Multiple and hereditary renal tumors: a review for radiologists.

80% of renal carcinomas (RC) are diagnosed incidentally by imaging. 2-4% of "sporadic" multifocality and 5-8% of hereditary syndromes are accepted, probably with underestimation. Multifocality, young age, familiar history, syndromic data, and certain histologies lead to suspicion of hereditary syndrome. Each tumor must be studied individually, with a multidisciplinary evaluation of the patient. Nephron-sparing therapeutic strategies and a radioprotective diagnostic approach are recommended. Relevant data for the radiologist in major RC hereditary syndromes are presented: von-Hippel-Lindau, Chromosome-3 translocation, BRCA-associated protein-1 mutation, RC associated with succinate dehydrogenase deficiency, PTEN, hereditary papillary RC, Papillary thyroid cancer- Papillary RC, Hereditary leiomyomatosis and RC, Birt-Hogg-Dubé, Tuberous sclerosis complex, Lynch, Xp11.2 translocation/TFE3 fusion, Sickle cell trait, DICER1 mutation, Hereditary hyperparathyroidism and jaw tumor, as well as the main syndromes of Wilms tumor predisposition. The concept of "non-hereditary" familial RC and other malignant and benign entities that can present as multiple renal lesions are discussed.

FGFR1 fusions as a novel molecular driver in rhabdomyosarcoma.

The wide application of RNA sequencing in clinical practice has allowed the discovery of novel fusion genes, which have contributed to a refined molecular classification of rhabdomyosarcoma (RMS). Most fusions in RMS result in aberrant transcription factors, such as PAX3/7::FOXO1 in alveolar RMS (ARMS) and fusions involving VGLL2 or NCOA2 in infantile spindle cell RMS. However, recurrent fusions driving oncogenic kinase activation have not been reported in RMS. Triggered by an index case of an unclassified RMS (overlapping features between ARMS and sclerosing RMS) with a novel FGFR1::ANK1 fusion, we reviewed our molecular files for cases harboring FGFR1-related fusions. One additional case with an FGFR1::TACC1 fusion was identified in a tumor resembling embryonal RMS (ERMS) with anaplasia, but with no pathogenic variants in TP53 or DICER1 on germline testing. Both cases occurred in males, aged 7 and 24, and in the pelvis. The 2nd case also harbored additional alterations, including somatic TP53 and TET2 mutations. Two additional RMS cases (one unclassified, one ERMS) with FGFR1 overexpression but lacking FGFR1 fusions were identified by RNA sequencing. These two cases and the FGFR1::TACC1-positive case clustered together with the ERMS group by RNAseq. This is the first report of RMS harboring recurrent FGFR1 fusions. However, it remains unclear if FGFR1 fusions define a novel subset of RMS or alternatively, whether this alteration can sporadically drive the pathogenesis of known RMS subtypes, such as ERMS. Additional larger series with integrated genomic and epigenetic datasets are needed for better subclassification, as the resulting oncogenic kinase activation underscores the potential for targeted therapy.

DEAD Box Helicase 24 Is Increased in the Brain in Alzheimer's Disease and AppN-LF Mice and Influences Presymptomatic Pathology.

At the time of diagnosis, Alzheimer's disease (AD) patients already suffer from significant neuronal loss. The identification of proteins that influence disease progression before the onset of symptoms is thus an essential part of the development of new effective drugs and biomarkers. Here, we used an unbiased 18O labelling proteomics approach to identify proteins showing altered levels in the AD brain. We studied the relationship between the protein with the highest increase in hippocampus, DEAD box Helicase 24 (DDX24), and AD pathology. We visualised DDX24 in the human brain and in a mouse model for Aß42-induced AD pathology-AppNL-F-and studied the interaction between Aß and DDX24 in primary neurons. Immunohistochemistry in the AD brain confirmed the increased levels and indicated an altered subcellular distribution of DDX24. Immunohistochemical studies in AppNL-F mice showed that the increase of DDX24 starts before amyloid pathology or memory impairment is observed. Immunocytochemistry in AppNL-F primary hippocampal neurons showed increased DDX24 intensity in the soma, nucleus and nucleolus. Furthermore, siRNA targeting of DDX24 in neurons decreased APP and Aß42 levels, and the addition of Aß42 to the medium reduced DDX24. In conclusion, we have identified DDX24 as a protein with a potential role in Aß-induced AD pathology.

m6A-dependent upregulation of DDX21 by super-enhancer-driven IGF2BP2 and IGF2BP3 facilitates progression of acute myeloid leukaemia.

