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International Journal of Biological... 2023Non-small cell lung cancer (NSCLC) is a highly lethal disease worldwide. We found the pseudogene-derived lncRNA PTTG3P is upregulated in NSCLC and associated with larger...
Non-small cell lung cancer (NSCLC) is a highly lethal disease worldwide. We found the pseudogene-derived lncRNA PTTG3P is upregulated in NSCLC and associated with larger tumor size, advanced staging, and poor prognosis. This study investigated the oncogenic roles and mechanisms of PTTG3P in NSCLC. We demonstrate that PTTG3P promoted NSCLC cell proliferation, migration, tumorigenesis, and metastasis while inhibiting apoptosis and . Mechanistically, PTTG3P formed an RNA-protein complex with ILF3 to maintain MAP2K6 and E2F1 mRNA stability, two oncogenic factors involved in NSCLC progression. RNA-seq revealed MAP2K6 and E2F1 were downregulated upon PTTG3P knockdown. RIP and RNA stability assays showed PTTG3P/ILF3 interaction stabilized MAP2K6 and E2F1 transcripts. Interestingly, E2F1 transcriptionally upregulated PTTG3P by binding its promoter, forming a positive feedback loop. Knockdown of E2F1 or PTTG3P attenuated their mutual regulatory effects on cell growth and migration. Thus, a PTTG3P/ILF3/E2F1 axis enhances oncogene expression to promote NSCLC pathogenesis. Our study reveals PTTG3P exerts oncogenic functions in NSCLC via mRNA stabilization and a feedback loop, highlighting its potential as a prognostic biomarker and therapeutic target.
Topics: Humans; RNA, Long Noncoding; Carcinoma, Non-Small-Cell Lung; Feedback; Lung Neoplasms; Cell Transformation, Neoplastic; Carcinogenesis; RNA Stability; Nuclear Factor 90 Proteins; E2F1 Transcription Factor
PubMed: 37705754
DOI: 10.7150/ijbs.81738 -
Frontiers in Genetics 2023Classical-like Ehlers-Danlos syndrome (clEDS) is an autosomal recessive disorder caused by complete absence of tenascin-X resulting from biallelic variation in . Thus...
Classical-like Ehlers-Danlos syndrome (clEDS) is an autosomal recessive disorder caused by complete absence of tenascin-X resulting from biallelic variation in . Thus far, 50 patients from 43 families with biallelic variants have been identified. Accurate detection of variants is challenging because of the presence of the pseudogene , which can undergo non-allelic homologous recombination. Therefore, we designed a genetic screening system that is performed using similar operations to other next-generation sequencing (NGS) panel analyses and can be applied to accurately detect variants and the recombination of -derived sequences into . Using this system, we identified biallelic variants in nine unrelated clEDS patients. -derived variations were found in >75% of the current cohort, comparable to previous reports. The current cohort generally exhibited similar clinical features to patients in previous reports, but had a higher frequency of gastrointestinal complications (e.g., perforation, diverticulitis, gastrointestinal bleeding, intestinal obstruction, rectal/anal prolapse, and gallstones). This report is the first to apply an NGS-based screening for variants and represents the third largest cohort of clEDS, highlighting the importance of increasing awareness of the risk of gastrointestinal complications.
PubMed: 37712068
DOI: 10.3389/fgene.2023.1234804 -
Journal of Cancer Research and Clinical... Nov 2023Hepatocellular carcinoma (HCC) remains a highly deadly malignant tumor with high recurrence and metastasis rates. Cancer stem cells (CSCs) are involved in tumor...
PURPOSE
Hepatocellular carcinoma (HCC) remains a highly deadly malignant tumor with high recurrence and metastasis rates. Cancer stem cells (CSCs) are involved in tumor metastasis, recurrence, and resistance to drugs, which have attracted widespread attention in recent years. Research has shown that pseudogenes may regulate stemness to promote the progression of HCC, but its specific mechanisms and impact on prognosis remain unclear.
METHODS
In this study, clinical prognosis information of HCC was first downloaded from The Cancer Genome Atlas (TCGA) database. Then we calculated the mRNA expression-based stemness index (mRNAsi) of HCC. We also screened the differentially expressed pseudogene (DEPs) and conducted univariate Cox regression analysis to investigate their effect on the prognosis of HCC. Further, genomic mutation frequency analysis and weighted gene co-expression network analysis (WGCNA) were performed to compare the role of pseudogenes and stemness in promoting the progression of HCC. Finally, we conducted the correlation analysis to examine the potential mechanism of pseudogenes regulating stemness to promote the progression of HCC and detected the possible pathways through the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis.
