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BACKGROUND: Using natural killer (NK) cells to treat hematopoietic and solid tumors has great promise. Despite their availability from peripheral blood and cord blood, stem cell-derived NK cells provide an "off-the-shelf" solution. METHODS: In this study, we developed two CAR-NK cells targeting PD-L1 derived from lentiviral transduction of human umbilical cord blood (UCB)-CD34+ cells and UCB-CD34+-derived NK cells. The transduction efficiencies and in vitro cytotoxic functions including degranulation, cytokine production, and cancer cell necrosis of both resultants PD-L1 CAR-NK cells were tested in vitro on two different PD-L1 low and high-expressing solid tumor cell lines. RESULTS: Differentiated CARmodified UCB-CD34+ cells exhibited enhanced transduction efficiency. The expression of anti-PD-L1 CAR significantly (P < 0.05) enhanced the cytotoxicity of differentiated CARmodified UCB-CD34+ cells and CAR-modified UCB-CD34+-derived NK cells against PD-L1 high-expressing tumor cell line. In addition, CAR-modified UCB-CD34+-derived NK cells significantly (P < 0.05) restored the tumor-killing ability of exhausted PD-1 high T cells. CONCLUSION: Considering the more efficient transduction in stem cells and the possibility of producing CAR-NK cell products with higher yields, this approach is recommended for studies in the field of CAR-NK cells. Also, a pre-clinical study is now necessary to evaluate the safety and efficacy of these two CAR-NK cells individually and in combination with other therapeutic approaches.
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Antígenos CD34 , Antígeno B7-H1 , Sangue Fetal , Células Matadoras Naturais , Humanos , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/metabolismo , Antígeno B7-H1/metabolismo , Antígeno B7-H1/genética , Antígeno B7-H1/imunologia , Sangue Fetal/citologia , Antígenos CD34/metabolismo , Linfócitos T/imunologia , Linfócitos T/metabolismo , Diferenciação Celular , Receptores de Antígenos Quiméricos/metabolismo , Receptores de Antígenos Quiméricos/imunologia , Receptor de Morte Celular Programada 1/metabolismo , Linhagem Celular Tumoral , Imunoterapia Adotiva/métodos , Neoplasias/terapia , Neoplasias/imunologia , Neoplasias/patologiaRESUMO
Adoptive immunotherapies that use functional NK cells depend on the availability of sufficient numbers of these cells. We expanded umbilical cord blood (UCB)-CD34+ HSCs for 2 weeks and then differentiated them into NK cells and compared their function to peripheral blood (PB) NK cells. We assessed NKG2D, NKG2A, NKp30, NKp44, NKp46, and the expression of CD107a, CD57, CD69, FasL, PD-1, and IFN-γ level in two groups after co-culture with K562 cell line. We found that UCB-CD34+-derived NK cells express significantly more NKG2D, NKp44, and NKp46 receptors than PB NK cells. PB NK cells expressed significantly higher NKG2A and CD57 than UCB-CD34+-derived NK cells. In addition, UCB-CD34+-derived NK cells significantly expressed CD107a more than PB NK cells. Based on our findings, UCB-CD34+ cells can be a potentially advantageous source with strong cytotoxic function to produce allogeneic NK cells for adoptive cancer immunotherapy.
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Renal cell carcinoma (RCC), a prevalent form of renal malignancy, is distinguished by its proclivity for robust tumor proliferation and metastatic dissemination. Long non-coding RNAs (lncRNAs) have emerged as pivotal modulators of gene expression, exerting substantial influence over diverse biological processes, encompassing the intricate landscape of cancer development. Metastasis-associated lung adenocarcinoma transcript 1 (MALAT-1), an exemplar among lncRNAs, has been discovered to assume functional responsibilities within the context of RCC. The conspicuous expression of MALAT-1 in RCC cells has been closely linked to the advancement of tumors and an unfavorable prognosis. Experimental evidence has demonstrated the pronounced ability of MALAT-1 to stimulate RCC cell proliferation, migration, and invasion, thereby underscoring its active participation in facilitating the metastatic cascade. Furthermore, MALAT-1 has been implicated in orchestrating angiogenesis, an indispensable process for tumor expansion and metastatic dissemination, through its regulatory influence on pro-angiogenic factor expression. MALAT-1 has also been linked to the evasion of immune surveillance in RCC, as it can regulate the expression of immune checkpoint molecules and modulate the tumor microenvironment. Hence, the potential utility of MALAT-1 as a diagnostic and prognostic biomarker in RCC emerges, warranting further investigation and validation of its clinical significance. This comprehensive review provides an overview of the diverse functional roles exhibited by MALAT-1 in RCC.
