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Post-translational modifications play crucial roles in regulating protein functions and stabilities. PTEN is a critical tumor suppressor involved in regulating cellular proliferation, survival, and migration processes. However, dysregulation of PTEN is common in various human cancers. PTEN stability and activation/suppression have been extensively studied in the context of tumorigenesis through inhibition of the PI3K/AKT signaling pathway. PTEN undergoes various post-translational modifications, primarily including phosphorylation, acetylation, ubiquitination, SUMOylation, neddylation, and oxidation, which finely tune its activity and stability. Generally, phosphorylation modulates PTEN activity through its lipid phosphatase function, leading to altered power of the signaling pathways. Acetylation influences PTEN protein stability and degradation rate. SUMOylation has been implicated in PTEN localization and interactions with other proteins, affecting its overall function. Neddylation, as a novel modification of PTEN, is a key regulatory mechanism in the loss of tumor suppressor function of PTEN. Although current therapeutic approaches focus primarily on inhibiting PI3 kinase, understanding the post-translational modifications of PTEN could help provide new therapeutic strategies that can restore PTEN's role in PIP3-dependent tumors. The present review summarizes the major recent developments in the regulation of PTEN protein level and activity. We expect that these insights will contribute to better understanding of this critical tumor suppressor and its potential implications for cancer therapy in the future.
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Objective: The objective of this study is to investigate the aggressive infiltration of glioblastoma into adjacent brain tissue, considering its challenging prognosis. Initially classified as an intergenic non-coding RNA, we aim to elucidate the functional implications of LINC01138 in glioblastoma. Method: Glioma grading was performed utilizing H&E staining, which unveiled distinct nuclear morphology in high-grade gliomas. The downregulation of LINC01138 in glioma tissues was corroborated through qRT-PCR and gel electrophoresis, concurrently identifying two previously unrecognized LINC01138 isoforms. Expression profiling of all four LINC01138 isoforms was executed in glioma cell lines (A172, SHG-44, U251, U87-MG). The impact of LINC01138 overexpression in U87-MG and U251 cells was evaluated for cell proliferation, migration, and invasion through cell counting, CCK-8 analysis, and Transwell assays. Furthermore, the suppression of LINC01138 in SHG-44 cells substantiated its involvement in fostering tumor malignancy. Transcriptome sequencing revealed the inhibitory influence of LINC01138 on IGF1 expression. These findings contribute to an enriched comprehension of glioma biology by exploring the engagement of LINC01138 through diverse methodologies, thereby elucidating its potential therapeutic significance. Results: Our investigation elucidates the intricate involvement of LINC01138 in gliomas. High-grade gliomas are characterized by elevated cell density and distinctive nuclear features. LINC01138 demonstrates a substantial downregulation in glioma tissues, with the identification of two novel isoforms. The expression of all four LINC01138 isoforms is notably diminished in both glioma tissues and cell lines. Elevated expression of LINC01138 demonstrates inhibitory effects on tumor cell proliferation, migration, and invasion, while its downregulation exacerbates malignancy. The regulatory function of LINC01138 as a repressor of IGF1 expression was elucidated through transcriptome sequencing. Conclusion: The LINC01138 isoforms display notable tumor-suppressive effects, suggesting a promising potential for impeding glioma progression.
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Protein methylation, similar to DNA methylation, primarily involves post-translational modification (PTM) targeting residues of nitrogen-containing side-chains and other residues. Protein arginine methylation, occurred on arginine residue, is mainly mediated by protein arginine methyltransferases (PRMTs), which are ubiquitously present in a multitude of organisms and are intricately involved in the regulation of numerous biological processes. Specifically, PRMTs are pivotal in the process of gene transcription regulation, and protein function modulation. Abnormal arginine methylation, particularly in histones, can induce dysregulation of gene expression, thereby leading to the development of cancer. The recent advancements in modification mediated by PRMTs and cancer research have had a profound impact on our understanding of the abnormal modification involved in carcinogenesis and progression. This review will provide a defined overview of these recent progression, with the aim of augmenting our knowledge on the role of PRMTs in progression and their potential application in cancer therapy.