BACKGROUND: Acute myeloid leukaemia (AML) is a haematological malignancy with unfavourable prognosis. Despite the effectiveness of chemotherapy and targeted therapy, relapse or drug resistance remains a major threat to AML patients. N6-methyladenosine (m6A) RNA methylation and super-enhancers (SEs) are extensively involved in the leukaemogenesis of AML. However, the potential relationship between m6A and SEs in AML has not been elaborated. METHODS: Chromatin immunoprecipitation (ChIP) sequencing data from Gene Expression Omnibus (GEO) cohort were analysed to search SE-related genes. The mechanisms of m6 A-binding proteins IGF2BP2 and IGF2BP3 on DDX21 were explored via methylated RNA immunoprecipitation (MeRIP) assays, RNA immunoprecipitation (RIP) assays and luciferase reporter assays. Then we elucidated the roles of DDX21 in AML through functional assays in vitro and in vivo. Finally, co-immunoprecipitation (Co-IP) assays, RNA sequencing and ChIP assays were performed to investigate the downstream mechanisms of DDX21. RESULTS: We identified two SE-associated transcripts IGF2BP2 and IGF2BP3 in AML. High enrichment of H3K27ac, H3K4me1 and BRD4 was observed in IGF2BP2 and IGF2BP3, whose expression were driven by SE machinery. Then IGF2BP2 and IGF2BP3 enhanced the stability of DDX21 mRNA in an m6A-dependent manner. DDX21 was highly expressed in AML patients, which indicated a poor survival. Functionally, knockdown of DDX21 inhibited cell proliferation, promoted cell apoptosis and led to cell cycle arrest. Mechanistically, DDX21 recruited transcription factor YBX1 to cooperatively trigger ULK1 expression. Moreover, silencing of ULK1 could reverse the promoting effects of DDX21 overexpression in AML cells. CONCLUSIONS: Dysregulation of SE-IGF2BP2/IGF2BP3-DDX21 axis facilitated the progression of AML. Our findings provide new insights into the link between SEs and m6A modification, elucidate the regulatory mechanisms of IGF2BP2 and IGF2BP3 on DDX21, and reveal the underlying roles of DDX21 in AML.

Combination therapy with venetoclax and azacitidine for the treatment of myelodysplastic syndromes with DDX41 mutations.

Myelodysplastic syndromes (MDS) patients with DEAD-box helicase 41 (DDX41) mutations have been reported to be treated effectively with lenalidomide; however, there are no randomized studies to prove it. Venetoclax and azacitidine are safe and effective in high-risk MDS/AML. In this study, we evaluated the efficacy of venetoclax and azacitidine combination therapy in eight consecutive MDS patients with DDX41 mutations at our centre from March 2021 to November 2023. We retrospectively analyzed the genetic features and clinical characteristics of these patients. Our findings suggest that MDS patients with DDX41 mutation may benefit from the therapy, for six subjects received this regimen as initial therapy and five of the six subjects achieved complete remission.

Clinicopathological analysis of 22 Müllerian adenosarcomas and the sequencing of DICER1 mutation.

