PTHrP contributes to the anti-proliferative and integrin α6β4-regulating effects of 1,25-dihydroxyvitamin D₃

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• 作者：Xiaoli Shen ; Ramanjaneya V.R. Mula ; Jing Li ; Nancy L. Weigel ; Miriam Falzon
• 关键词：PTHrP ; 1 ; 25-Dihydroxyvitamin D ; Integrin α ; 6β ; 4 ; Prostate cancer
• 刊名：Steroids
• 出版年：2007
• 出版时间：December 2007
• 年：2007
• 卷：72
• 期：14
• 页码：930-938
• 全文大小：654 K

文摘

Parathyroid hormone-related protein (PTHrP) increases the growth and metastatic potential of prostate cancer cells, making it important to control PTHrP expression in these cells. 1,25-Dihydroxyvitamin D₃ [1,25(OH)₂D₃] suppresses PTHrP expression and exerts an anti-proliferative effect in prostate carcinoma cells. We used the human prostate cancer cell line C4-2 as a model system to ask whether down-regulation of PTHrP expression by 1,25(OH)₂D₃ plays a role in the anti-proliferative effects of 1,25(OH)₂D₃. Since PTHrP increases the expression of the pro-invasive integrin α6β4, we also asked whether 1,25(OH)₂D₃ decreases integrin α6β4 expression in C4-2 cells, and whether modulation of PTHrP expression by 1,25(OH)₂D₃ plays a role in the effects of 1,25(OH)₂D₃ on integrin α6β4 expression. Two strategies were utilized to modulate PTHrP levels: overexpression of PTHrP (−36 to +139) and suppression of endogenous PTHrP expression using siRNAs. We report a direct correlation between PTHrP expression, C4-2 cell proliferation and integrin α6β4 expression at the mRNA and cell surface protein level. Treatment of parental C4-2 cells with 1,25(OH)₂D₃ decreased cell proliferation and integrin α6 and β4 expression. These 1,25(OH)₂D₃ effects were significantly attenuated in cells with suppressed PTHrP expression. 1,25(OH)₂D₃ regulates PTHrP expression via a negative vitamin D response element (nVDRE) within the noncoding region of the PTHrP gene. The effects of 1,25(OH)₂D₃ on cell proliferation and integrin α6β4 expression were significantly attenuated in cells overexpressing PTHrP (−36 to +139), which lacks the nVDRE. These findings suggest that one of the pathways via which 1,25(OH)₂D₃ exerts its anti-proliferative effects is through down-regulation of PTHrP expression.