Vitamin D less-calcemic analog modulates the expression of estrogen receptors, vitamin D receptor and 1α-hydroxylase 25-hydroxy vitamin D in human thyroid cancer cell lines

Estrogen receptors (ERs) are expressed in various "non- reproductive" cancer cell types. Some cancer types express 1α-hydroxylase 25-hydroxy vitamin D (1OHase) whose product, 1,25(OH)2D3 can retard cancer cell proliferation. Thyroid carcinoma cell growth is apparently promoted by estrogens, but whether or not this interaction is modified by vitamin D metabolites/analogs is presently unknown. Here we assessed the effect of a less calcemic vitamin D analog [JK 1624 F₂-2 (JKF)] in three human thyroid cancer cell lines: ARO (anaplastic carcinoma), NPA (papillary carcinoma) and MRO (follicular carcinoma). (1) All cell lines expressed both ERα and ERκ, vitamin D receptor (VDR) and 1OHase mRNA quantified by Real Time PCR. There was a general abundance of ERκ over ERα expression, such that the ratio of ERκ to ERα mRNA was >1000:1, 228:1 and 7.7:1 in ARO, MRO and NPA cells, respectively. (2) JKF up regulated ERκ expression in ARO (by 110 ± 15%) and MRO (by 280 ± 10%) but down regulated ERκ in NPA cells (by 40 ± 15%). The expression of VDR was up regulated by JKF in NPA (21 ± 6%), down regulated in ARO (-24 ± 7%) and not affected in MRO. (3) All three human thyroid cancer cell lines were found to express 1OHase, which was up regulated by JKF in MRO (350 ± 25%) and NPA (35 ± 8%) but down regulated in ARO (-20 ± 5%). This is the first report to describe direct regulation of VDR and 1OHase expression by a vitamin D analog in human thyroid cancer cells. A functional role for the vitamin D system in human thyroid cancer is suggested by the finding that the vitamin D analog can affect ERs expression which is in turn involved in estrogen-induced cell growth in an ER-type specific manner in these cells.