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Therapeutic efficacy of Vitamin D in experimental c-MET-beta-catenin-driven hepatocellular cancer

Akiko Matsuda, Kaori Ishiguro, Irene K Yan, Tushar Patel
Gene Expression 2018 August 29
Aberrant activation of β -catenin signaling is frequently observed in hepatocellular cancer. Although Wnt/ β-catenin signaling can be targeted by Vitamin D, therapeutic use of Vitamin D for this purpose is not currently established. We evaluated the therapeutic use of Vitamin D or its analogues using a synthetic transgenic mouse of hepato-carcinogenesis induced by mutant β-catenin, and MET overexpression in which 75% of mice develop well differentiated HCC within 8 weeks in the absence of fibrosis. Vitamin D receptor expression was similar in both tumoral and non-tumoral tissue. There was no significant difference in overall survival, or in tumor progression assessed by imaging, biochemical or tumor cell burden assessments in mice receiving a vitamin D supplemented diet containing 12.0 IU VD/g (HVD) compared with a standard diet (SD) containing 2.3 IU VD/g. Furthermore, systemic treatment with Calcitriol (vitamin D analogue 1α,25(OH)₂D₃), or EB1089 (synthetic vitamin D analogue) by intraperitoneally injection for 4 weeks prolonged median survival but did not increase overall survival compared with controls. Although tumor formation was delayed in males compared with females, there was no difference in overall survival between males and females. In conclusion, although 1α,25(OH)₂D₃ is reported to inhibit β-catenin signaling, as well as proliferation, migration, and differentiation in cancer cells, neither dietary supplementation with Vitamin D nor treatment with Vitamin D analogues altered the formation or growth of HCC associated with β-catenin activation. These results conclusively demonstrate the lack of utility of targeting Vitamin D for therapy of HCC in this setting.


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