Mass General Cancer Center, Harvard Medical School, Charlestown, Massachusetts, USA.
Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
J Clin Invest. 2022 Aug 15;132(16). doi: 10.1172/JCI155931.
Aberrant expression of viral-like repeat elements is a common feature of epithelial cancers, and the substantial diversity of repeat species provides a distinct view of the cancer transcriptome. Repeatome profiling across ovarian, pancreatic, and colorectal cell lines identifies distinct clustering independent of tissue origin that is seen with coding gene analysis. Deeper analysis of ovarian cancer cell lines demonstrated that human satellite II (HSATII) satellite repeat expression was highly associated with epithelial-mesenchymal transition (EMT) and anticorrelated with IFN-response genes indicative of a more aggressive phenotype. SATII expression - and its correlation with EMT and anticorrelation with IFN-response genes - was also found in ovarian cancer RNA-Seq data and was associated with significantly shorter survival in a second independent cohort of patients with ovarian cancer. Repeat RNAs were enriched in tumor-derived extracellular vesicles capable of stimulating monocyte-derived macrophages, demonstrating a mechanism that alters the tumor microenvironment with these viral-like sequences. Targeting of HSATII with antisense locked nucleic acids stimulated IFN response and induced MHC I expression in ovarian cancer cell lines, highlighting a potential strategy of modulating the repeatome to reestablish antitumor cell immune surveillance.
病毒样重复元件的异常表达是上皮性癌症的一个共同特征，重复物种的大量多样性为癌症转录组提供了独特的视角。对卵巢、胰腺和结肠癌细胞系的重复组谱进行分析，确定了与组织起源无关的独特聚类，这在编码基因分析中可见。对卵巢癌细胞系的更深入分析表明，人类卫星 II（HSATII）卫星重复表达与上皮-间充质转化（EMT）高度相关，与 IFN 反应基因呈反相关，表明具有更具侵袭性的表型。在卵巢癌 RNA-Seq 数据中也发现了 SATII 表达及其与 EMT 的相关性以及与 IFN 反应基因的负相关性，并与另一组卵巢癌患者的生存时间显著缩短相关。重复 RNA 在肿瘤衍生的能够刺激单核细胞衍生的巨噬细胞的细胞外囊泡中富集，证明了一种通过这些病毒样序列改变肿瘤微环境的机制。用反义锁核酸靶向 HSATII 可刺激卵巢癌细胞系中的 IFN 反应并诱导 MHC I 表达，突出了一种调节重复组以重新建立抗肿瘤细胞免疫监视的潜在策略。