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Post-transcriptional RNA modification is an emerging epigenetic control mechanism in cells that is important in many different cellular and organismal processes. N6-methyladenosine (m6A) is one of the most prevalent, prolific, and ubiquitous internal transcriptional alterations in eukaryotic mRNAs, making it an important topic in the field of Epigenetics. m6A methylation acts as a dynamical regulatory process that regulates the activity of genes and participates in multiple physiological processes, by supporting multiple aspects of essential mRNA metabolic processes, including pre-mRNA splicing, nuclear export, translation, miRNA synthesis, and stability. Extensive research has linked aberrations in m6A modification and m6A-associated proteins to a wide range of human diseases. However, the impact of m6A on mRNA metabolism and its pathological connection between m6A and other non-communicable diseases, including cardiovascular disease, neurodegenerative disorders, liver diseases, and cancer remains in fragmentation. Here, we review the existing understanding of the overall role of mechanisms by which m6A exerts its activities and address new discoveries that highlight m6A's diverse involvement in gene expression regulation. We discuss m6A deposition on mRNA and its consequences on degradation, translation, and transcription, as well as m6A methylation of non-coding chromosomal-associated RNA species. This study could give new information about the molecular process, early detection, tailored treatment, and predictive evaluation of human non-communicable diseases like cancer. We also explore more about new data that suggests targeting m6A regulators in diseases may have therapeutic advantages.
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As a novel post-translational modification of proteins, succinylation is widely present in both prokaryotes and eukaryotes. By regulating protein translocation and activity, particularly involved in regulation of gene expression, succinylation actively participates in diverse biological processes such as cell proliferation, differentiation and metabolism. Dysregulation of succinylation is closely related to many diseases. Consequently, it has increasingly attracted attention from basic and clinical researchers. For a thorough understanding of succinylation dysregulation and its implications for disease development, such as inflammation, tumors, cardiovascular and neurological diseases, this paper provides a comprehensive review of the research progress on abnormal succinylation. This understanding of association of dysregulation of succinylation with pathological processes will provide valuable directions for disease prevention/treatment strategies as well as drug development.
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Noroviruses (NoVs) are the chief cause of acute viral gastroenteritis worldwide. By employing the major capsid protein VP1 of a GII.6 NoV strain as an immunogen, we generated two monoclonal antibodies (mAbs) with wide-spectrum binding activities against NoV genogroup II (GII) VP1 proteins. One mAb (10G7) could bind to native and denatured GII-specific VP1 proteins. The other mAb (10F2) could bind to all tested native GII VP1 proteins, but not to denatured GII.3, GII.4, GII.7, or GII.17 VP1 proteins. Using GII.6/GII.4 fusion proteins, the mAb 10F2 binding region was confirmed to be located in the C-terminal P1 domain. An enzyme-linked immunosorbent assay based on peptides covering the P domain did not detect any binding. Using a panel of VP1 proteins with swapped regions, deletions, and mutations, the mAb 10F2 binding region was determined to be located between residues 496 and 513. However, the residue(s) responsible for its varied binding affinity for different denatured GII VP1 proteins remain to be identified. In summary, two NoV GII-specific cross-reactive mAbs were generated, and their binding regions were determined. Our results might facilitate the detection and immunogenic study of NoVs.
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Anticorpos Monoclonais , Anticorpos Antivirais , Proteínas do Capsídeo , Epitopos , Norovirus , Norovirus/genética , Norovirus/imunologia , Anticorpos Monoclonais/imunologia , Proteínas do Capsídeo/imunologia , Proteínas do Capsídeo/genética , Proteínas do Capsídeo/química , Epitopos/imunologia , Epitopos/genética , Anticorpos Antivirais/imunologia , Animais , Antígenos Virais/imunologia , Antígenos Virais/genética , Camundongos , Humanos , Infecções por Caliciviridae/virologia , Infecções por Caliciviridae/imunologia , Camundongos Endogâmicos BALB C , Mapeamento de Epitopos , Reações CruzadasRESUMO
Virus-induced genomic remodeling and altered gene expression contribute significantly to cancer development. Some oncogenic viruses such as Human papillomavirus (HPV) specifically trigger certain cancers by integrating into the host's DNA, disrupting gene regulation linked to cell growth and migration. The effect can be through direct integration of viral genomes into the host genome or through indirect modulation of host cell pathways/proteins by viral proteins. Viral proteins also disrupt key cellular processes like apoptosis and DNA repair by interacting with host molecules, affecting signaling pathways. These disruptions lead to mutation accumulation and tumorigenesis. This review focuses on recent studies exploring virus-mediated genomic structure, altered gene expression, and epigenetic modifications in tumorigenesis.
