The anti-tumor effect of vitamin D has been well recognized but its translational application is hindered by side effects induced by supra-physiological concentration of vitamin D required for cancer treatment. Thus, exploring the vitamin D tumor suppressive functional mechanism can facilitate improvement of its clinical application.
A team of researchers from the University of Rochester and the University of Tainan, Taiwan used to screen miRNA profiles in response to vitamin D and found that a tumor suppressive miRNA, miR-98, is transcriptionally induced by 1α,25-dihydroxyvitamin (1,25-VD) in LNCaP. Mechanistic dissection revealed that 1,25-VD-induced miR-98 is mediated through both a direct mechanism, enhancing the VDR binding response element in the promoter region of miR-98, and an indirect mechanism, down-regulating LIN-28 expression. Knockdown of miR-98 led to a reduction of 1,25-VD anti-growth effect and overexpression of miR-98 suppressed the LNCaP cells growth via inducing G2/M arrest. And CCNJ, a protein controlling cell mitosis, is down-regulated by miR-98 via targeting 3′-untranslated region of CCNJ. Interestingly, miR-98 levels in blood are increased upon 1,25-VD treatment in mice suggesting the biomarker potential of miR-98 in predicting 1,25-VD response.
Biomarker potential of miRNAs relies on their high stability and existence in formalin-fixed tissue, cell free serum/plasma, and urine. The biological response to vitamin D varied among individuals. Factors contributing to a broad range of sensitivity to vitamin D include genomic polymorphisms of VDR and metabolism enzymes and pathological conditions altering VDR activity.
Biomarkers representing biological response of vitamin D treatment will be more meaningful than measurement of serum vitamin D level due to a broad range of sensitivity to vitamin D and other factors. Therefore the research team explored the biomarker potential of miR-98 representing vitamin D treatment in mice bearing prostate cancer. The cellular fraction of blood contains miR-98 whose expression correlated well with vitamin D treatment in both wild type and cancerous mice. Further investigation correlating expression levels of miR-98 and other vitamin D-regulated anti-tumor miRNAs (such as miR-22) in blood or other body fluid with anti-tumor effect of vitamin D is demanded.
Together, the finding that growth inhibitive miR-98 is induced by 1,25-VD provides a potential therapeutic target for prostate cancer and a potential biomarker for 1,25-VD anti-tumor action.
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Reference
Ting HJ, Messing J, Yasmin-Karim S, Lee YF. (2013) Identification of microRNA-98 as a therapeutic target inhibiting prostate cancer growth and a biomarker induced by vitamin. J Biol Chem 288(1), 1-9. . [abstract]