Jóźwicki Wojciech, Brożyna Anna A, Siekiera Jerzy, Slominski Andrzej T
Department of Tumour Pathology and Pathomorphology, Nicolaus Copernicus University Collegium Medicum in Bydgoszcz, Bydgoszcz 85-796, Poland.
Department of Tumour Pathology and Pathomorphology, Oncology Centre-Prof. Franciszek Łukaszczyk Memorial Hospital, Bydgoszcz 85-796, Poland.
Int J Mol Sci. 2015 Oct 15;16(10):24369-86. doi: 10.3390/ijms161024369.
Vitamin D3 shows tumoristatic and anticancer effects by acting through the vitamin D receptor (VDR), while hydroxylation of 25-hydroxyvitamin D3 at position 1α by CYP27B1 is an essential step in its activation. The expression of both the VDR and CYP27B1 has been found in many normal and cancer tissues, but there is a lack of information about its expression in human bladder cancers. The aim of the present research was to examine whether the expression of the VDR and CYP27B1 in bladder cancer was related to the prognostic markers and disease outcome. We analyzed VDR and CYP27B1 in samples of tumor and normal tissues obtained from 71 urinary bladder cancer patients. The highest VDR immunostaining was found in normal epithelium and was significantly lower in bladder cancer cells (p<0.001 with Mann-Whitney U test). VDR expression was lowest in more advanced (pT2b-pT4) (p=0.005 with Mann-Whitney U test) and metastasizing cancers (p<0.05 and p=0.004 with Mann-Whitney U test for nuclear and cytoplasmic VDR immunostaining, respectively). The lack of cytoplasmic and nuclear VDR was also related to shorter overall survival (for cytoplasmic VDR immunolocalization 13.3 vs. 55.3 months of survival, HR=1.92, p=0.04 and for nuclear VDR immunostaining 13.5 vs. 55.3 months of survival, HR=2.47, p=0.002 with Mantel-Cox test). In cases with the lack of high cytoplasmic VDR staining the non-classic differentiations (NDs) was observed in higher percentage of tumor area. CYP27B1 expression was lower in cancer cells than in normal epithelial cells (p=0.03 with Mann-Whitney U test), but its expression did not correlate with tumor stage (pT), metastasizing, grade, mitotic activity or overall survival. In conclusion, expression of the VDR and CYP27B1 are deregulated in urothelial bladder cancers. Although our results showing a relationship between the decreased VDR expression and prognostic markers and survival time indicate potential usefulness of VDR as a new indicator of a poorer prognosis, further studies are needed in different patient cohorts by independent groups to validate this hypothesis. We also suggest that vitamin D-based therapies may represent an adjuvant strategy in treatment for bladder cancers expressing VDR.
维生素D3通过作用于维生素D受体（VDR）发挥肿瘤抑制和抗癌作用，而细胞色素P450 27B1（CYP27B1）将25-羟基维生素D3在1α位进行羟基化是其激活的关键步骤。在许多正常组织和癌组织中均发现了VDR和CYP27B1的表达，但关于其在人膀胱癌中的表达情况却缺乏相关信息。本研究的目的是探讨VDR和CYP27B1在膀胱癌中的表达是否与预后标志物及疾病转归相关。我们分析了71例膀胱癌患者肿瘤组织和正常组织样本中的VDR和CYP27B1。VDR免疫染色在正常上皮中最高，在膀胱癌细胞中显著降低（Mann-Whitney U检验，p<0.001）。VDR表达在更晚期（pT2b - pT4）肿瘤中最低（Mann-Whitney U检验，p = 0.005），在发生转移的癌症中也最低（Mann-Whitney U检验，核VDR免疫染色p<0.05，胞质VDR免疫染色p = 0.004）。胞质和核VDR缺失还与总生存期缩短相关（胞质VDR免疫定位，生存期分别为13.3个月和55.3个月，HR = 1.92，p = 0.04；核VDR免疫染色，生存期分别为13.5个月和55.3个月，Mantel-Cox检验，HR = 2.47，p = 0.002）。在缺乏高胞质VDR染色的病例中，肿瘤区域出现非典型分化（NDs）的比例更高。CYP27B1在癌细胞中的表达低于正常上皮细胞（Mann-Whitney U检验，p = 0.03），但其表达与肿瘤分期（pT）、转移、分级、有丝分裂活性或总生存期均无相关性。总之，VDR和CYP27B1在膀胱尿路上皮癌中表达失调。尽管我们的结果显示VDR表达降低与预后标志物及生存时间之间存在关联，提示VDR可能作为预后较差的新指标具有潜在应用价值，但仍需要不同独立研究团队在不同患者队列中进一步研究以验证这一假设。我们还建议基于维生素D的疗法可能是治疗表达VDR的膀胱癌的一种辅助策略。