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Carcinoma de Células Renais , Neoplasias Renais , RNA Longo não Codificante , Humanos , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/patologia , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Neoplasias Renais/genética , Neoplasias Renais/patologia , Proliferação de Células/genética , Prognóstico , Linhagem Celular Tumoral , Microambiente Tumoral/genéticaRESUMO
Ischemic stroke, which occurs due to the occlusion of cerebral arteries, is a common type of stroke. Recent research has highlighted the important role of long non-coding RNAs (lncRNAs) in the development of cerebrovascular diseases, specifically ischemic stroke. Understanding the functional roles of lncRNAs in ischemic stroke is crucial, given their potential contribution to the disease pathology. One noteworthy lncRNA is X-inactive specific transcript (XIST), which exhibits downregulation during the early stages of ischemic stroke and subsequent upregulation in later stages. XIST exert its influence on the development of ischemic stroke through interactions with multiple miRNAs and transcription factors. These interactions play a significant role in the pathogenesis of the condition. In this review, we have provided a comprehensive summary of the functional roles of XIST in ischemic stroke. By investigating the involvement of XIST in the disease process, we aim to enhance our understanding of the mechanisms underlying ischemic stroke and potentially identify novel therapeutic targets.
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It is now widely recognized that mesenchymal stem cells (MSCs) possess the capacity to differentiate into a wide array of cell types. Numerous studies have identified the role of lncRNA in the regulation of MSC differentiation. It is important to elucidate the role and interplay of microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) in the regulation of signalling pathways that govern MSC function. Furthermore, miRNAs and lncRNAs are important clinical for innovative strategies aimed at addressing a wide spectrum of existing and emerging disease. Hence it is important to consider their impact on MSC function and differentiation. Examining the data available in public databases, we have collected the literature containing the latest discoveries pertaining to human stem cells and their potential in both fundamental research and clinical applications. Furthermore, we have compiled completed clinical studies that revolve around the application of MSCs, shedding light on the opportunities presented by harnessing the regulatory potential of miRNAs and lncRNAs. This exploration of the therapeutic possibilities offered by miRNAs and lncRNAs within MSCs unveils exciting prospects for the development of precision therapies and personalized treatment approaches. Ultimately, these advancements promise to augment the efficacy of regenerative strategies and produce positive outcomes for patients. As research in this field continues to evolve, it is imperative to explore and exploit the vast potential of miRNAs and lncRNAs as therapeutic agents. The findings provide a solid basis for ongoing investigations, fuelling the quest to fully unlock the regenerative potential of MSCs.
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Células-Tronco Mesenquimais , MicroRNAs , RNA Longo não Codificante , Humanos , MicroRNAs/genética , MicroRNAs/metabolismo , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Diferenciação Celular/genética , Células-Tronco Mesenquimais/metabolismo , Osteoblastos/metabolismoRESUMO
Recurrent pregnancy loss (RPL) or recurrent miscarriage is the failure of pregnancy before 20-24 weeks that influences around 2-5% of couples. Several genetic, immunological, environmental and physical factors may influence RPL. Although various traditional methods have been used to treat post-implantation failures, identifying the mechanisms underlying RPL may improve an effective treatment. Recent evidence suggested that gene expression alterations presented essential roles in the occurrence of RPL. It has been found that long non-coding RNAs (lncRNAs) play functional roles in pregnancy pathologies, such as recurrent miscarriage. lncRNAs can function as dynamic scaffolds, modulate chromatin function, guide and bind to microRNAs (miRNAs) or transcription factors. lncRNAs, by targeting various miRNAs and mRNAs, play essential roles in the progression or suppression of RPL. Therefore, targeting lncRNAs and their downstream targets might be a suitable strategy for diagnosis and treatment of RPL. In this review, we summarized emerging roles of several lncRNAs in stimulation or suppression of RPL.
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Long non-coding RNAs (lncRNAs) present pivotal roles in cancer tumorigenesis and progression. Recently, nuclear paraspeckle assembly transcript 1 (NEAT1) as a lncRNA has been shown to mediate cell proliferation, migration, and EMT in tumor cells. NEAT1 by targeting several miRNAs/mRNA axes could regulate cancer cell behavior. Therefore, NEAT1 may function as a potent biomarker for the prediction and treatment of some human cancers. In this review, we summarized various NEAT1-related signaling pathways that are critical in cancer initiation and progression.