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Carcinogênese , Transformação Celular Neoplásica , Humanos , Carcinogênese/genética , Proteínas Virais , Genômica , Expressão GênicaRESUMO
Modifications of protein post-translation are critical modulatory processes, which alters target protein biological activityï¼function and/or location, even involved in pathogenesis of some diseases. So far, there are at least 16 types of post-translation modifications identified, particularly through recent mass spectrometry analysis. Among them, succinylation (Ksuc) on protein lysine residues causes a variety of biological changes. Succinylation of proteins contributes to many cellular processes such as proliferation, growth, differentiation, metabolism and even tumorigenesis. Mechanically, Succinylation leads to conformation alteration of chromatin or remodeling. As a result, transcription/expression of target genes is changed accordingly. Recent research indicated that succinylation mainly contributes to metabolism modulations, from gene expression of metabolic enzymes to their activity modulation. In this review, we will conclude roles of succinylation in metabolic regulation of glucose, fat, amino acids and related metabolic disease launched by aberrant succinylation. Our goal is to stimulate extra attention to these still not well researched perhaps important succinylation modification on proteins and cell processes.
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RNA-binding proteins (RBPs) modulate the expression level of several target RNAs (such as mRNAs) post-transcriptionally through interactions with unique binding sites in the 3'-untranslated region. There is mounting information that suggests RBP dysregulation plays a significant role in carcinogenesis. However, the function of FMR1 autosomal homolog 1(FXR1) in malignancies is just beginning to be unveiled. Due to the diversity of their RNA-binding domains and functional adaptability, FXR1 can regulate diverse transcript processing. Changes in FXR1 interaction with RNA networks have been linked to the emergence of cancer, although the theoretical framework defining these alterations in interaction is insufficient. Alteration in FXR1 expression or localization has been linked to the mRNAs of cancer suppressor genes, cancer-causing genes, and genes involved in genomic expression stability. In particular, FXR1-mediated gene regulation involves in several cellular phenomena related to cancer growth, metastasis, epithelial-mesenchymal transition, senescence, apoptosis, and angiogenesis. FXR1 dysregulation has been implicated in diverse cancer types, suggesting its diagnostic and therapeutic potential. However, the molecular mechanisms and biological effects of FXR1 regulation in cancer have yet to be understood. This review highlights the current knowledge of FXR1 expression and function in various cancer situations, emphasizing its functional variety and complexity. We further address the challenges and opportunities of targeting FXR1 for cancer diagnosis and treatment and propose future directions for FXR1 research in oncology. This work intends to provide an in-depth review of FXR1 as an emerging oncotarget with multiple roles and implications in cancer biology and therapy.
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Neoplasias , Proteínas de Ligação a RNA , Humanos , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo , RNA Mensageiro/genética , RNA , Neoplasias/genética , Regulação da Expressão Gênica , Proteína do X Frágil da Deficiência Intelectual/metabolismoRESUMO
Prostate cancer (PC) is one of the most common cancers in men and becoming the second leading cause of cancer fatalities. At present, the lack of effective strategies for prognosis of PC patients is still a problem to be solved. Therefore, it is significant to identify potential gene signatures for PC patients' prognosis. Here, we summarized 71 different prognostic gene signatures for PC and concluded 3 strategies for signature construction after extensive investigation. In addition, 14 genes frequently appeared in 71 different gene signatures, which enriched in mitotic and cell cycle. This review provides extensive understanding and integrated analysis of current prognostic signatures of PC, which may help researchers to construct gene signatures of PC and guide future clinical treatment.