BACKGROUND: Müllerian adenosarcoma, a rare malignancy, presents diagnostic and therapeutic challenges. In this study, we conducted an analysis of the clinicopathological characteristics of 22 adenosarcomas, with a particular focus on screening for DICER1 hot mutations. METHODS: The cohort consisted of patients with adenosarcoma who were registered at the West China Second Hospital between the years 2020 and June 2022. Sanger sequencing was employed to screen for somatic Hotspot mutations in the RNase IIIb domain of DICER1 in the 22 adenosarcomas. RESULTS: Only one patient exhibited a DICER1 mutation that was not a DICER1 Hotspot mutation. Among the 22 patients, all underwent total hysterectomy with bilateral salpingo-oophorectomy, and 14 out of these 22 patients received adjuvant treatment. CONCLUSION: In summary, our study of 22 Müllerian adenosarcomas focused on the clinicopathological features and the presence of DICER1 Hotspot mutations. Although our findings did not reveal any DICER1 mutations in the studied samples, this negative result provides valuable information for the field by narrowing down the genetic landscape of adenosarcomas and highlighting the need for further research into alternative molecular pathways driving this malignancy.

Role of Hsa_circ_0000880 in the Regulation of High Glucose-Induced Apoptosis of Retinal Microvascular Endothelial Cells.

Purpose: Circular RNAs (circRNAs) have been verified to participate in multiple biological processes and disease progression. Yet, the role of circRNAs in the pathogenesis of diabetic retinopathy (DR) is still poorly understood and deserves further study. This study aimed to investigate the role of circRNAs in the regulation of high glucose (HG)-induced apoptosis of retinal microvascular endothelial cells (RMECs). Methods: Epiretinal membranes from patients with DR and nondiabetic patients with idiopathic macular epiretinal membrane were collected for this study. The circRNA microarrays were performed using high-throughput sequencing. Hierarchical clustering, functional enrichment, and network regulation analyses were used to analyze the data generated by high-throughput sequencing. Next, RMECs were subjected to HG (25 mM) conditions to induce RMECs apoptosis in vitro. A series of experiments, such as Transwell, the Scratch wound, and tube formation, were conducted to explore the regulatory effect of circRNA on RMECs. Fluorescence in situ hybridization (FISH), immunofluorescence staining, and Western blot were used to study the mechanism underlying circRNA-mediated regulation. Results: A total of 53 differentially expressed circRNAs were found in patients with DR. Among these, hsa_circ_0000880 was significantly upregulated in both the diabetic epiretinal membranes and in an in vitro DR model of HG-treated RMECs. Hsa_circ_0000880 knockout facilitated RMECs vitality and decreased the paracellular permeability of RMECs under hyperglycemia. More importantly, silencing of hsa_circ_0000880 significantly inhibited HG-induced ROS production and RMECs apoptosis. Hsa_circ_0000880 acted as an endogenous sponge for eukaryotic initiation factor 4A-III (EIF4A3). Knockout of hsa_circ_0000880 reversed HG-induced decrease in EIF4A3 protein level. Conclusions: Our findings suggest that hsa_circ_0000880 is a novel circRNA can induce RMECs apoptosis in response to HG conditions by sponging EIF4A3, offering an innovative treatment approach against DR. Translational Relevance: The circRNAs participate in the dysregulation of microvascular endothelial function induced by HG conditions, indicating a promising therapeutic target for DR.

DHX9 maintains epithelial homeostasis by restraining R-loop-mediated genomic instability in intestinal stem cells.

Epithelial barrier dysfunction and crypt destruction are hallmarks of inflammatory bowel disease (IBD). Intestinal stem cells (ISCs) residing in the crypts play a crucial role in the continuous self-renewal and rapid recovery of intestinal epithelial cells (IECs). However, how ISCs are dysregulated in IBD remains poorly understood. Here, we observe reduced DHX9 protein levels in IBD patients, and mice with conditional DHX9 depletion in the intestinal epithelium (Dhx9ΔIEC) exhibit an increased susceptibility to experimental colitis. Notably, Dhx9ΔIEC mice display a significant reduction in the numbers of ISCs and Paneth cells. Further investigation using ISC-specific or Paneth cell-specific Dhx9-deficient mice demonstrates the involvement of ISC-expressed DHX9 in maintaining epithelial homeostasis. Mechanistically, DHX9 deficiency leads to abnormal R-loop accumulation, resulting in genomic instability and the cGAS-STING-mediated inflammatory response, which together impair ISC function and contribute to the pathogenesis of IBD. Collectively, our findings highlight R-loop-mediated genomic instability in ISCs as a risk factor in IBD.

