RESUMEN
The utilization of PD-1/PD-L1 inhibitors marks a significant advancement in cancer therapy. However, the efficacy of monotherapy is still disappointing in a substantial subset of patients, necessitating the exploration of combinational strategies. Emerging from the promising results of the KEYNOTE-942 trial, RNA-based therapies, particularly circRNAs and piRNAs, have distinguished themselves as innovative sensitizers to immune checkpoint inhibitors (ICIs). These non-coding RNAs, notable for their stability and specificity, were once underrecognized but are now known for their crucial roles in regulating PD-L1 expression and bolstering anti-cancer immunity. Our manuscript offers a comprehensive analysis of selected circRNAs and piRNAs, elucidating their immunomodulatory effects and mechanisms, thus underscoring their potential as ICIs enhancers. In conjunction with the recent Nobel Prize-awarded advancements in mRNA vaccine technology, our review highlights the transformative implications of these findings for cancer treatment. We also discuss the prospects of circRNAs and piRNAs in future therapeutic applications and research. This study pioneers the synergistic application of circRNAs and piRNAs as novel sensitizers to augment PD-1/PD-L1 inhibition therapy, demonstrating their unique roles in regulating PD-L1 expression and modulating immune responses. Our findings offer a groundbreaking approach for enhancing the efficacy of cancer immunotherapy, opening new avenues for treatment strategies. This abstract aims to encapsulate the essence of our research and the burgeoning role of these non-coding RNAs in enhancing PD-1/PD-L1 inhibition therapy, encouraging further investigation into this promising field.
Asunto(s)
Antígeno B7-H1 , Inhibidores de Puntos de Control Inmunológico , Neoplasias , Receptor de Muerte Celular Programada 1 , ARN Circular , ARN Interferente Pequeño , Humanos , Inhibidores de Puntos de Control Inmunológico/farmacología , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Antígeno B7-H1/inmunología , Antígeno B7-H1/genética , Antígeno B7-H1/antagonistas & inhibidores , ARN Interferente Pequeño/genética , ARN Circular/genética , Receptor de Muerte Celular Programada 1/inmunología , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Neoplasias/inmunología , Neoplasias/tratamiento farmacológico , Neoplasias/terapia , Neoplasias/genética , Inmunoterapia/métodos , Animales , ARN de Interacción con PiwiRESUMEN
P-element-induced wimpy testis (PIWI)-interacting RNAs (piRNAs/piRs) are a class of small noncoding RNAs that play a crucial role in regulating various biological processes, including carcinogenesis. One specific piRNA, piR-651, has been reported to be overexpressed in both human blood serum and solid cancer tissues, that can be used a viable biomarker in cancer diagnosis. Early diagnosis of cancer can help reduce the burden of the disease and improve survival rates. In the present work, we report for the first time a smartphone-based colorimetric biosensor for highly sensitive and specific detection of piR-651 thanks to an enzymatic signal amplification, which yielded high colorimetric intensities. Indeed, a heteroduplex DNA:RNA was formed in the presence of piR-651 with the capture DNA probe immobilized on the magnetic beads for easy magnetic separation. Then, a HRP tethered to anti-DNA:RNA (S9.6) was used to reveal the DNA-RNA heteroduplex formed by catalyzing the oxidation of TMB substrate into colorimetric TMBox, which absorbs at 630 nm. The absorbance is positively proportional to the piR-651 concentrations. On the other hand, the colorimetric product of the assay can be photographed with a smartphone camera and analyzed using ImageJ software. Using a smartphone and under optimal conditions, the biosensor responded linearly to the logarithm of piRNA-651 from 8 fM to 100 pM with a detection limit of 2.3 fM and discriminates against other piRNAs. It was also successfully applied to the determination of piRNA-651 levels in spiked human serum.
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Técnicas Biosensibles , ARN Interferente Pequeño , Teléfono Inteligente , Humanos , ARN Interferente Pequeño/química , Técnicas Biosensibles/métodos , Colorimetría , ADN/química , Límite de Detección , ARN de Interacción con PiwiRESUMEN
Sandflies are known vectors of leishmaniasis. In the Old World, sandflies are also vectors of viruses while little is known about the capacity of New World insects to transmit viruses to humans. Here, we relate the identification of RNA sequences with homology to rhabdovirus nucleocapsids (NcPs) genes, initially in the Lutzomyia longipalpis LL5 cell lineage, named NcP1.1 and NcP2. The Rhabdoviridae family never retrotranscribes its RNA genome to DNA. The sequences here described were identified in cDNA and DNA from LL-5 cells and in adult insects indicating that they are transcribed endogenous viral elements (EVEs). The presence of NcP1.1 and NcP2 in the L. longipalpis genome was confirmed in silico. In addition to showing the genomic location of NcP1.1 and NcP2, we identified another rhabdoviral insertion named NcP1.2. Analysis of small RNA molecules derived from these sequences showed that NcP1.1 and NcP1.2 present a profile consistent with elements targeted by primary piRNAs, while NcP2 was restricted to the degradation profile. The presence of NcP1.1 and NcP2 was investigated in sandfly populations from South America and the Old World. These EVEs are shared by different sandfly populations in South America while none of the Old World species studied presented the insertions.
