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Cancer Res ; 80(19): 4046-4057, 2020 10 01.
Artículo en Inglés | MEDLINE | ID: mdl-32616503

RESUMEN

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.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/radioterapia , Cromosomas Humanos Y/genética , Regulación Neoplásica de la Expresión Génica/efectos de la radiación , Neoplasias Pulmonares/radioterapia , ARN Largo no Codificante/genética , Animales , Carcinoma de Pulmón de Células no Pequeñas/genética , Línea Celular Tumoral , Relación Dosis-Respuesta en la Radiación , Genes myc , Proteína HMGA2/genética , Humanos , Neoplasias Pulmonares/genética , Masculino , Ratones Desnudos , Pronóstico , Estabilidad del ARN , Proteínas de Unión al ARN/genética , Tolerancia a Radiación/genética , Ensayos Antitumor por Modelo de Xenoinjerto
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