Physiological functions of RIG-I-like receptors.

RIG-I-like receptors (RLRs) are crucial for pathogen detection and triggering immune responses and have immense physiological importance. In this review, we first summarize the interferon system and innate immunity, which constitute primary and secondary responses. Next, the molecular structure of RLRs and the mechanism of sensing non-self RNA are described. Usually, self RNA is refractory to the RLR; however, there are underlying host mechanisms that prevent immune reactions. Studies have revealed that the regulatory mechanisms of RLRs involve covalent molecular modifications, association with regulatory factors, and subcellular localization. Viruses have evolved to acquire antagonistic RLR functions to escape the host immune reactions. Finally, the pathologies caused by the malfunction of RLR signaling are described.

The DEAD-box ATPase Dbp10/DDX54 initiates peptidyl transferase center formation during 60S ribosome biogenesis.

DEAD-box ATPases play crucial roles in guiding rRNA restructuring events during the biogenesis of large (60S) ribosomal subunits, but their precise molecular functions are currently unknown. In this study, we present cryo-EM reconstructions of nucleolar pre-60S intermediates that reveal an unexpected, alternate secondary structure within the nascent peptidyl-transferase-center (PTC). Our analysis of three sequential nucleolar pre-60S intermediates reveals that the DEAD-box ATPase Dbp10/DDX54 remodels this alternate base pairing and enables the formation of the rRNA junction that anchors the mature form of the universally conserved PTC A-loop. Post-catalysis, Dbp10 captures rRNA helix H61, initiating the concerted exchange of biogenesis factors during late nucleolar 60S maturation. Our findings show that Dbp10 activity is essential for the formation of the ribosome active site and reveal how this function is integrated with subsequent assembly steps to drive the biogenesis of the large ribosomal subunit.

Transcriptome-wide analysis of the function of Ded1 in translation preinitiation complex assembly in a reconstituted in vitro system.

We have developed a deep sequencing-based approach, Rec-Seq, that allows simultaneous monitoring of ribosomal 48S preinitiation complex (PIC) formation on every mRNA in the translatome in an in vitro reconstituted system. Rec-Seq isolates key early steps in translation initiation in the absence of all other cellular components and processes. Using this approach, we show that the DEAD-box ATPase Ded1 promotes 48S PIC formation on the start codons of >1000 native mRNAs, most of which have long, structured 5'-untranslated regions (5'UTRs). Remarkably, initiation measured in Rec-Seq was enhanced by Ded1 for most mRNAs previously shown to be highly Ded1-dependent by ribosome profiling of ded1 mutants in vivo, demonstrating that the core translation functions of the factor are recapitulated in the purified system. Our data do not support a model in which Ded1acts by reducing initiation at alternative start codons in 5'UTRs and instead indicate it functions by directly promoting mRNA recruitment to the 43S PIC and scanning to locate the main start codon. We also provide evidence that eIF4A, another essential DEAD-box initiation factor, is required for efficient PIC assembly on almost all mRNAs, regardless of their structural complexity, in contrast to the preferential stimulation by Ded1 of initiation on mRNAs with long, structured 5'UTRs.

Sex matters in preclinical research.

International Women's Day 2024 has a theme of inclusion. As publishers of preclinical research, we aim to show how inclusion of females in research advances scientific rigor and improves treatment reliability. Sexual reproduction is key to all life across the plant and animal kingdoms. Biological sex takes many forms that are morphologically differentiated during development: stamens versus pistils in plants; color and plumage in birds; fallopian tubes versus vas deferens in mammals; and differences in size, for instance, males are smaller in the fruit fly Drosophila melanogaster. Physical differences may be obvious, but many traits may be more obscure, including hormonal, physiological and metabolic factors. These traits have a big influence on disease and responses to treatment. Thus, we call for improved inclusion, analysis and reporting of sex as a biological variable in preclinical animal modeling research.