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Leishmaniasis , Psychodidae , Rhabdoviridae , Humanos , Animales , América del Sur , ARN , ADN , BrasilRESUMEN
Arboviruses are an important group of pathogens that cause diseases of medical and veterinary concern worldwide. The interactions of these viruses with their host cells are complex, and frequently, the coexistence of two different viruses in the same cell results in the inhibition of replication in one of the viruses, which is a phenomenon called viral interference. This phenomenon can be exploited to develop antiviral strategies. Insect cell lines persistently infected with arboviruses are useful models with which to study viral interference. In this work, a model of C6/36-HT cells (from Aedes albopictus mosquitoes) persistently infected with Dengue virus, serotype 2, was used. Viral interference was evaluated via plaque and flow cytometry assays. The presence of heterotypic interference against the other serotypes of the same virus and homologous interference against yellow fever virus was determined; however, this cell line did not display heterologous viral interference against Sindbis virus. The mechanisms responsible for viral interference have not been fully elucidated, but small RNAs could be involved. However, the silencing of Ago3, a key protein in the genome-derived P-element-induced wimpy testis pathway, did not alter the viral interference process, suggesting that viral interference occurs independent of this pathway.
RESUMEN
Non-coding RNAs (ncRNAs) are, arguably, the enigma of the RNA transcriptome. Even though there are more annotated ncRNAs (25,967) compared to mRNAs (19,827), we know far less about each of the genes that produce ncRNA, especially in terms of their regulation, molecular functions, and interactions. Further, we are only beginning to understand the role of differential regulation or function of ncRNAs caused by genetic and epigenetic perturbations, such as single nucleotide variants (SNV), deletions, insertions, and histone/DNA modifications. The 22 papers in this Special Issue describe the emerging roles of ncRNAs in neurological, cardiovascular, immune, and hepatic systems, to name a few, as well as in diseases such as cancer, Prader-Willi Syndrome, cardiac arrhythmias, and diabetes. As we begin to understand the function and regulation of this class of RNAs, strategies targeting ncRNAs could lead to improved therapeutic interventions for some conditions.
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Neoplasias , ARN no Traducido , Humanos , ARN no Traducido/genética , Transcriptoma , Neoplasias/genética , ARNRESUMEN
Colorectal cancer is one of the most prevalent malignancies worldwide. Evidences indicate that piRNA-18 are closely involved and contributed to tumorigenesis and cancer progression. Therefore, it is very necessary to investigate the effects of piRNA-18 on the proliferation, migration, and invasiveness of colorectal cancer cells, so as to provide theoretical basis for finding new biomarkers and accurate diagnosis and treatment of colorectal cancer. Here, Five pairs of colorectal cancer tissue samples and their corresponding adjacent samples were analyzed by real-time immunofluorescence quantitative PCR and the difference in piRNA-18 expression among colorectal cancer cell lines was further verified. MTT assay were used to study the changes in the proliferation of colorectal cancer cell lines after piRNA-18 overexpression. Wound-healing assay and Transwell assay were used to study the changes in migration and invasion. Flow cytometry were used to study the changes in apoptosis and cycle. SC inoculation of colorectal cancer cell lines into nude mice were used to observe the effect in the proliferation. piRNA-18 was lowlier expressed than adjacent tissues and normal intestinal mucosal epithelial cells in colorectal cancer and colorectal cancer cell line. After overexpression of piRNA-18, cell proliferation and migration as well as invasiveness in SW480 and LOVO cells decreased. The cell lines with piRNA-18 overexpression had obvious G1/S phase arrest in cell cycle, and the weight and volume of subcutaneously transplanted tumors are decreased. Our findings highlighted that piRNA-18 may play an inhibitory role in colorectal cancer.
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Neoplasias Colorrectales , ARN de Interacción con Piwi , Animales , Ratones , Apoptosis , Línea Celular Tumoral , Movimiento Celular , Proliferación Celular , Neoplasias Colorrectales/metabolismo , Regulación Neoplásica de la Expresión Génica , Ratones Desnudos , Invasividad Neoplásica/genética , HumanosRESUMEN
Lung cancer has a high morbidity and mortality rate, and affected patients have a poor prognosis and low survival. The therapeutic approaches for lung cancer treatment, including surgery, radiotherapy, and chemotherapy, are not completely effective, due to late diagnosis. Although the identification of genetic drivers has contributed to the improvement of lung cancer clinical management, the discovery of new diagnostic and prognostic tools remains a critical issue. Liquid biopsy (LB) represents a minimally invasive approach and practical alternative source to investigate tumor-derived alterations and to facilitate the selection of targeted therapies. LB allows for the testing of different analytes such as circulating tumor cells, extracellular vesicles (EVs), tumor-educated platelets, and cell-free nucleic acids including DNAs, RNAs, and noncoding RNAs (ncRNAs). Several regulatory factors control the key cellular oncogenic pathways involved in cancers. ncRNAs have a wide range of regulatory effects in lung cancers. This review focuses on emerging regulatory ncRNAs, freely circulating in body fluids or shuttled by EVs, such as circular-RNAs, small nucleolar-RNAs, small nuclear-RNAs, and piwi-RNAs, as new biomarkers for early detection, prognosis, and monitoring of therapeutic strategy of lung cancer treatment.
