Avila Euclides, Hernández-Monterde Luis David, Cedro-Tanda Alberto, Lizardi-Aguilera Tomas Misael, Barrera David, Villegas-Rodriguez Francisco Vladimir, García-Quiroz Janice, Díaz Lorenza, Larrea Fernando
Departamento de Biología de la Reproducción Dr. Carlos Gual Castro, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico.
Instituto Nacional de Medicina Genómica, Mexico City, Mexico.
PLoS One. 2025 Apr 1;20(4):e0319812. doi: 10.1371/journal.pone.0319812. eCollection 2025.
The vitamin D endocrine system, primarily mediated by its main metabolite calcitriol and the vitamin D receptor (VDR), plays a critical role in numerous human physiological processes, ranging from calcium metabolism to the prevention of various tumors, including cervical cancer. In this study, we comprehensively investigated the genomic regulatory effects of calcitriol in a cervical cancer model. We examined the transcriptional changes induced by calcitriol in CaSki cells, a cervical cell line harboring multiple copies of HPV16, the primary causal agent of cervical cancer. Our microarray findings, revealed that calcitriol regulated over 1000 protein-coding genes, exhibiting a predominantly repressive effect on the CaSki cell transcriptome by suppressing twice as many genes as it induced. Calcitriol decreased EPHA2 and RARA expression while inducing KLK6 and CYP4F3 expression in CaSki cells, as validated by qPCR and Western blot. Functional analysis demonstrated that calcitriol effectively inhibited key processes involved in cancer progression, including cell proliferation and migration. This was further supported by the significant downregulation of MMP7 and MMP13 mRNA levels. Our microarray results also showed that, in addition to its effects on protein-coding genes, calcitriol significantly regulates non-coding RNAs, altering the expression of approximately 400 non-coding RNAs, including 111 microRNA precursors and 29 mature microRNAs, of which 17 were upregulated and 12 downregulated. Notably, among these calcitriol-regulated microRNAs are some involved in cervical cancer biology, such as miR-6129, miR-382, miR-655, miR-211, miR-590, miR-130a, miR-301a, and miR-1252. Collectively, these findings suggest that calcitriol exhibits a significant antitumor effect in this advanced cervical cancer model by blocking critical processes for tumor progression, underscoring the importance of maintaining adequate vitamin D nutritional status.
维生素D内分泌系统主要由其主要代谢产物骨化三醇和维生素D受体（VDR）介导，在众多人体生理过程中发挥着关键作用，涵盖从钙代谢到预防包括宫颈癌在内的各种肿瘤。在本研究中，我们全面研究了骨化三醇在宫颈癌模型中的基因组调控作用。我们检测了骨化三醇在CaSki细胞中诱导的转录变化，CaSki细胞是一种携带多拷贝HPV16（宫颈癌的主要致病因子）的宫颈细胞系。我们的微阵列研究结果显示，骨化三醇调控了1000多个蛋白质编码基因，对CaSki细胞转录组表现出主要的抑制作用，其抑制的基因数量是诱导基因数量的两倍。通过qPCR和蛋白质印迹验证，骨化三醇降低了CaSki细胞中EPHA2和RARA的表达，同时诱导了KLK6和CYP4F3的表达。功能分析表明，骨化三醇有效抑制了癌症进展所涉及的关键过程，包括细胞增殖和迁移。MMP7和MMP13 mRNA水平的显著下调进一步支持了这一点。我们的微阵列结果还表明，除了对蛋白质编码基因的影响外，骨化三醇还显著调节非编码RNA，改变了约400种非编码RNA的表达，包括111种微小RNA前体和29种成熟微小RNA，其中17种上调，12种下调。值得注意的是，在这些受骨化三醇调控的微小RNA中，有一些参与宫颈癌生物学过程，如miR-6129、miR-382、miR-655、miR-211、miR-590、miR-130a、miR-301a和miR-1252。总的来说，这些发现表明，骨化三醇通过阻断肿瘤进展的关键过程，在这个晚期宫颈癌模型中表现出显著的抗肿瘤作用，强调了维持充足维生素D营养状态的重要性。
