C/EBP beta mediates anti-proliferative effects of 1,25(OH)(2)D on differentiated thyroid carcinoma cells

Differentiated thyroid carcinoma (DTC) is the most common endocrine malignancy and highly expresses the receptor for 1,25-dihydroxyvitamin D (1,25(OH)(2)D). However, it is unclear whether 1,25(OH)(2)D regulates DTC proliferation and differentiation. Here, we found that 1,25(OH)(2)D-3 inhibited proliferation but not differentiation of the DTC cells. Notably, CYP27B1 was elevated in DTC cells and 25-hydroxyvitamin D-3(25(OH)D-3) reduced DTC cell proliferation. Knockdown of VDR did not affect the anti-proliferative effects of 1,25(OH)(2)D-3. However, knockdown of CCAAT enhancer-binding protein beta (C/EBP beta) abolished 1,25(OH)(2)D-3-suppressed DTC cell proliferation. In addition, 1,25(OH)(2)D-3 induced phosphorylation and translocation of C/EBP beta to the nucleus from the cytoplasm. However, inhibition of p38 mitogen-activated protein kinases (MAPK) abrogated 1,25(OH)(2)D-3-induced phosphorylation and nuclear translocation of C/EBP beta as well as 1,25(OH)(2)D-3-suppressed DTC cell proliferation. Knockdown of C/EBP beta reduced the expression of Notch3. Knockdown of Notch3 blocked 1,25(OH)(2)D-3-suppressed DTC cell proliferation. In the DTC cell-derived xenograft SCID mouse, knockdown of C/EBP beta markedly increased tumor growth and proliferation and decreased apoptosis. In DTC patients, C/EBP beta was predominantly located in the cytoplasm of DTC cells in the tumor tissue when compared with adjacent non-cancerous tissue in which C/EBP beta is located in the nucleus. In conclusion, C/EBP beta stimulated Notch3 signaling via the p38 MAPK-dependent pathway mediates the inhibitory effect of 1,25(OH)(2)D on DTC cell proliferation.