Differential Gene Expression Profiles in Inflammatory Bowel Disease Patients from Kurdistan, Iraq.

Objectives: Inflammatory bowel disease (IBD), generally comprising Crohn's disease (CD) and ulcerative colitis (UC), has become a significant global public health concern in the last decade. This study aimed to determine the alternations in the whole genomic expression profile of patients with IBD in this geographic location for the first time, as there are very few articles in the literature addressing this specific aspect of the field. Methods: The study was conducted in Erbil Governorate in the Kurdistan region of Iraq from July 2021 to July 2022. The genome expression profiles of 10 patients with IBD were compared to their matched controls. The sequences used in the design of the array were selected from GenBank®, dbEST and RefSeq. Whole blood RNA was extracted and hybridisation was conducted on the GeneChip® human genome U133A 2.0 array. The Scanner 3000 was used to scan high-resolution images and the General Comprehensive Operating System was used to read the results. Results: The upregulated genes shared between patients with UC and CD were RIT2, BCL2L1, MDM2 and FKBP8, while the downregulated genes they shared were the NFKBIB, DDX24 and RASA3 genes. Conclusions: Upregulated and downregulated gene expression patterns were detected in individuals with IBD, offering diagnostic potential and opportunities for treatment by targeting the associated pathways.

Targeting the DHX9 RNA Helicase to Induce Antitumor Immunity in Small-Cell Lung Cancer.

SUMMARY: Murayama and colleagues establish DHX9 as an exciting new target to induce viral mimicry and downstream antitumor immunity. The potential for use in combination with existing immune therapies is especially exciting in SCLC, an immunologically cold and deadly disease. See related article by Murayama et al., p. 468 (10) .

DDX6 modulates P-body and stress granule assembly, composition, and docking.

Stress granules and P-bodies are ribonucleoprotein (RNP) granules that accumulate during the stress response due to the condensation of untranslating mRNPs. Stress granules form in part by intermolecular RNA-RNA interactions and can be limited by components of the RNA chaperone network, which inhibits RNA-driven aggregation. Herein, we demonstrate that the DEAD-box helicase DDX6, a P-body component, can also limit the formation of stress granules, independent of the formation of P-bodies. In an ATPase, RNA-binding dependent manner, DDX6 limits the partitioning of itself and other RNPs into stress granules. When P-bodies are limited, proteins that normally partition between stress granules and P-bodies show increased accumulation within stress granules. Moreover, we show that loss of DDX6, 4E-T, and DCP1A increases P-body docking with stress granules, which depends on CNOT1 and PAT1B. Taken together, these observations identify a new role for DDX6 in limiting stress granules and demonstrate that P-body components can influence stress granule composition and docking with P-bodies.

DEAD box RNA helicase 5 is a new pro-viral host factor for Sindbis virus infection.

BACKGROUND: RNA helicases are emerging as key factors regulating host-virus interactions. The DEAD-box ATP-dependent RNA helicase DDX5, which plays an important role in many aspects of cellular RNA biology, was also found to either promote or inhibit viral replication upon infection with several RNA viruses. Here, our aim is to examine the impact of DDX5 on Sindbis virus (SINV) infection. METHODS: We analysed the interaction between DDX5 and the viral RNA using imaging and RNA-immunoprecipitation approaches. The interactome of DDX5 in mock- and SINV-infected cells was determined by mass spectrometry. We validated the interaction between DDX17 and the viral capsid by co- immunoprecipitation in the presence or absence of an RNase treatment. We determined the subcellular localization of DDX5, its cofactor DDX17 and the viral capsid protein by co-immunofluorescence. Finally, we investigated the impact of DDX5 depletion and overexpression on SINV infection at the viral protein, RNA and infectious particle accumulation level. The contribution of DDX17 was also tested by knockdown experiments. RESULTS: In this study we demonstrate that DDX5 interacts with the SINV RNA during infection. Furthermore, the proteomic analysis of the DDX5 interactome in mock and SINV-infected HCT116 cells identified new cellular and viral partners and confirmed the interaction between DDX5 and DDX17. Both DDX5 and DDX17 re-localize from the nucleus to the cytoplasm upon SINV infection and interact with the viral capsid protein. We also show that DDX5 depletion negatively impacts the viral replication cycle, while its overexpression has a pro-viral effect. Finally, we observed that DDX17 depletion reduces SINV infection, an effect which is even more pronounced in a DDX5-depleted background, suggesting a synergistic pro-viral effect of the DDX5 and DDX17 proteins on SINV. CONCLUSIONS: These results not only shed light on DDX5 as a novel and important host factor to the SINV life cycle, but also expand our understanding of the roles played by DDX5 and DDX17 as regulators of viral infections.

