tumor growth in nude mice. Knockdown of SOX4 expression was accompanied by reduced phosphorylation of AKT and ERK. Furthermore, CRABP2 expression correlated with SOX4 expression, and SOX4 silencing decreased CRABP2 expression and its downstream effectors such as integrin β1 and β4. These results indicate that SOX4 has both prognostic and therapeutic implications in differentiated thyroid cancer, and targeting SOX4 may modulate tumorigenic processes in the thyroid.