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MicroRNAs , RNA Longo não Codificante , Humanos , Carcinogênese/genética , Linhagem Celular Tumoral , Proliferação de Células/genética , Transformação Celular Neoplásica/genética , Regulação Neoplásica da Expressão Gênica/genética , MicroRNAs/genética , RNA Longo não Codificante/metabolismoRESUMO
Circular RNAs (circRNAs) as small non-coding RNAs with cell, tissue, or organ-specific expression accomplish a broad array of functions in physiological and pathological processes such as cancer development. Angiogenesis, a complicated multistep process driving a formation of new blood vessels, speeds up tumor progression by supplying nutrients as well as energy. Abnormal expression of circRNAs reported to affect tumor development through impressing angiogenesis. Such impacts are introduced as constant with different tumorigenic features known as "hallmarks of cancer". In addition, deregulated circRNAs show possibilities to prognosis and diagnosis both in the prophecy of prognosis in malignancies and also their prejudice from healthy individuals. In the present review article, we have evaluated the angiogenic impacts and anti-angiogenic managements of circRNAs in human cancers.
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Neoplasias , RNA Circular , Humanos , Neoplasias/genética , Neoplasias/diagnóstico , Prognóstico , Carcinogênese , ImunoterapiaRESUMO
Long non-coding RNAs (lncRNAs) are non-coding RNAs that contain more than 200 nucleotides but do not code for proteins. In tumorigenesis, lncRNAs can have both oncogenic and tumor-suppressive properties. X inactive-specific transcript (XIST) is a known lncRNA that has been implicated in X chromosome silencing in female cells. Dysregulation of XIST is associated with an increased risk of various cancers. Therefore, XIST can be a beneficial prognostic biomarker for human malignancies. In this review, we attempt to summarize the emerging roles of XIST in human cancers.
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MicroRNAs , Neoplasias , RNA Longo não Codificante , Humanos , Feminino , MicroRNAs/genética , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , RNA Mensageiro , Neoplasias/genética , CarcinogêneseRESUMO
Natural killer (NK) cells are unique innate immune cells that mediate anti-viral and anti-tumor responses. Thus, they might hold great potential for cancer immunotherapy. NK cell adoptive immunotherapy in humans has shown modest efficacy. In particular, it has failed to demonstrate therapeutic efficiency in the treatment of solid tumors, possibly due in part to the immunosuppressive tumor microenvironment (TME), which reduces NK cell immunotherapy's efficiencies. It is known that immune checkpoints play a prominent role in creating an immunosuppressive TME, leading to NK cell exhaustion and tumor immune escape. Therefore, NK cells must be reversed from their dysfunctional status and increased in their effector roles in order to improve the efficiency of cancer immunotherapy. Blockade of immune checkpoints can not only rescue NK cells from exhaustion but also augment their robust anti-tumor activity. In this review, we discussed immune checkpoint blockade strategies with a focus on chimeric antigen receptor (CAR)-NK cells to redirect NK cells to cancer cells in the treatment of solid tumors.
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Células Matadoras Naturais , Neoplasias , Humanos , Neoplasias/patologia , Imunoterapia Adotiva , Imunoterapia , Microambiente TumoralRESUMO
Long noncoding RNAs (lncRNA) play pivotal roles in every level of gene and genome regulation. MCM3AP-AS1 is a lncRNA that has an oncogenic role in several kinds of cancers. Aberrant expression of MCM3AP-AS1 has been reported to be involved in the progression of diverse malignancies, including colorectal, cervical, prostate, lymphoma, lung, ovary, liver, bone, and breast cancers. It is generally believed that MCM3AP-AS1 expression is associated with cancer cell growth, proliferation, angiogenesis, and metastasis. MCM3AP-AS1 by targeting various signaling pathways and microRNAs (miRNAs) presents an important role in cancer pathogenesis. MCM3AP-AS1 as a competitive endogenous RNA has the ability to sponge miRNA, inhibit their expressions, and bind to different target mRNAs related to cancer development. Therefore, MCM3AP-AS1 by targeting several signaling pathways, including the FOX family, Wnt, EGF, and VEGF can be a potent target for cancer prediction and diagnosis. In this review, we will summarize the role of MCM3AP-AS1 in various human cancers.