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Obesity, a worldwide epidemic in recent years, is mainly due to the uncontrolled development of adipose tissues, which includes adipocyte hypertrophy and hyperplasia. Adipocyte differentiation is a process involving multiple transcription factor cascades, and the exact mechanism has not yet been defined. As a bHLH transcription factor, Twist1 exerts its activity by forming homo- or heterodimers with other factors. In this study, we showed Twist1 restricts adipogenesis through PPARγ. Expression of various differentiation markers (including PPARγ and adiponectin) and triglyceride-containing lipid droplets were decreased with overexpression of Twist1. Pathway enrichment analysis of RNA-seq data showed that differentially expressed genes (DEGs) caused by Twist1 overexpression were significantly related to lipolysis and PPARγ signaling. This implicates that Twist1 plays important regulatory roles in these processes. ChIP and dual luciferase assays showed that Twist1 could bind either PPARγ or adiponectin promoter to repress their respective transcription or directly to PPARγ protein to regulate its transcriptional activity. Furthermore, Twist1 directly interacted RXRα, which usually forms heterodimer with PPARγ to regulate adipogenesis. Taken together, our results suggest that Twist1 is an inhibitory modulator of adipogenesis and its function is likely through direct interaction with PPARγ protein or its gene promoter.
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Adiponectina , PPAR gama , Camundongos , Animais , Adiponectina/genética , Adiponectina/metabolismo , PPAR gama/genética , PPAR gama/metabolismo , Adipócitos/metabolismo , Regulação da Expressão Gênica , Fatores de Transcrição/metabolismo , Adipogenia/genética , Células 3T3-L1 , Diferenciação Celular/genéticaRESUMO
BACKGROUND: Long non-coding RNAs (lncRNAs)-related immune genes (lrRIGs) play a crucial role in the development and progression of lung adenocarcinoma (LUAD). However, reliable prognostic signatures based on lrRIGs have not yet been identified. METHODS: We screened lrRIGs associated with the prognosis of LUAD using The Cancer Genome Atlas (TCGA) database and then established a novel prognostic nine-gene signature composed of CD79A, INHA, SHC3, LIFR, TNFRSF11A, GPI, F2RL1, SEMA7A and WFDC2 through bioinformatic approaches. A risk score derived from this gene signature was used to divide LUAD patients into the low- and high-risk groups. The latter was confirmed to have markedly worse overall survival (O.S.). A nomogram was developed using the risk score and other independent prognostic elements, demonstrating excellent performance in predicting the O.S. rate of LUAD patients. RESULTS: We observed that the infiltration of diverse immune cell subtypes and response to immunotherapy and chemotherapy significantly differed between the low- and high-risk groups. CONCLUSIONS: Overall, stratification based on this gene signature could be used to guide better therapeutic management and improve outcomes for LUAD patients.
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Adenocarcinoma , Neoplasias Pulmonares , RNA Longo não Codificante , Humanos , Imunoterapia , Biologia Computacional , Pulmão , PrognósticoRESUMO
Liposarcoma (LPS) is one of the most common subtypes of sarcoma with a high recurrence rate. CENPF is a regulator of cell cycle, differential expression of which has been shown to be related with various cancers. However, the prognostic value of CENPF in LPS has not been deciphered yet. Using data from TCGA and GEO datasets, the expression difference of CENPF and its effects on the prognosis or immune infiltration of LPS patients were analyzed. As results show, CENPF was significantly upregulated in LPS compared to normal tissues. Survival curves illustrated that high CENPF expression was significantly associated with adverse prognosis. Univariate and multivariate analysis suggested that CENPF expression could be an independent risk factor for LPS. CENPF was closely related to chromosome segregation, microtubule binding and cell cycle. Immune infiltration analysis elucidated a negative correlation between CENPF expression and immune score. In conclusion, CENPF not only could be considered as a potential prognostic biomarker but also a potential malignant indicator of immune infiltration-related survival for LPS. The elevated expression of CENPF reveals an unfavorable prognostic outcome and worse immune score. Thus, therapeutically targeting CENPF combined with immunotherapy might be an attractive strategy for the treatment of LPS.
