Department of Biochemistry, BK21 Plus and Research Institute for Veterinary Science, School of Veterinary Medicine, Seoul National University, Seoul, Korea.
Comparative Medicine Disease Research Center, Seoul National University, Seoul, Republic of Korea.
PLoS One. 2023 Jun 23;18(6):e0286814. doi: 10.1371/journal.pone.0286814. eCollection 2023.
Retroelements (REs) had been considered 'Junk' until the encyclopedia of DNA elements (ENCODE) project demonstrated that most genome is functional. Although the function of retroelements has been reported in diverse cancers including human breast cancer (HBC) and subtypes, only a few studies have suggested the putative functions of REs via their random genome integration. A canine mammary tumor (CMT) has been highlighted due to the similarities in molecular and pathophysiology with HBC. This study investigated the putative roles of REs common in both HBC and CMT. The human LINE and HERV-K sequences harbor many miRNAs responsive elements (MREs) for tumor-suppressive miRNA such as let-7. We also observed that various MREs are exist in the ERV and LINE highly expressed in the transcriptome data of CMT as well as HBC sets. MREs against miR-126 were highly expressed in both HBC and CMT while the levels of miR-126 were down-regulated. Oppositely, the expression of miR-126 target genes was significantly up-regulated in the cancers. Moreover, cancer patients with an increased level of miR-126 showed better overall survival. The expression of ENPP5, a putative miR-126 target gene, was downregulated by miR-126 mimic. Importantly, overexpression of LINE fragment significantly suppressed miR-126 function on the target gene expression. We propose the functional role of REs expression in tumorigenesis as competing endogenous RNAs (ceRNA) against tumor-suppressive miRNAs. This study provided pieces of evidence that LINE expression, even partial and fragmented, have a regulatory function in ENPP5 gene expression via the competition with miR-126.
逆转录元件 (REs) 一直被认为是“垃圾”，直到 DNA 元件百科全书 (ENCODE) 项目表明大多数基因组是有功能的。虽然逆转录元件的功能已在包括人类乳腺癌 (HBC) 和亚型在内的多种癌症中得到报道，但只有少数研究通过它们的随机基因组整合来暗示逆转录元件的可能功能。由于犬乳腺肿瘤 (CMT) 在分子和病理生理学上与 HBC 相似，因此该研究受到了关注。本研究调查了在 HBC 和 CMT 中共同存在的 REs 的可能作用。人类 LINE 和 HERV-K 序列包含许多针对肿瘤抑制 miRNA（如 let-7）的 miRNA 反应元件 (MRE)。我们还观察到，CMT 以及 HBC 数据集转录组数据中高表达的 ERV 和 LINE 中存在各种 MRE。针对 miR-126 的 MRE 在 HBC 和 CMT 中均高度表达，而 miR-126 的水平则下调。相反，miR-126 靶基因的表达在癌症中显著上调。此外，miR-126 水平升高的癌症患者总体生存率更好。ENPP5，一个假定的 miR-126 靶基因的表达，被 miR-126 模拟物下调。重要的是，LINE 片段的过表达显著抑制了 miR-126 对靶基因表达的功能。我们提出 REs 表达在肿瘤发生中的功能作用，作为对肿瘤抑制 miRNA 的竞争性内源 RNA (ceRNA)。本研究提供了一些证据，表明 LINE 表达，即使是部分和片段化的，通过与 miR-126 的竞争，对 ENPP5 基因表达具有调节功能。
