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.
Neutrophil extracellular traps (NETs) occur when chromatin is decondensed and extruded from the cell, generating a web-like structure. NETs have been implicated in the pathogenesis of several sterile disease states and thus a potential therapeutic target. Various pathways have been shown to induce NETs, including autophagy, with several key enzymes being activated like peptidyl arginine deiminase 4 (PAD4), an enzyme responsible for citrullination of histones, allowing for DNA unwinding and subsequent release from the cell. Pre-clinical studies have already demonstrated that chloroquine (CQ) and hydroxychloroquine (HCQ) are able to reduce NETs and slow disease progression. The exact mechanism as to how these drugs reduce NETs has yet to be elucidated. CQ and HCQ decrease NET formation from various NET activators, independent of their autophagy inhibitory function. CQ and HCQ were found to inhibit PAD4 exclusively, in a dose dependent manner, confirmed with reduced CitH3+ NETs after CQ or HCQ treatment. Circulating CitH3 levels were reduced in pancreatic cancer patients after HCQ treatment. In silico screening of PAD4 protein structure identified a likely binding site interaction at Arg639 for CQ and Trp347, Ser468 and Glu580 for HCQ. SPR analysis confirmed binding of HCQ and CQ with PAD4 with KD values of 54.1 µM (CQ) and 88.1 µM (HCQ). This data provides evidence of direct PAD4 inhibition as a mechanism for CQ/HCQ inhibition of NETs. We propose that these drugs likely reduce NET formation through multiple mechanisms; the previously established TLR9 and autophagy inhibitory mechanism and the novel PAD4 inhibitory mechanism.
Uveal melanoma is a cancer that develops from melanocytes in the posterior uveal tract. Metastatic uveal melanoma is an extremely rare disease that has a poor long-term prognosis, limited treatment options and a strong predilection for liver metastasis. Median overall survival has been reported to be 6 months and 1 year mortality of 80%. Traditional chemotherapy used in cutaneous melanoma is ineffective in uveal cases. Surgical resection and ablation is the preferred therapy for liver metastasis but is often not feasible due to extent of disease. In this review, we will explore treatment options for liver metastases from uveal melanoma, with a focus on isolated hepatic perfusion (IHP). IHP offers an aggressive regional therapy approach that can be used in bulky unresectable disease and allows high-dose chemotherapy with melphalan to be delivered directly to the liver without systemic effects. Long-term median overall survival has been reported to be as high as 27 months. We will also highlight the poor responses associated with checkpoint inhibitors, including an overview of the biological rationale driving this lack of immunotherapy effect for this disease. The persistent failure of traditional treatments and immunotherapy suggest an ongoing need for regional surgical approaches such as IHP in this disease.
Gastric adenocarcinoma (GC) is a devastating disease and is the third leading cause of cancer deaths worldwide. This heterogeneous disease has several different classification systems that consider histological appearance and genomic alterations. Understanding the etiology of GC, including infection, hereditary conditions, and environmental factors, is of particular importance and is discussed in this review. To improve survival in GC, we also must improve our therapeutic strategies. Here, we discuss new targets that warrant further exploration.
<p>Table S1 to S4; Figures S1 to S12</p>
<div>Abstract<p>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 <i>linc-SPRY3-2/3/4</i> 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 <i>linc-SPRY3-2/3/4</i> 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 <i>linc-SPRY3-2/3/4</i> RNA. The presence of <i>linc-SPRY3-2/3/4</i> reduced the half-life of known IGF2BP3 binding mRNA, such as the antiapoptotic <i>HMGA2</i> mRNA, as well as the oncogenic <i>c-MYC</i> mRNA. Assessment of Y chromosome in NSCLC tissue microarrays and expression of <i>linc-SPRY3-2/3/4</i> in NSCLC RNA-seq and microarray data revealed a negative correlation between the loss of the Y chromosome or <i>linc-SPRY3-2/3/4</i> and overall survival. Thus, <i>linc-SPRY3-2/3/4</i> expression and LOY could represent an important marker of radiotherapy in NSCLC.</p>Significance:<p>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.</p></div>
<div>Abstract<p>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 <i>linc-SPRY3-2/3/4</i> 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 <i>linc-SPRY3-2/3/4</i> 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 <i>linc-SPRY3-2/3/4</i> RNA. The presence of <i>linc-SPRY3-2/3/4</i> reduced the half-life of known IGF2BP3 binding mRNA, such as the antiapoptotic <i>HMGA2</i> mRNA, as well as the oncogenic <i>c-MYC</i> mRNA. Assessment of Y chromosome in NSCLC tissue microarrays and expression of <i>linc-SPRY3-2/3/4</i> in NSCLC RNA-seq and microarray data revealed a negative correlation between the loss of the Y chromosome or <i>linc-SPRY3-2/3/4</i> and overall survival. Thus, <i>linc-SPRY3-2/3/4</i> expression and LOY could represent an important marker of radiotherapy in NSCLC.</p>Significance:<p>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.</p></div>
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