Center of Excellence in Precision Medicine, Pfizer Chile, Obispo Arturo Espinoza Campos 2526, 7810305, Santiago, Chile.
Centro de Investigación y Tratamiento del Cáncer, Facultad de Medicina, Universidad de Chile, Independencia 1027, Santiago, Chile.
Biol Res. 2018 Oct 5;51(1):36. doi: 10.1186/s40659-018-0185-4.
Whole transcriptome RNA variant analyses have shown that adenosine deaminases acting on RNA (ADAR) enzymes modify a large proportion of cellular RNAs, contributing to transcriptome diversity and cancer evolution. Despite the advances in the understanding of ADAR function in breast cancer, ADAR RNA editing functional consequences are not fully addressed.
We characterized A to G(I) mRNA editing in 81 breast cell lines, showing increased editing at 3'UTR and exonic regions in breast cancer cells compared to immortalized non-malignant cell lines. In addition, tumors from the BRCA TCGA cohort show a 24% increase in editing over normal breast samples when looking at 571 well-characterized UTRs targeted by ADAR1. Basal-like subtype breast cancer patients with high level of ADAR1 mRNA expression shows a worse clinical outcome and increased editing in their 3'UTRs. Interestingly, editing was particularly increased in the 3'UTRs of ATM, GINS4 and POLH transcripts in tumors, which correlated with their mRNA expression. We confirmed the role of ADAR1 in this regulation using a shRNA in a breast cancer cell line (ZR-75-1).
Altogether, these results revealed a significant association between the mRNA editing in genes related to cancer-relevant pathways and clinical outcomes, suggesting an important role of ADAR1 expression and function in breast cancer.
全转录组 RNA 变体分析表明，作用于 RNA 的腺苷脱氨酶（ADAR）酶修饰了大量细胞 RNA，有助于转录组多样性和癌症进化。尽管人们对 ADAR 在乳腺癌中的功能有了更多的了解，但 ADAR RNA 编辑的功能后果仍未得到充分解决。
我们对 81 个乳腺癌细胞系中的 A 到 G（I）mRNA 编辑进行了表征，与永生化非恶性细胞系相比，乳腺癌细胞中 3'UTR 和外显子区域的编辑增加。此外，在查看 ADAR1 靶向的 571 个经过充分表征的 UTR 时，来自 BRCA TCGA 队列的肿瘤显示编辑水平比正常乳腺样本增加了 24%。当观察高表达 ADAR1mRNA 的基底样乳腺癌患者时，其临床结局较差，并且其 3'UTR 中的编辑增加。有趣的是，在肿瘤中 ATM、GINS4 和 POLH 转录物的 3'UTR 中，编辑特别增加，这与它们的 mRNA 表达相关。我们使用乳腺癌细胞系（ZR-75-1）中的 shRNA 证实了 ADAR1 在这种调控中的作用。
总的来说，这些结果揭示了与癌症相关途径的基因的 mRNA 编辑与临床结果之间存在显著关联，表明 ADAR1 表达和功能在乳腺癌中具有重要作用。