The DDX6/KIFC1 signaling axis, as regulated by YY1, contributes to the malignant behavior of pancreatic cancer.

Human DEAD/H box RNA helicase DDX6 acts as an oncogene in several different types of cancer, where it participates in RNA processing. Nevertheless, the role of DDX6 in pancreatic cancer (PC), together with the underlying mechanism, has yet to be fully elucidated. In the present study, compared with adjacent tissues, the level of DDX6 was abnormally increased in human PC tissues, and this increased level of expression was associated with poor prognosis. Furthermore, the role of DDX6 in PC was investigated by overexpressing or silencing the DDX6 in the PC cell lines, SW1990 and PaTu-8988t. A xenograft model was established by injecting nude mice with either DDX6-overexpressing or DDX6-silenced SW1990 cells. DDX6 overexpression promoted the proliferation and cell cycle transition, inhibited the cell apoptosis of PC cells, and accelerated tumor formation, whereas DDX6 knockdown elicited the opposite effects. DDX6 exerted positive effects on PC. RNA immunoprecipitation assay showed that DDX6 bound to kinesin family member C1 (KIFC1) mRNA, which was further confirmed by RNA pull-down assay. These results suggested that DDX6 positively regulated the expression of KIFC1. KIFC1 overexpression enhanced the proliferative capability of PC cells with DDX6 knockdown and inhibited their apoptosis. By contrast, DDX6 overexpression reversed the inhibitory effect of KIFC1 silencing on tumor proliferation. Subsequently, the transcription factor Yin Yang 1 (YY1) was shown to negatively regulate DDX6 at both the mRNA and protein levels. Dual-luciferase reporter assay verified that YY1 targeted the promoter of DDX6 and inhibited its transcription. High expression levels of YY1 decreased the proliferation of PC cells and promoted cell apoptosis, although these effects were reversed by DDX6 overexpression. Taken together, YY1 may target the DDX6/KIFC1 axis, thereby negatively regulating its expression, leading to an inhibitory effect on pancreatic tumor.

Induction of Viral Mimicry Upon Loss of DHX9 and ADAR1 in Breast Cancer Cells.

Detection of viral double-stranded RNA (dsRNA) is an important component of innate immunity. However, many endogenous RNAs containing double-stranded regions can be misrecognized and activate innate immunity. The IFN-inducible ADAR1-p150 suppresses dsRNA sensing, an essential function for adenosine deaminase acting on RNA 1 (ADAR1) in many cancers, including breast. Although ADAR1-p150 has been well established in this role, the functions of the constitutively expressed ADAR1-p110 isoform are less understood. We used proximity labeling to identify putative ADAR1-p110-interacting proteins in breast cancer cell lines. Of the proteins identified, the RNA helicase DHX9 was of particular interest. Knockdown of DHX9 in ADAR1-dependent cell lines caused cell death and activation of the dsRNA sensor PKR. In ADAR1-independent cell lines, combined knockdown of DHX9 and ADAR1, but neither alone, caused activation of multiple dsRNA sensing pathways leading to a viral mimicry phenotype. Together, these results reveal an important role for DHX9 in suppressing dsRNA sensing by multiple pathways. SIGNIFICANCE: These findings implicate DHX9 as a suppressor of dsRNA sensing. In some cell lines, loss of DHX9 alone is sufficient to cause activation of dsRNA sensing pathways, while in other cell lines DHX9 functions redundantly with ADAR1 to suppress pathway activation.