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Majority of the human genome is transcribed to RNAs that do not encode proteins. These non-coding RNAs (ncRNAs) play crucial roles in regulating the initiation and progression of various cancers. Given the importance of the ncRNAs, the roles of ncRNAs in cancers have been reviewed elsewhere. Thus, in this review, we mainly focus on the recent studies of the function, regulatory mechanism and therapeutic potential of the ncRNAs including microRNA (miRNA), long ncRNA (lncRNA), circular RNA (circRNA) and PIWI interacting RNA (piRNA), in different type of cancers.
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MicroARNs , Neoplasias , ARN Largo no Codificante , Humanos , MicroARNs/genética , Neoplasias/genética , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , ARN Interferente Pequeño , ARN no Traducido/genética , ARN no Traducido/metabolismoRESUMEN
Gastric cancer remains a major unmet clinical problem with over 1 million new cases worldwide. It is the fourth most commonly occurring cancer in men and the seventh most commonly occurring cancer in women. A major fraction of gastric cancer has been linked to variety of pathogenic infections including but not limited to Helicobacter pylori (H. pylori) or Epstein Barr virus (EBV). Strategies are being pursued to prevent gastric cancer development such as H. pylori eradication, which has helped to prevent significant proportion of gastric cancer. Today, treatments have helped to manage this disease and the 5-year survival for stage IA and IB tumors treated with surgery are between 60 and 80%. However, patients with stage III tumors undergoing surgery have a dismal 5-year survival rate between 18 and 50% depending on the dataset. These figures indicate the need for more effective molecularly driven treatment strategies. This review discusses the molecular profile of gastric tumors, the success, and challenges with available therapeutic targets along with newer biomarkers and emerging targets.
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Neoplasias Gástricas/terapia , Animales , Biomarcadores de Tumor/metabolismo , Ensayos Clínicos Fase II como Asunto , Ensayos Clínicos Fase III como Asunto , Terapia Combinada , Infecciones por Virus de Epstein-Barr/patología , Infecciones por Helicobacter/patología , Helicobacter pylori/aislamiento & purificación , Herpesvirus Humano 4/aislamiento & purificación , Humanos , Terapia Molecular Dirigida , Estadificación de Neoplasias , Ensayos Clínicos Controlados Aleatorios como Asunto , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/microbiología , Neoplasias Gástricas/patologíaRESUMEN
Sjögren's Syndrome (SS) is an autoimmune disease characterized by lymphocytic infiltration and loss of function of moisture-producing exocrine glands as well as systemic inflammation. SS diagnosis is cumbersome, subjective and complicated by manifestation of symptoms that overlap with those of other rheumatic and ocular diseases. Definitive diagnosis averages 4-5 years and this delay may lead to irreversible tissue damage. Thus, there is an urgent need for diagnostic biomarkers for earlier detection of SS. Extracellular vesicles called exosomes carry functional small non-coding RNAs which play a critical role in maintaining cellular homeostasis via transcriptional and translational regulation of mRNA. Alterations in levels of specific exosomal miRNAs may be predictive of disease status. Here, we have assessed serum exosomal RNA using next generation sequencing in a discovery cohort of the NOD mouse, a model of early-intermediate SS, to identify dysregulated miRNAs that may be indicative of SS. We found five miRNAs upregulated in serum exosomes of NOD mice with an adjusted p < 0.05-miRNA-127-3p, miRNA-409-3p, miRNA-410-3p, miRNA-541-5p, and miRNA-540-5p. miRNAs 127-3p and 541-5p were also statistically significantly upregulated in a validation cohort of NOD mice. Pathway analysis and existing literature indicates that differential expression of these miRNAs may dysregulate pathways involved in inflammation. Future studies will apply these findings in a human cohort to understand how they are correlated with manifestations of SS as well as understanding their functional role in systemic autoimmunity specific to SS.
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Biomarcadores/metabolismo , MicroARN Circulante/genética , Exosomas/genética , Marcadores Genéticos/genética , Síndrome de Sjögren/diagnóstico , Animales , Modelos Animales de Enfermedad , Exosomas/metabolismo , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Inflamación/genética , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos NOD , TranscriptomaRESUMEN
Aims: To identify differential expression of noncoding RNAs after trypsinization in human mesenchymal stromal cells (hMSCs), focusing on miRNAs, piRNAs and circRNAs. Methods: hMSCs from the bone marrow of three donors were collected for RNA extraction, either lysed directly in monolayer or trypsinized and lysed within 30 min. Total RNA was isolated and sequenced for the evaluation of miRNA and piRNA expression or RNaseR treated and labeled for circRNA array hybridization. RT-qPCR was performed to evaluate the stability of candidate reference genes. Results & conclusions: Alterations in levels of several noncoding RNAs are rapidly induced after trypsinization of hMSCs, affecting critical pathways. This should be carefully considered for a proper experimental design.