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.

Risk stratification of COVID‐19 patients is essential for pandemic management. Changes in the cell fitness marker, hFwe‐Lose , can precede the host immune response to infection, potentially making such a biomarker an earlier triage tool. Here, we evaluate whether hFwe‐Lose gene expression can outperform conventional methods in predicting outcomes (e.g., death and hospitalization) in COVID‐19 patients. We performed a post‐mortem examination of infected lung tissue in deceased COVID‐19 patients to determine hFwe‐Lose’ s biological role in acute lung injury. We then performed an observational study ( n = 283) to evaluate whether hFwe‐Lose expression (in nasopharyngeal samples) could accurately predict hospitalization or death in COVID‐19 patients. In COVID‐19 patients with acute lung injury, hFwe‐Lose is highly expressed in the lower respiratory tract and is co‐localized to areas of cell death. In patients presenting in the early phase of COVID‐19 illness, hFwe‐Lose expression accurately predicts subsequent hospitalization or death with positive predictive values of 87.8–100% and a negative predictive value of 64.1–93.2%. hFwe‐Lose outperforms conventional inflammatory biomarkers and patient age and comorbidities, with an area under the receiver operating characteristic curve (AUROC) 0.93–0.97 in predicting hospitalization/death. Specifically, this is significantly higher than the prognostic value of combining biomarkers (serum ferritin, D‐dimer, C‐reactive protein, and neutrophil–lymphocyte ratio), patient age and comorbidities (AUROC of 0.67–0.92). The cell fitness marker, hFwe‐Lose , accurately predicts outcomes in COVID‐19 patients. This finding demonstrates how tissue fitness pathways dictate the response to infection and disease and their utility in managing the current COVID‐19 pandemic.

Historically, the Y chromosome has presented challenges to classical methodology and philosophy of understanding the differences between males and females. A genetic unsolved puzzle, the Y chromosome was the last chromosome to be fully sequenced. With the advent of the Human Genome Project came a realization that the human genome is more than just genes encoding proteins, and an entire universe of RNA was discovered. This dark matter of biology and the black box surrounding the Y chromosome have collided over the last few years, as increasing numbers of non-coding RNAs have been identified across the length of the Y chromosome, many of which have played significant roles in disease. In this review, we will uncover what is known about the connections between the Y chromosome and the non-coding RNA universe that originates from it, particularly as it relates to long non-coding RNAs, microRNAs and circular RNAs.

Lung cancer is the leading cause of cancer related deaths worldwide. Unfortunately, radiation resistance remains a major problem facing lung cancer patients. Recently, we identified a group of long non-coding RNAs (lncRNAs) known as linc-SPRY3 RNAs, expressed on the Y-chromosome, which play a role in radiation sensitivity by decreasing tumor burden in vitro and in vivo after radiation. In this study, we found that the linc-SPRY3 RNAs are one large lncRNA that we named Radiation Induced Y-chromosome linked long non-coding RNA (lnc-RAINY). Through ATAC-seq and immunoprecipitation experiments, we show that lnc-RAINY interacts with DNA in a triple helix to induce chromatin remodeling and gene expression. We also identified that lnc-RAINY regulates CDC6 and CDC25A expression affecting senescence induction, cell migration patterns, and cell cycle regulation. Furthermore, the administration of Lnc-RAINY encapsulated in FDA-approved nanoparticles into a lung cancer patient-derived xenograft model dramatically reduces tumor progression demonstrating therapeutic potential.

Within the glioblastoma (GBM) microenvironment, macrophages are widely implicated in immunosuppression. The neuro-oncology community is interested in modulating this immune suppression to improve therapies for GBM, but this approach poses significant challenges. Non-coding RNAs present an attractive target for therapeutic modulation of the immune system, and they are implicated, broadly, in macrophage polarization and the pathophysiology of GBM. Here, we discuss the extant literature on non-coding RNAs and how they impact the polarization of macrophages with particular emphasis on their impact within glioblastoma. We further discuss the clinical relevance of these non-coding RNAs and macrophage polarization to disease progression and associated therapeutic opportunities.

Table S1 to S4; Figures S1 to S12