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Communications Biology Oct 2023Glioma is the most common primary malignancy of the central nervous system. Glioblastoma (GBM) has the highest degree of malignancy among the gliomas and the strongest...
Glioma is the most common primary malignancy of the central nervous system. Glioblastoma (GBM) has the highest degree of malignancy among the gliomas and the strongest resistance to chemotherapy and radiotherapy. Vasculogenic mimicry (VM) provides tumor cells with a blood supply independent of endothelial cells and greatly restricts the therapeutic effect of anti-angiogenic tumor therapy for glioma patients. Vascular endothelial growth factor receptor 2 (VEGFR2) and vascular endothelial cadherin (VE-cadherin) are currently recognized molecular markers of VM in tumors. In the present study, we show that pseudogene MAPK6P4 deficiency represses VEGFR2 and VE-cadherin protein expression levels, as well as inhibits the proliferation, migration, invasion, and VM development of GBM cells. The MAPK6P4-encoded functional peptide P4-135aa phosphorylates KLF15 at the S238 site, promoting KLF15 protein stability and nuclear entry to promote GBM VM formation. KLF15 was further confirmed as a transcriptional activator of LDHA, where LDHA binds and promotes VEGFR2 and VE-cadherin lactylation, thereby increasing their protein expression. Finally, we used orthotopic and subcutaneous xenografted nude mouse models of GBM to verify the inhibitory effect of the above factors on GBM VM development. In summary, this study may represent new targets for the comprehensive treatment of glioma.
Topics: Animals; Humans; Mice; Cell Line, Tumor; Endothelial Cells; Glioblastoma; Glioma; Neovascularization, Pathologic; Pseudogenes; Vascular Endothelial Growth Factor Receptor-2
PubMed: 37853052
DOI: 10.1038/s42003-023-05438-1 -
Clinical Genetics Mar 2018Digenic inheritance (DI) concerns pathologies with the simplest form of multigenic etiology, implicating more than 1 gene (and perhaps the environment). True DI is when... (Review)
Review
Digenic inheritance (DI) concerns pathologies with the simplest form of multigenic etiology, implicating more than 1 gene (and perhaps the environment). True DI is when biallelic or even triallelic mutations in 2 distinct genes, in cis or in trans, are necessary and sufficient to cause pathology with a defined diagnosis. In true DI, a heterozygous mutation in each of 2 genes alone is not associated with a recognizable phenotype. Well-documented diseases with true DI are so far rare and follow non-Mendelian inheritance. DI is also encountered when by serendipity, pathogenic mutations responsible for 2 distinct disease entities are co-inherited, leading to a mixed phenotype. Also, we can consider many true monogenic Mendelian conditions, which show impressively broad spectrum of phenotypes due to pseudo-DI, as a result of co-inheriting genetic modifiers (GMs). I am herewith reviewing examples of GM and embark on presenting some recent notable examples of true DI, with wider discussion of the literature. Undeniably, the advent of high throughput sequencing is bound to unravel more patients suffering with true DI conditions and elucidate many important GM, thus impacting precision medicine.
Topics: Alleles; Animals; Epistasis, Genetic; Genes, Modifier; Genetic Association Studies; Genetic Predisposition to Disease; Genotype; Humans; Models, Genetic; Multifactorial Inheritance; Mutation; Phenotype; Pseudogenes
PubMed: 28977688
DOI: 10.1111/cge.13150 -
Methods in Molecular Biology (Clifton,... 2021Pseudogenes have been considered as nonfunctional copies of their parental genes for a long time. Indeed, they have been often defined "junk DNA" or "transcriptional...
Pseudogenes have been considered as nonfunctional copies of their parental genes for a long time. Indeed, they have been often defined "junk DNA" or "transcriptional noise." However, with the identification of their involvement in several biological processes, the necessity of their study is inevitably growing up. The manipulation of pseudogene expression is complicated by their high homology with parental genes and by the fact that most of them work at the transcriptional level as noncoding RNAs. With the advent of CRISPR/Cas technology, these problems can be overcome. Particularly, as we describe in this chapter, it is possible: To perform genome editing, obtaining the complete elimination of the pseudogene genomic sequence (knock-out), preventing pseudogene transcription, introducing specific mutations in the pseudogene sequence, or introducing a specific sequence (knock-in). To positively or negatively manipulate pseudogene transcription. To target pseudogene RNA and negatively regulate its expression. To edit pseudogene DNA and RNA and alter a specific sequence. Moreover, CRISPR/Cas technology can be used as an RNA Binding Protein system for molecular biology techniques (such as RNA immunoprecipitation and pull-down), as well as for transcript tracking and live imaging.