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Lipopolissacarídeos , Lipossarcoma , Humanos , Prognóstico , Biomarcadores , Lipossarcoma/genética , Lipossarcoma/terapia , Segregação de Cromossomos , Microambiente Tumoral/genéticaRESUMO
Targeting of the PD-1/PD-L1 immunologic checkpoint is believed to have provided a real breakthrough in the field of cancer therapy in recent years. Due to the intrinsic limitations of antibodies, the discovery of small-molecule inhibitors blocking PD-1/PD-L1 interaction has gradually opened valuable new avenues in the past decades. In an effort to discover new PD-L1 small molecular inhibitors, we carried out a structure-based virtual screening strategy to rapidly identify the candidate compounds. Ultimately, CBPA was identified as a PD-L1 inhibitor with a KD value at the micromolar level. It exhibited effective PD-1/PD-L1 blocking activity and T-cell-reinvigoration potency in cell-based assays. CBPA could dose-dependently elevate secretion levels of IFN-γ and TNF-α in primary CD4+ T cells in vitro. Notably, CBPA exhibited significant in vivo antitumor efficacy in two different mouse tumor models (a MC38 colon adenocarcinoma model and a melanoma B16F10 tumor model) without the induction of observable liver or renal toxicity. Moreover, analyses of the CBPA-treated mice further showed remarkably increased levels of tumor-infiltrating CD4+ and CD8+ T cells and cytokine secretion in the tumor microenvironment. A molecular docking study suggested that CBPA embedded relatively well into the hydrophobic cleft formed by dimeric PD-L1, occluding the PD-1 interaction surface of PD-L1. This study suggests that CBPA could work as a hit compound for the further design of potent inhibitors targeting the PD-1/PD-L1 pathway in cancer immunotherapy.
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Inibidores de Checkpoint Imunológico , Receptor de Morte Celular Programada 1 , Animais , Camundongos , Adenocarcinoma/metabolismo , Antígeno B7-H1/metabolismo , Linfócitos T CD8-Positivos/metabolismo , Neoplasias do Colo/metabolismo , Simulação de Acoplamento Molecular , Receptor de Morte Celular Programada 1/metabolismo , Microambiente Tumoral , Inibidores de Checkpoint Imunológico/química , Inibidores de Checkpoint Imunológico/farmacologiaRESUMO
Purpose: ZnO quantum dots (QDs) are composed of less toxic metals than other QDs but have the same interesting photochemical properties. Thus, they have received considerable attention recently. Nevertheless, their toxicity cannot be ignored. Methods: In this study, we incubated ZnO QDs with human SMMC-7721 cells for 24 h to assess their nanotoxicity through proteomics (Fold change >1.5 and p-value <0.05) and metabolomics (Fold change ≥ 1.5; VIP ≥ 1; p-value < 0.05) analyses. Results: Both of 174 and 219 significantly changed metabolites were identified in human SMMC-7721 cells treated with 20 and 50 µg/mL ZnO QDs, respectively. ZnO QDs significantly modified metabolic pathways, including purine metabolism, ferroptosis, morphine addiction, alcoholism, cGMP-PKG signaling, and Cushing syndrome. Moreover, we identified 105 and 8 differentially expressed proteins in cells treated with 20 and 50 µg/mL ZnO QDs, and the pathways of alcoholism and Cushing syndrome were enriched. Conclusion: ZnO QDs did not affect cell viability in a CCK8 assay, but disturbed the level of intracellular metabolites and proteins at 20 µg/mL. The KEGG analyses of the metabolomics and proteomics data both enriched the alcoholism and Cushing syndrome pathways. These results provide an experimental basis for future research on the safe use of nanomaterials.
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Pontos Quânticos , Óxido de Zinco , Humanos , Alcoolismo/metabolismo , Síndrome de Cushing/metabolismo , Proteômica , Pontos Quânticos/toxicidade , Pontos Quânticos/química , Óxido de Zinco/toxicidade , Óxido de Zinco/químicaRESUMO
BACKGROUND: The aim of this study was to uncover the ability of PM
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Células Epiteliais Alveolares , Enfisema , Camundongos , Masculino , Animais , Células Epiteliais Alveolares/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais , Apoptose , Enfisema/metabolismo , Material Particulado/toxicidadeRESUMO
Pseudogenes have been considered as non-functional genes. However, peptides and long non-coding RNAs produced by pseudogenes are expressed in different tumors. Moreover, the dysregulation of pseudogenes is associated with cancer, and their expressions are higher in tumors compared to normal tissues. Recent studies show that pseudogenes can influence the liquid phase condensates formation. Liquid phase separation involves regulating different epigenetic stages, including transcription, chromatin organization, 3D DNA structure, splicing, and post-transcription modifications like m6A. Several membrane-less organelles, formed through the liquid phase separate, are also involved in the epigenetic regulation, and their defects are associated with cancer development. However, the association between pseudogenes and liquid phase separation remains unrevealed. The current study sought to investigate the relationship between pseudogenes and liquid phase separation in cancer development, as well as their therapeutic implications.