RESULTS
Herein, we revealed that the high stemness of HCC correlated with an unfavorable prognosis. We obtained 31 up-regulated and 8 down-regulated DEPs in HCC and screened CTB-63M22.1, a poor prognostic indicator of HCC. In addition, CTB-63M22.1 had a mutation frequency similar to mRNAsi and acted in a module similar to that of mRNAsi on HCC. We then screened two RNA-binding proteins (RBPs) LIN28B and NOP56 with the highest correlation with stemness. We also discovered that they were primarily enriched in the biological process as examples of mitotic nuclear division and cell cycle.
CONCLUSIONS
Collectively, these results revealed that pseudogenes CTB-63M22.1 may regulate cancer stemness by regulating RBPs, suggesting that CTB-63M22.1 may serve as an innovative therapeutic target and a reliable prognostic marker for HCC.
PubMed: 37553422
DOI: 10.1007/s00432-023-05241-9 -
Cancer Medicine Oct 2023Long noncoding RNAs (lncRNAs) play crucial roles in regulating various hallmarks in cancers. Triple-negative (Estrogen receptor, ER; Human epidermal growth factor... (Review)
Review
INTRODUCTION
Long noncoding RNAs (lncRNAs) play crucial roles in regulating various hallmarks in cancers. Triple-negative (Estrogen receptor, ER; Human epidermal growth factor receptor 2, HER2; Progesterone receptor, PR) breast cancer (TNBC) is the most aggressive form of breast cancers with a poor prognosis and no available molecular targeted therapy.
METHODS
We reviewed the current literature on the roles of lncRNAs in the pathogenesis, therapy resistance, and prognosis of patients with TBNC.
RESULTS
LncRNAs are associated with TNBC pathogenesis, therapy resistance, and prognosis. For example, lncRNAs such as small nucleolar RNA host gene 12 (SNHG12), highly upregulated in liver cancer (HULC) HOX transcript antisense intergenic RNA (HOTAIR), lincRNA-regulator of reprogramming (LincRNA-ROR), etc., are aberrantly expressed in TNBC and are involved in the pathogenesis of the disease. LncRNAs act as a decoy, scaffold, or sponge to regulate the expression of genes, miRNAs, and transcription factors associated with pathogenesis and progression of TNBC. Moreover, lncRNAs such as ferritin heavy chain 1 pseudogene 3 (FTH1P3), BMP/OP-responsive gene (BORG) contributes to the therapy resistance property of TNBC through activating ABCB1 (ATP-binding cassette subfamily B member 1) drug efflux pumps by increasing DNA repair capacity or by inducing signaling pathway involved in therapeutic resistance.
CONCLUSION
In this review, we outline the functions of various lncRNAs along with their molecular mechanisms involved in the pathogenesis, therapeutic resistance of TBNC. Also, the prognostic implications of lncRNAs in patients with TNBC is illustrated. Moreover, potential strategies targeting lncRNAs against highly aggressive TNBC is discussed in this review.
Topics: Humans; RNA, Long Noncoding; Triple Negative Breast Neoplasms; MicroRNAs; Prognosis; Gene Expression Regulation, Neoplastic
PubMed: 37795578
DOI: 10.1002/cam4.6600 -
Molecular Ecology Resources Jul 2023Inserts of DNA from extranuclear sources, such as organelles and microbes, are common in eukaryote nuclear genomes. However, sequence similarity between the nuclear and...
