Department of Microbiology, Immunology & Cell Biology, West Virginia University Cancer Institute, School of Medicine, West Virginia University, Morgantown, West Virginia.
Modulation Therapeutics, West Virginia University, Morgantown, West Virginia.
Cancer Res. 2020 Oct 1;80(19):4046-4057. doi: 10.1158/0008-5472.CAN-19-4032. Epub 2020 Jul 2.
Numerous studies have implicated changes in the Y chromosome in male cancers, yet few have investigated the biological importance of Y chromosome noncoding RNA. Here we identify a group of Y chromosome-expressed long noncoding RNA (lncRNA) that are involved in male non-small cell lung cancer (NSCLC) radiation sensitivity. Radiosensitive male NSCLC cell lines demonstrated a dose-dependent induction of following irradiation, which was not observed in radioresistant male NSCLC cell lines. Cytogenetics revealed the loss of chromosome Y (LOY) in the radioresistant male NSCLC cell lines. Gain- and loss-of-function experiments indicated that transcripts affect cell viability and apoptosis. Computational prediction of RNA binding proteins (RBP) motifs and UV-cross-linking and immunoprecipitation (CLIP) assays identified IGF2BP3, an RBP involved in mRNA stability, as a binding partner for RNA. The presence of reduced the half-life of known IGF2BP3 binding mRNA, such as the antiapoptotic mRNA, as well as the oncogenic mRNA. Assessment of Y chromosome in NSCLC tissue microarrays and expression of in NSCLC RNA-seq and microarray data revealed a negative correlation between the loss of the Y chromosome or and overall survival. Thus, expression and LOY could represent an important marker of radiotherapy in NSCLC. SIGNIFICANCE: This study describes previously unknown Y chromosome-expressed lncRNA regulators of radiation response in male NSCLC and show a correlation between loss of chromosome Y and radioresistance. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/19/4046/F1.large.jpg.
许多研究表明 Y 染色体的变化与男性癌症有关，但很少有研究调查 Y 染色体非编码 RNA 的生物学重要性。在这里，我们鉴定了一组参与男性非小细胞肺癌（NSCLC）放射敏感性的 Y 染色体表达的长非编码 RNA（lncRNA）。放射敏感的男性 NSCLC 细胞系在照射后表现出剂量依赖性的 诱导，而在放射抗性的男性 NSCLC 细胞系中则没有观察到这种情况。细胞遗传学显示放射抗性的男性 NSCLC 细胞系中存在 Y 染色体丢失（LOY）。增益和缺失功能实验表明， 转录本影响细胞活力和细胞凋亡。RNA 结合蛋白（RBP）基序的计算预测和紫外线交联和免疫沉淀（CLIP）实验鉴定了 IGF2BP3，一种参与 mRNA 稳定性的 RBP，作为 RNA 的结合伴侣。 的存在降低了已知的 IGF2BP3 结合 mRNA（如抗凋亡的 mRNA）和致癌的 mRNA 的半衰期。在 NSCLC 组织微阵列中评估 Y 染色体和在 NSCLC RNA-seq 和微阵列数据中表达 发现 Y 染色体丢失或 与总生存时间呈负相关。因此， 的表达和 LOY 可能代表 NSCLC 放射治疗的一个重要标志物。 意义：本研究描述了以前未知的 Y 染色体表达的 lncRNA 调节男性 NSCLC 的放射反应，并显示染色体 Y 丢失与放射抗性之间存在相关性。
