1. Y Chromosome LncRNA Are Involved in Radiation Response of Male Non-Small Cell Lung Cancer Cells.
- Author
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Brownmiller T, Juric JA, Ivey AD, Harvey BM, Westemeier ES, Winters MT, Stevens AM, Stanley AN, Hayes KE, Sprowls SA, Ammer ASG, Walker M, Bey EA, Wu X, Lim ZF, Zhu L, Wen S, Hu G, Ma PC, and Martinez I
- Subjects
- Animals, Carcinoma, Non-Small-Cell Lung genetics, Cell Line, Tumor, Dose-Response Relationship, Radiation, Genes, myc, HMGA2 Protein genetics, Humans, Lung Neoplasms genetics, Male, Mice, Nude, Prognosis, RNA Stability, RNA-Binding Proteins genetics, Radiation Tolerance genetics, Xenograft Model Antitumor Assays, Carcinoma, Non-Small-Cell Lung radiotherapy, Chromosomes, Human, Y genetics, Gene Expression Regulation, Neoplastic radiation effects, Lung Neoplasms radiotherapy, RNA, Long Noncoding genetics
- Abstract
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 linc-SPRY3-2/3/4 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 linc-SPRY3-2/3/4 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 linc-SPRY3-2/3/4 RNA. The presence of linc-SPRY3-2/3/4 reduced the half-life of known IGF2BP3 binding mRNA, such as the antiapoptotic HMGA2 mRNA, as well as the oncogenic c-MYC mRNA. Assessment of Y chromosome in NSCLC tissue microarrays and expression of linc-SPRY3-2/3/4 in NSCLC RNA-seq and microarray data revealed a negative correlation between the loss of the Y chromosome or linc-SPRY3-2/3/4 and overall survival. Thus, linc-SPRY3-2/3/4 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., (©2020 American Association for Cancer Research.)
- Published
- 2020
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