Wang Chao, Liang Chun
Department of Biology, Miami University, Oxford, OH 45056, USA.
Genes (Basel). 2025 Apr 29;16(5):528. doi: 10.3390/genes16050528.
Understanding the role of repetitive elements (REs) in cancer development is crucial for identifying novel biomarkers and therapeutic targets. This study investigated the locus-specific dysregulation of REs, including the differential expression and methylation of REs, across 12 TCGA cancer types stratified by their genomic context (i.e., genic and intergenic REs). We found uniquely dysregulated genic REs co-regulated with their corresponding transcripts and associated with distinct biological functions in different cancer types. Uniquely dysregulated intergenic REs were identified in each cancer type and used to cluster different sample types. Recurrently dysregulated REs were identified in several cancer types, with genes associated with up-regulated genic REs involved in cell cycle processes and those associated with down-regulated REs involved in the extracellular matrix. Interestingly, four out of five REs consistently down-regulated in all 12 cancer types were located in the intronic region of the , a recently discovered tumor suppressor gene. expression was also down-regulated in 10 of 12 cancer types, suggesting its potential importance across a wide range of cancer types. With the corresponding DNA methylation array data, we found a higher prevalence of hypo-methylated REs in most cancer types (10 out of 12). Despite the slight overlaps between differentially expressed REs and differentially methylated REs, we showed that the methylation of locus-specific REs negatively correlates with their expression in some of these 12 cancer types. Our findings highlight the cancer-specific and recurrent deregulation of REs, their functional associations, and the potential role of as a pan-cancer tumor suppressor, providing new insights into biomarker discovery and therapeutic development.
了解重复元件（REs）在癌症发展中的作用对于识别新型生物标志物和治疗靶点至关重要。本研究调查了REs在12种TCGA癌症类型中的位点特异性失调情况，包括REs的差异表达和甲基化，并根据其基因组背景（即基因内和基因间REs）进行分层。我们发现，独特失调的基因内REs与其相应的转录本共同调控，并与不同癌症类型中的不同生物学功能相关。在每种癌症类型中都鉴定出了独特失调的基因间REs，并用于对不同样本类型进行聚类。在几种癌症类型中发现了反复失调的REs，与上调的基因内REs相关的基因参与细胞周期过程，而与下调的REs相关的基因参与细胞外基质。有趣的是，在所有12种癌症类型中持续下调的5种REs中有4种位于最近发现的肿瘤抑制基因的内含子区域。在12种癌症类型中的10种中，其表达也下调，表明其在广泛的癌症类型中具有潜在重要性。通过相应的DNA甲基化阵列数据，我们发现大多数癌症类型（12种中的10种）中低甲基化REs的发生率更高。尽管差异表达的REs和差异甲基化的REs之间存在轻微重叠，但我们表明，在这12种癌症类型中的一些类型中，位点特异性REs的甲基化与其表达呈负相关。我们的研究结果突出了REs的癌症特异性和反复失调、它们的功能关联以及作为泛癌肿瘤抑制因子的潜在作用，为生物标志物发现和治疗开发提供了新的见解。