Topics: CRISPR-Associated Protein 9; CRISPR-Cas Systems; DNA; Forecasting; Gene Editing; Gene Expression Regulation; Gene Targeting; Humans; Molecular Diagnostic Techniques; Mutation; Protein Domains; Pseudogenes; RNA; RNA, Messenger; Substrate Specificity; Transcription, Genetic
PubMed: 34165721
DOI: 10.1007/978-1-0716-1503-4_17 -
Experimental Hematology Nov 2021Pseudogenes are DNA regions comprising defective copies of functional genes, the majority of which were generated by RNA- or DNA-level duplications. They exist across... (Review)
Review
Pseudogenes are DNA regions comprising defective copies of functional genes, the majority of which were generated by RNA- or DNA-level duplications. They exist across almost all forms of life and account for about one-quarter of the annotated genes in the human genome. Although these have been considered nonfunctional for decades, a growing number of pseudogenes have been found to be transcribed and to play crucial regulatory roles. Accumulating evidence indicates that they regulate gene expression through molecular interactions at the protein, RNA, and DNA levels. However, pseudogenes are often excluded in multiple genomewide analyses and functional screening, and their biological activities remain to be systematically disclosed. Here, we summarize the features of and progress of research on pseudogenes, in addition to discussing what is unknown about these genetic elements. Our previous findings, together with evidence of their poor conservation, prompted us to propose that pseudogenes may contribute to primate- or human-specific regulation, especially in hematopoiesis.
Topics: Animals; Gene Expression Regulation, Developmental; Gene Expression Regulation, Leukemic; Hematopoiesis; Humans; Leukemia; Pseudogenes
PubMed: 34517065
DOI: 10.1016/j.exphem.2021.09.001 -
Current Opinion in Microbiology Feb 2015Pseudogenes are defined as fragments of once-functional genes that have been silenced by one or more nonsense, frameshift or missense mutations. Despite continuing... (Review)
Review
Pseudogenes are defined as fragments of once-functional genes that have been silenced by one or more nonsense, frameshift or missense mutations. Despite continuing increases in the speed of sequencing and annotating bacterial genomes, the identification and categorisation of pseudogenes remains problematic. Even when identified, pseudogenes are considered to be rare and tend to be ignored. On the contrary, pseudogenes are surprisingly prevalent and can persist for long evolutionary time periods, representing a record of once-functional genetic characteristics. Most importantly, pseudogenes provide an insight into prokaryotic evolutionary history as a record of phenotypic traits that have been lost. Focusing on the intracellular and symbiotic bacteria in which pseudogenes predominate, this review discusses the importance of identifying pseudogenes to fully understand the abilities of bacteria, and to understand prokaryotes within their evolutionary context.
Topics: Bacteria; Evolution, Molecular; Pseudogenes
PubMed: 25461580
DOI: 10.1016/j.mib.2014.11.012 -
Journal of Cellular and Molecular... Jan 2017The concept of competitive endogenous RNA (ceRNA) was first proposed by Salmena and colleagues. Evidence suggests that pseudogene RNAs can act as a 'sponge' through... (Review)
Review
The concept of competitive endogenous RNA (ceRNA) was first proposed by Salmena and colleagues. Evidence suggests that pseudogene RNAs can act as a 'sponge' through competitive binding of common miRNA, releasing or attenuating repression through sequestering miRNAs away from parental mRNA. In theory, ceRNAs refer to all transcripts such as mRNA, tRNA, rRNA, long non-coding RNA, pseudogene RNA and circular RNA, because all of them may become the targets of miRNA depending on spatiotemporal situation. As binding of miRNA to the target RNA is not 100% complementary, it is possible that one miRNA can bind to multiple target RNAs and vice versa. All RNAs crosstalk through competitively binding to miRNAvia miRNA response elements (MREs) contained within the RNA sequences, thus forming a complex regulatory network. The ratio of a subset of miRNAs to the corresponding number of MREs determines repression strength on a given mRNA translation or stability. An increase in pseudogene RNA level can sequester miRNA and release repression on the parental gene, leading to an increase in parental gene expression. A massive number of transcripts constitute a complicated network that regulates each other through this proposed mechanism, though some regulatory significance may be mild or even undetectable. It is possible that the regulation of gene and pseudogene expression occurring in this manor involves all RNAs bearing common MREs. In this review, we will primarily discuss how pseudogene transcripts regulate expression of parental genes via ceRNA network and biological significance of regulation.
Topics: Animals; Gene Expression; Gene Regulatory Networks; Humans; Pseudogenes; RNA; Response Elements
PubMed: 27561207
DOI: 10.1111/jcmm.12952 -
Methods in Molecular Biology (Clifton,... 2018Our understanding of cancer pathways has been changed by the determination of noncoding transcripts in the human genome in recent years. miRNAs and pseudogenes are key... (Review)
Review
Our understanding of cancer pathways has been changed by the determination of noncoding transcripts in the human genome in recent years. miRNAs and pseudogenes are key players of the noncoding transcripts from the genome, and alteration of their expression levels provides clues for significant biomarkers in pathogenesis of diseases. Especially, miRNAs and pseudogenes have both oncogenic and tumor-suppressive roles in each step of cancer tumorigenesis. In this current study, association between oncogenes and miRNAs-pseudogenes was reviewed and determined in human cancer by the CellMiner web-tool.