CircGLIS3 promotes gastric cancer progression by regulating the miR-1343-3p/PGK1 pathway and inhibiting vimentin phosphorylation.

BACKGROUND: Circular RNAs (circRNAs) have been proved to play crucial roles in the development of various cancers. However, the molecular mechanism of circGLIS3 involved in gastric cancer (GC) tumorigenesis has not been elucidated. METHODS: The higher expression level of circGLIS3 was identified in GC through RNA sequencing and subsequent tissue verification using Quantitative real-time PCR (qRT-PCR). A series of functional experiments in vitro and in vivo were performed to evaluated the effects of circGLIS3 on tumor growth and metastasis in GC. The interaction and regulation of circGLIS3/miR-1343-3p/PGK1 axis was confirmed by RNA pulldown, western blot, and rescue experiments. RIP and western blot were performed to demonstrate the role of circGLIS3 in regulating phosphorylation of VIMENTIN. We then used qRT-PCR and co culture system to trace circGLIS3 transmission via exosomal communication and identify the effect of exosomal circGLIS3 on gastric cancer and macrophages. Finally, RIP experiments were used to determine that EIF4A3 regulates circGLIS3 expression. RESULTS: CircGLIS3(hsa_circ_0002874) was significantly upregulated in GC tissues and high circGLIS3 expression was associated with advanced TNM stage and lymph node metastasis in GC patients. We discovered that overexpression of circGLIS3 promoted GC cell proliferation, migration, invasion in vitro and in vivo, while suppression of circGLIS3 exhibited the opposite effect. Mechanistically, circGLIS3 could sponge miR-1343-3p and up-regulate the expression of PGK1 to promote GC tumorigenesis. We also found that circGLIS3 reduced the phosphorylation of VIMENTIN at ser 83 site by binding with VIMENTIN. Moreover, it was proven that exosomal circGLIS3 could promote gastric cancer metastasis and the M2 type polarization of macrophages. In the final step, the mechanism of EIF4A3 regulating the generation of circGLIS3 was determined. CONCLUSION: Our findings demonstrate that circGLIS3 promotes GC progression through sponging miR-1343-3p and regulating VIMENTIN phosphorylation. CircGLIS3 is a potential therapeutic target for GC patients.

Complex Genomic Rearrangement Patterns in Malignant Pleural Mesothelioma due to Environmental Asbestos Exposure.

Malignant pleural mesothelioma (MPM) is a rare type of cancer, and its main risk factor is exposure to asbestos. Accordingly, our knowledge of the genomic structure of an MPM tumor is limited when compared to other cancers. In this study, we aimed to characterize complex genomic rearrangement patterns and variations to better understand the genomics of MPM tumors. We comparatively scanned 3 MPM tumor genomes by Whole-Genome Sequencing and High-Resolution SNP array. We also used various computational algorithms to detect both CNAs and complex chromosomal rearrangements. Genomic data obtained from each bioinformatics tool are interpreted comparatively to better understand CNAs and cancer-related Nucleotide variations in MPM tumors. In patients 1 and 2, we found pathogenic nucleotide variants of BAP1, RB1, and TP53. These two MPM genomes exhibited a highly rearranged chromosomal rearrangement pattern resembling Chromomanagesis particularly in the form of Chromoanasynthesis. In patient 3, we found nucleotide variants of important cancer-related genes, including TGFBR1, KMT2C, and PALLD, to have lower chromosomal rearrangement complexity compared with patients 1 and 2. We also detected several actionable nucleotide variants including XRCC1, ERCC2. We also discovered the SKA3-DDX10 fusion in two MPM genomes, which is a novel finding for MPM. We found that MPM genomes are very complex, suggesting that this highly rearranged pattern is strongly related to driver mutational status like BAP1, TP53 and RB1.