Inserts of DNA from extranuclear sources, such as organelles and microbes, are common in eukaryote nuclear genomes. However, sequence similarity between the nuclear and extranuclear DNA, and a history of multiple insertions, make the assembly of these regions challenging. Consequently, the number, sequence and location of these vagrant DNAs cannot be reliably inferred from the genome assemblies of most organisms. We introduce two statistical methods to estimate the abundance of nuclear inserts even in the absence of a nuclear genome assembly. The first (intercept method) only requires low-coverage (<1×) sequencing data, as commonly generated for population studies of organellar and ribosomal DNAs. The second method additionally requires that a subset of the individuals carry extranuclear DNA with diverged genotypes. We validated our intercept method using simulations and by re-estimating the frequency of human NUMTs (nuclear mitochondrial inserts). We then applied it to the grasshopper Podisma pedestris, exceptional for both its large genome size and reports of numerous NUMT inserts, estimating that NUMTs make up 0.056% of the nuclear genome, equivalent to >500 times the mitochondrial genome size. We also re-analysed a museomics data set of the parrot Psephotellus varius, obtaining an estimate of only 0.0043%, in line with reports from other species of bird. Our study demonstrates the utility of low-coverage high-throughput sequencing data for the quantification of nuclear vagrant DNAs. Beyond quantifying organellar inserts, these methods could also be used on endosymbiont-derived sequences. We provide an R implementation of our methods called "vagrantDNA" and code to simulate test data sets.
Topics: Humans; DNA, Mitochondrial; Mitochondria; Eukaryota; Genome, Mitochondrial; Cell Nucleus; Sequence Analysis, DNA; Phylogeny
PubMed: 36740932
DOI: 10.1111/1755-0998.13764 -
Nucleic Acids Research Jul 2023Several atlasing efforts aim to profile human gene and protein expression across tissues, cell types and cell lines in normal physiology, development and disease. One...
Several atlasing efforts aim to profile human gene and protein expression across tissues, cell types and cell lines in normal physiology, development and disease. One utility of these resources is to examine the expression of a single gene across all cell types, tissues and cell lines in each atlas. However, there is currently no centralized place that integrates data from several atlases to provide this type of data in a uniform format for visualization, analysis and download, and via an application programming interface. To address this need, GeneRanger is a web server that provides access to processed data about gene and protein expression across normal human cell types, tissues and cell lines from several atlases. At the same time, TargetRanger is a related web server that takes as input RNA-seq data from profiled human cells and tissues, and then compares the uploaded input data to expression levels across the atlases to identify genes that are highly expressed in the input and lowly expressed across normal human cell types and tissues. Identified targets can be filtered by transmembrane or secreted proteins. The results from GeneRanger and TargetRanger are visualized as box and scatter plots, and as interactive tables. GeneRanger and TargetRanger are available from https://generanger.maayanlab.cloud and https://targetranger.maayanlab.cloud, respectively.
Topics: Humans; Cell Line; Proteomics; Pseudogenes; RNA-Seq; Software; Internet
PubMed: 37166966
DOI: 10.1093/nar/gkad399 -
MedRxiv : the Preprint Server For... Oct 2023Biallelic mutations in result in Gaucher disease (GD), the inherited deficiency of glucocerebrosidase. Variants in are also a common genetic risk factor for Parkinson...
Biallelic mutations in result in Gaucher disease (GD), the inherited deficiency of glucocerebrosidase. Variants in are also a common genetic risk factor for Parkinson disease (PD). Currently, some PD centers screen for mutant alleles to stratify patients who may ultimately benefit from -targeted therapeutics. However, accurately detecting variants, especially recombinant alleles resulting from a crossover between and its pseudogene, is challenging, impacting studies of both GD and -associated parkinsonism. Recently, the software tool Gauchian was introduced to identify variants from whole genome sequencing. We evaluated Gauchian in 90 Sanger-sequenced patients with GD and five heterozygotes. While Gauchian genotyped most patients correctly, it missed some rare or mutations due to its limited internal database and over-reliance on intergenic structural variants. This resulted in misreported homozygosity, incomplete genotypes, and undetected recombination events, limiting Gauchian's utility in variant screening and precluding its use in diagnostics.
PubMed: 37986861
DOI: 10.1101/2023.10.26.23297627 -
Scientific Reports Nov 2023Hematopoietic cancers (HCs) are a heterogeneous group of malignancies that affect blood, bone marrow and lymphatic system. Here, by analyzing 1960 RNA-Seq samples from...
Hematopoietic cancers (HCs) are a heterogeneous group of malignancies that affect blood, bone marrow and lymphatic system. Here, by analyzing 1960 RNA-Seq samples from three independent datasets, we explored the co-expression landscape in HCs, by inferring gene co-expression networks (GCNs) with four cancer phenotypes (B and T-cell acute leukemia -BALL, TALL-, acute myeloid leukemia -AML-, and multiple myeloma -MM-) as well as non-cancer bone marrow. We characterized their structure (topological features) and function (enrichment analyses). We found that, as in other types of cancer, the highest co-expression interactions are intra-chromosomal, which is not the case for control GCNs. We also detected a highly co-expressed group of overexpressed pseudogenes in HC networks. The four GCNs present only a small fraction of common interactions, related to canonical functions, like immune response or erythrocyte differentiation. With this approach, we were able to reveal cancer-specific features useful for detection of disease manifestations.