Topics: Biomarkers, Tumor; Databases, Nucleic Acid; Gene Expression Regulation, Neoplastic; Humans; MicroRNAs; Neoplasms; Oncogenes; Pseudogenes
PubMed: 29086367
DOI: 10.1007/978-1-4939-7435-1_3 -
International Journal of Molecular... Apr 2018Noncoding RNAs (ncRNAs) constitute the majority of the human transcribed genome. This largest class of RNA transcripts plays diverse roles in a multitude of cellular... (Review)
Review
Noncoding RNAs (ncRNAs) constitute the majority of the human transcribed genome. This largest class of RNA transcripts plays diverse roles in a multitude of cellular processes, and has been implicated in many pathological conditions, especially cancer. The different subclasses of ncRNAs include microRNAs, a class of short ncRNAs; and a variety of long ncRNAs (lncRNAs), such as lincRNAs, antisense RNAs, pseudogenes, and circular RNAs. Many studies have demonstrated the involvement of these ncRNAs in competitive regulatory interactions, known as competing endogenous RNA (ceRNA) networks, whereby lncRNAs can act as microRNA decoys to modulate gene expression. These interactions are often interconnected, thus aberrant expression of any network component could derail the complex regulatory circuitry, culminating in cancer development and progression. Recent integrative analyses have provided evidence that new computational platforms and experimental approaches can be harnessed together to distinguish key ceRNA interactions in specific cancers, which could facilitate the identification of robust biomarkers and therapeutic targets, and hence, more effective cancer therapies and better patient outcome and survival.
Topics: Biomarkers, Tumor; Carcinogenesis; Gene Expression; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Humans; MicroRNAs; Neoplasms; Pseudogenes; RNA; RNA Transport; RNA, Circular; RNA, Long Noncoding
PubMed: 29702599
DOI: 10.3390/ijms19051310 -
Nature Reviews. Genetics May 2016The competitive endogenous RNA (ceRNA) hypothesis proposes that transcripts with shared microRNA (miRNA) binding sites compete for post-transcriptional control. This... (Review)
Review
The competitive endogenous RNA (ceRNA) hypothesis proposes that transcripts with shared microRNA (miRNA) binding sites compete for post-transcriptional control. This hypothesis has gained substantial attention as a unifying function for long non-coding RNAs, pseudogene transcripts and circular RNAs, as well as an alternative function for messenger RNAs. Empirical evidence supporting the hypothesis is accumulating but not without attracting scepticism. Recent studies that model transcriptome-wide binding-site abundance suggest that physiological changes in expression of most individual transcripts will not compromise miRNA activity. In this Review, we critically evaluate the evidence for and against the ceRNA hypothesis to assess the impact of endogenous miRNA-sponge interactions.
Topics: Animals; Gene Expression Regulation; Humans; MicroRNAs; Pseudogenes; RNA Interference; RNA, Long Noncoding; Transcriptome
PubMed: 27040487
DOI: 10.1038/nrg.2016.20 -
Methods in Molecular Biology (Clifton,... 2021Pseudogenes are commonly labeled as "junk DNA" given their perceived nonfunctional status. However, the advent of large-scale genomics projects prompted a revisit of... (Review)
Review
Pseudogenes are commonly labeled as "junk DNA" given their perceived nonfunctional status. However, the advent of large-scale genomics projects prompted a revisit of pseudogene biology, highlighting their key functional and regulatory roles in numerous diseases, including cancers. Integrative analyses of cancer data have shown that pseudogenes can be transcribed and even translated, and that pseudogenic DNA, RNA, and proteins can interfere with the activity and function of key protein coding genes, acting as regulators of oncogenes and tumor suppressors. Capitalizing on the available clinical research, we are able to get an insight into the spread and variety of pseudogene biomarker and therapeutic potential. In this chapter, we describe pseudogenes that fulfill their role as diagnostic or prognostic biomarkers, both as unique elements and in collaboration with other genes or pseudogenes. We also report that the majority of prognostic pseudogenes are overexpressed and exert an oncogenic role in colorectal, liver, lung, and gastric cancers. Finally, we highlight a number of pseudogenes that can establish future therapeutic avenues.
Topics: Antineoplastic Agents; Biomarkers, Tumor; DNA, Neoplasm; Forecasting; Gene Expression Regulation, Neoplastic; Genes, Neoplasm; Humans; Molecular Targeted Therapy; Neoplasms; Organ Specificity; Prognosis; Pseudogenes; Transcription, Genetic
PubMed: 34165724
DOI: 10.1007/978-1-0716-1503-4_20