TheUGT1Alocus generates over 60 different alternatively spliced transcripts and 30 circular RNAs. To date, v2 and v3 transcripts are the only variant UGT1A transcripts that have been functionally characterized. Both v2 and v3 transcripts encode the same inactive variant UGT1A proteins (i2s) that can negatively regulate glucuronidation activity and influence cancer cell metabolism. However, the abundance and interindividual variability in the expression of v2 and v3 transcripts in human tissues and their potential deregulation in cancers have not been comprehensively assessed. To address this knowledge gap, we quantified the expression levels of v1, v2, and v3 transcripts using RNA-seq datasets with large cohorts of normal tissues and paired normal and tumor tissues from patients with six different cancer types (liver, kidney, colon, stomach, esophagus, and bladder cancer). We found that v2 and v3 abundance varied significantly between different tissue types, and that interindividual variation was also high within the same tissue type. Moreover, the ratio of v2 to v3 variants varied between tissues, implying their differential regulation. Our results showed higher v2 abundance in gastrointestinal tissues than liver and kidney tissues, suggesting a more significant negative regulation of glucuronidation by i2 proteins in gastrointestinal tissues than in liver and kidney tissues. We further showed differential deregulation of wildtype (v1) and variant transcripts (v2, v3) in cancers that generally increased the v2/v1 and/or v3/v1 expression ratios in tumors compared to normal tissues, indicating a more significant role of the variants in tumors. Finally, we report ten novel UGT1A transcripts with novel 3′ terminal exons, most of which encode variant proteins with a similar structure to UGT1A_i2 proteins. These findings further emphasize the diversity of the UGT1A transcriptome and proteome.
UGT1A基因座可产生超过60种不同的选择性剪接转录本和30种环状RNA。迄今为止，v2和v3转录本是唯一完成功能表征的UGT1A变异转录本。这两种转录本编码相同的失活型UGT1A变异蛋白（i2s），该蛋白可负向调控葡萄糖醛酸化活性并影响癌细胞代谢。然而，v2和v3转录本在人体组织中的表达丰度与个体间差异，及其在癌症中的潜在失调机制尚未得到系统评估。为填补这一知识空白，本研究利用大规模正常组织RNA测序数据集及六种癌症类型（肝癌、肾癌、结肠癌、胃癌、食管癌和膀胱癌）患者的癌组织-配对正常组织样本，对v1、v2和v3转录本的表达水平进行定量分析。研究发现：v2和v3的丰度在不同组织类型间存在显著差异，同一组织类型内个体间变异度较高；v2与v3变异体的比例存在组织特异性差异，提示其调控机制具有分化特征。结果显示胃肠道组织中v2丰度高于肝肾组织，表明i2蛋白在胃肠道组织中对葡萄糖醛酸化的负向调控作用较肝肾组织更为显著。进一步研究发现，癌症中野生型（v1）与变异转录本（v2、v3）呈现差异化失调：与正常组织相比，肿瘤中v2/v1和/或v3/v1表达比值普遍升高，提示变异转录本在肿瘤中发挥更重要作用。此外，本研究新发现10个具有新型3′末端外显子的UGT1A转录本，其中多数编码与UGT1A_i2蛋白结构相似的变异蛋白。这些发现进一步凸显了UGT1A转录组与蛋白质组的多样性。
肿瘤(癌症)患者之家