Topics: Humans; Hematologic Neoplasms; Bone Marrow; Leukemia, Myeloid, Acute; Leukemia-Lymphoma, Adult T-Cell
PubMed: 37963971
DOI: 10.1038/s41598-023-46655-2 -
Cancer Research Oct 2023Resistance to endocrine therapy represents a major concern for patients with estrogen receptor α-positive (ERα+) breast cancer. Endocrine therapy resistance is...
UNLABELLED
Resistance to endocrine therapy represents a major concern for patients with estrogen receptor α-positive (ERα+) breast cancer. Endocrine therapy resistance is commonly mediated by activated E2F signaling. A better understanding of the mechanisms governing E2F1 activity in resistant cells could reveal strategies for overcoming resistance. Here, we identified the long noncoding RNA (lncRNA) actin gamma 1 pseudogene 25 (AGPG) as a regulator of E2F1 activity in endocrine-resistant breast cancer. Expression of AGPG was increased in endocrine-resistant breast cancer cells, which was driven by epigenomic activation of an enhancer. AGPG was also abnormally upregulated in patient breast tumors, especially in the luminal B subtype, and high AGPG expression was associated with poor survival of patients with ERα+ breast cancer receiving endocrine therapy. The upregulation of AGPG mediated resistance to endocrine therapy and cyclin-dependent kinase 4/6 inhibition in breast cancer cells. Mechanistically, AGPG physically interacted with PURα, thus releasing E2F1 from PURα and leading to E2F1 signaling activation in ERα+ breast cancer cells. In patients with breast cancer, E2F1 target genes were positively and negatively correlated with expression of AGPG and PURα, respectively. Coadministration of chemically modified AGPG siRNA and tamoxifen strongly suppressed tumor growth in endocrine-resistant cell line-derived xenografts. Together, these results demonstrate that AGPG can drive endocrine therapy resistance and indicate that it is a promising biomarker and potential therapeutic target in breast cancer.
SIGNIFICANCE
Blockade of formation of the PURα/E2F1 complex by lncRNA AGPG activates E2F1 and promotes endocrine resistance, providing potential strategies for combatting endocrine-resistant breast cancer.
PubMed: 37463119
DOI: 10.1158/0008-5472.CAN-23-0015 -
Gene Aug 2023MicroRNAs (miRNAs) are a class of single-stranded small non-coding RNAs with a length of 21-23 nucleotides. One such miRNA, miR-492, is located in the KRT19 pseudogene 2... (Review)
Review
MicroRNAs (miRNAs) are a class of single-stranded small non-coding RNAs with a length of 21-23 nucleotides. One such miRNA, miR-492, is located in the KRT19 pseudogene 2 (KRT19P2) of chromosome 12q22 and can also be generated from the processing of the KRT19 transcript at chromosome 17q21. Aberrant expression of miR-492 has been observed in cancers of various physiological systems. miR-492 has been shown to target at least 11 protein-coding genes, which are involved in the regulation of cellular behaviors such as growth, cell cycle, proliferation, epithelial- mesenchymal transition (EMT), invasion and migration. The expression of miR-492 can be regulated by both endogenous and exogenous factors. Furthermore, miR-492 is involved in the regulation of several signaling pathways including the PI3K/AKT signaling pathway, WNT/β-catenin signaling pathway, and MAPK signaling pathway. High expression of miR-492 has been closely associated with shorter overall survival in patients with gastric cancer, ovarian cancer, oropharyngeal carcinoma, colorectal cancer, and hepatocellular carcinoma. This study systematically summarizes the related research findings on miR-492, providing potential insights for future investigations.
Topics: Humans; Phosphatidylinositol 3-Kinases; MicroRNAs; Carcinoma, Hepatocellular; Wnt Signaling Pathway; Liver Neoplasms; Gene Expression Regulation, Neoplastic; Cell Movement; Cell Proliferation; Cell Line, Tumor; Epithelial-Mesenchymal Transition
PubMed: 37295631
DOI: 10.1016/j.gene.2023.147518