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Apelin, an endogenous ligand for the G protein-coupled receptor (APJ), is widely distributed within the central nervous system and diverse organs in human and animals. Recent studies indicate that the apelin/APJ system plays an important role in physiological and pathophysiological situations. Apelin/APJ could inhibit inflammatory response by down-regulation of the nuclear factor-κB (NF-κB) pathway and by up-regulation of the extracellular signal-regulated kinase 1 and 2 (ERK1/2) pathway etc. Basic and preliminary research demonstrated that apelin/APJ system was involved in multiple diseases such as cardiovascular system diseases, liver and kidney diseases, neurological diseases, inflammatory intestinal diseases, pancreatitis, lung injury, aging, and obesity. Further, deficiency or overabundance of apelin can aggravate disease states in that inflammation is not only an important physiologic defense mechanism but also a potential mediator of organ damage. In this review, we summarize recent apelin/APJ system research progress with emphasis on the influence of the system on inflammation. Further, the mechanistic basis by which apelin regulates various inflammation-related diseases is analyzed. Finally, apelin and APJ might be presented as potential therapeutic targets for treatment of diseases mediated or exacerbated by inflammation.
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Inflamação , Receptores Acoplados a Proteínas G , Animais , Apelina , Receptores de Apelina/metabolismo , Ligantes , Receptores Acoplados a Proteínas G/genéticaRESUMO
Lung adenocarcinoma (LUAD) is one of the most common malignant tumors with high morbidity and mortality in China and worldwide. Long non-coding RNAs (lncRNAs) as the competing endogenous RNA (ceRNA) play an essential role in the occurrence and development of LUAD. However, identifying lncRNA-related biomarkers to improve the accuracy of LUAD prognosis remains to be determined. This study downloaded RNA sequence data from The Cancer Genome Atlas (TCGA) database and identified the differential RNAs by bioinformatics. A total of 214 lncRNA, 198 miRNA and 2989 mRNA were differentially identified between LUAD and adjacent nontumor samples. According to the ceRNA hypothesis, we constructed a lncRNA-miRNA-mRNA network including 95 protein-coding mRNAs, 7 lncRNAs and 15 miRNAs, and found 24 node genes in this network were significantly associated with the overall survival of LUAD patients. Subsequently, through LASSO regression and multivariate Cox regression analyses, a four-gene prognostic signature composed of GPI, IL22RA1, CCT6A and SPOCK1 was developed based on the node genes of the lncRNA-mediated ceRNA network, demonstrating high performance in predicting the survival and chemotherapeutic responses of low- and high-risk LUAD patients. Finally, independent prognostic factors were further analyzed and combined into a well-executed nomogram that showed strong potential for clinical applications. In summary, the data from the current study suggested that the four-gene signature obtained from analysis of lncRNA-mediated ceRNA could serve as a reliable biomarker for LUAD prognosis and evaluation of chemotherapeutic response.
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The discovery of circular RNAs and exploration of their biological functions are increasingly attracting attention in cell bio-sciences. Owing to their unique characteristics of being highly conserved, having a relatively longer half-life, and involvement in RNA maturation, transportation, epigenetic regulation, and transcription of genes, it has been accepted that circRNAs play critical roles in the variety of cellular processes. One of the critical importance of these circRNAs is the presence of small open reading frames that enable them to encode peptides/proteins. In particular, these encoded peptides/proteins mediate essential cellular activities such as proliferation, invasion, epithelial-mesenchymal transition, and apoptosis and develop an association with the development and progression of cancers by modulating diverse signaling pathways. In addition, these peptides have potential roles as biomarkers for the prognosis of cancer and are being used as drug targets against tumorigenesis. In the present review, we thoroughly discussed the biogenesis of circRNAs and their functional mechanisms along with a special emphasis on the reported chimeric peptides/proteins encoded by circRNAs. Additionally, this review provides a perspective regarding the opportunities and challenges to the potential use of circRNAs in cancer diagnosis and therapeutic targets in clinics.