Cancer Research UK Laboratories, Imperial Centre for Translational and Experimental Medicine, Division of Cancer, Imperial College London, Du Cane Road, London W12 0NN, UK.
Br J Cancer. 2012 Jul 10;107(2):375-81. doi: 10.1038/bjc.2012.231. Epub 2012 May 29.
Calcium is an important intracellular messenger that mediates many biological processes that are relevant to the malignant process. Calcium ion channels are key in controlling the intracellular calcium, and little is known about their role in human cancer.
We used qPCR and pyrosequencing to investigate expression and epigenetic regulation of the calcium channel regulatory subunit α(2)δ-3 (CACNA2D3) in breast cancer cell lines, primary cancers and metastatic lesions.
Expression of CACNA2D3 mRNA is regulated in breast cancer cell lines by methylation in the CpG island located in the 5' regulatory region of the gene. Expression is upregulated by azacytidine (AZA) in cells with CpG island methylation but unaffected in cells lacking methylation. In primary breast carcinomas, methylation is more common in cancers, which subsequently relapse with loco-regional and, particularly, visceral metastatic disease in both oestrogen receptor-α (ER)-positive and -negative cases. Furthermore, CACNA2D3 CpG island is frequently methylated in breast cancer that has metastasised to the central nervous system.
Methylation-dependent transcriptional silencing of CACNA2D3 may contribute to the metastatic phenotype of breast cancer. Analysis of methylation in the CACNA2D3 CpG island may have potential as a biomarker for risk of development of metastatic disease.
钙是一种重要的细胞内信使，介导许多与恶性过程相关的生物学过程。钙离子通道是控制细胞内钙的关键，但其在人类癌症中的作用知之甚少。
我们使用 qPCR 和焦磷酸测序来研究钙通道调节亚基 α(2)δ-3（CACNA2D3）在乳腺癌细胞系、原发性癌症和转移性病变中的表达和表观遗传调控。
CACNA2D3 mRNA 的表达在乳腺癌细胞系中受位于基因 5'调控区的 CpG 岛甲基化调控。在存在 CpG 岛甲基化的细胞中，AZA（氮杂胞苷）上调表达，但在缺乏甲基化的细胞中不受影响。在原发性乳腺癌中，CpG 岛甲基化在随后发生局部区域和内脏转移疾病（包括雌激素受体-α（ER）阳性和阴性病例）的癌症中更为常见。此外，CACNA2D3 CpG 岛在转移到中枢神经系统的乳腺癌中经常发生甲基化。
CACNA2D3 的甲基化依赖性转录沉默可能导致乳腺癌的转移表型。CACNA2D3 CpG 岛的甲基化分析可能具有作为转移性疾病发展风险的生物标志物的潜力。
