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Vitamin D and its analogs have been shown to display anti-proliferative effects in a wide variety of cancer types including glioblastoma multiforme (GBM). These anticancer effects are mediated by its active metabolite, 1α, 25-dihydroxyvitamin D3 (calcitriol) acting mainly through vitamin D receptor (VDR) signaling. In addition to its involvement in calcitriol action, VDR has also been demonstrated to be useful as a prognostic factor for some types of cancer. However, to our knowledge, there are no studies evaluating the expression of VDR protein and its association with outcome in gliomas. Therefore, we investigated VDR expression by using immunohistochemical analysis in human glioma tissue microarrays, and analyzed the association between VDR expression and clinico-pathological parameters. We further investigated the effects of genetic and pharmacologic modulation of VDR on survival and migration of glioma cell lines. Our data demonstrate that VDR is increased in tumor tissues when compared with VDR in non-malignant brains, and that VDR expression is associated with an improved outcome in patients with GBM. We also show that both genetic and pharmacologic modulation of VDR modulates GBM cellular migration and survival and that VDR is necessary for calcitriol-mediated effects on migration. Altogether these results provide some limited evidence supporting a role for VDR in glioma progression.

In human glioma tumors, heme oxygenase-1 (HO-1) has been shown to be upregulated both when compared with normal brain tissues and also during oligodendroglioma progression. The cell types that express HO-1 have been shown to be mainly macrophages/microglia and T cells. However, many other reports also demonstrated that cell lines derived from glioma tumors and astrocytes express HO-1 after the occurrence of a wide variety of cell injuries and stressors. In addition, the significance of HO-1 upregulation in glioma had not, so far, been addressed. We therefore aimed at investigating the expression and significance of HO-1 in human glial tumors. For this purpose, we performed a wide screening of HO-1 expression in gliomas by using tissue microarrays containing astrocytomas, oligodendrogliomas, mixed tumors, and normal brain tissues. We subsequently correlated protein expression with patient clinicopathological data. We found differences in HO-1 positivity rates between non-malignant brain (22 %) and gliomas (54%, p = 0.01). HO-1 was expressed by tumor cells and showed cytoplasmic localization, although 19% of tumor samples also depicted nuclear staining. Importantly, a significant decrease in the overall survival time of grade II and III astrocytoma patients with HO-1 expression was observed. This result was validated at the mRNA level in a cohort of 105 samples. However, no association of HO-1 nuclear localization with patient survival was detected. In vitro experiments aimed at investigating the role of HO-1 in glioma progression showed that HO-1 modulates glioma cell proliferation, but has no effects on cellular migration. In conclusion, our results corroborate the higher frequency of HO-1 protein expression in gliomas than in normal brain, demonstrate that HO-1 is expressed by glial malignant cells, and show an association of HO-1 expression with patients’ shorter survival time.

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