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Neoplasias da Mama , MicroRNAs , RNA Longo não Codificante , Masculino , Feminino , Humanos , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , MicroRNAs/genética , Neoplasias da Mama/genética , Transdução de Sinais , Fígado , Regulação Neoplásica da Expressão Gênica , Proliferação de Células , Acetiltransferases/genética , Acetiltransferases/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/genéticaRESUMO
Glioma is the most common malignant brain tumor that develops in the glial tissue. Several studies have identified that glioma cancer stem cells (GCSCs) play important roles in tumor-initiating features in malignant gliomas. GCSCs are a small population in the brain that presents an essential role in the metastasis of glioma cells to other organs. These cells can self-renew and differentiate, which are thought to be involved in the pathogenesis of glioma. Therefore, targeting GCSCs might be a novel strategy for the treatment of glioma. Accumulating evidence revealed that several signaling pathways, including Notch, TGF-ß, Wnt, STAT3, AKT, and EGFR mediated GCSC growth, proliferation, migration, and invasion. Besides, non-coding RNAs (ncRNAs), including miRNAs, circular RNAs, and long ncRNAs have been found to play pivotal roles in the regulation of GCSC pathogenesis and drug resistance. Therefore, targeting these pathways could open a new avenue for glioma management. In this review, we summarized critical signaling pathways involved in the stimulation or prevention of GCSCs tumorigenesis and invasiveness.
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Neoplasias Encefálicas , Glioma , RNA Longo não Codificante , Humanos , Regulação Neoplásica da Expressão Gênica , Glioma/metabolismo , Células-Tronco Neoplásicas/metabolismo , Neoplasias Encefálicas/metabolismo , Transdução de Sinais , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismoRESUMO
INTRODUCTION: Retinoblastoma (RB) is the most common childhood tumor that can occur in the retina and develop in a sporadic or heritable form. Although various traditional treatment options have been used for patients with RB, identifying novel strategies for childhood cancers is necessary. MATERIAL AND METHODS: Recently, molecular-based targeted therapies have opened a greater therapeutic window for RB. Long non-coding RNAs (lncRNAs) presented a potential role as a biomarker for the detection of RB in various stages. CONCLUSION: LncRNAs by targeting several miRNA/transcription factors play critical roles in the stimulation or suppression of RB. In this review, we summarized recent progress on the functions of tumor suppressors or oncogenes lncRNAs in RB.
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MicroRNAs , RNA Longo não Codificante , Neoplasias da Retina , Retinoblastoma , Humanos , Criança , Retinoblastoma/genética , Retinoblastoma/patologia , RNA Longo não Codificante/genética , MicroRNAs/genética , Biomarcadores , Neoplasias da Retina/genética , Neoplasias da Retina/patologiaRESUMO
Colorectal cancer (CRC) is a gastrointestinal tumor that develops from the colon, rectum, or appendix. The prognosis of CRC patients especially those with metastatic lesions remains unsatisfactory. Although various conventional methods have been used for the treatment of patients with CRC, the early detection and identification of molecular mechanisms associated with CRC is necessary. The scientific literature reports that altered expression of long non-coding RNAs (lncRNAs) contributed to the pathogenesis of CRC cells. LncRNA TUG1 was reported to target various miRNAs and signaling pathways to mediate CRC cell proliferation, migration, and metastasis. Therefore, TUG1 might be a potent predictive/prognostic biomarker for diagnosis of CRC.
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Hepatocellular carcinoma (HCC) or hepatoma is malignant cancer that starts from the main liver cells. Although various classical methods have been used for patients with HCC, various molecular mechanisms involved in HCC progression should be invested. Previous studies demonstrated that abnormal expression of long non-coding RNAs (lncRNAs) presented important roles in the pathogenesis of HCC cells. LncRNA TUG1 was found to mediate HCC cell growth, EMT, and metastasis. Therefore, targeting TUG1 and its downstream genes may be a suitable approach for patients with HCC. In this review, we summarized the potential roles of TUG1 in HCC.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , RNA Longo não Codificante , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Proliferação de Células/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismoRESUMO
Colorectal cancer (CRC) is the third cause of cancer death in the world that arises from the glandular and epithelial cells of the large intestine, during a series of genetic or epigenetic alternations. Recently, long non-coding RNAs (lncRNAs) has opened a separate window of research in molecular and translational medicine. Emerging evidence has supported that lncRNAs can regulate cell cycle of CRC cells. LncRNA NEAT1 has been verified to participate in colon cancer development and progression. NEAT1 as a competing endogenous RNA could suppress the expression of miRNAs, and then regulate molecules downstream of these miRNAs. In this review, we summarized emerging roles of NEAT1 in CRC cells.
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Histone lysine methylation plays a key role in gene activation and repression. The trimethylation of histone H3 on lysine-27 (H3K27me3) is a critical epigenetic event that is controlled by Jumonji domain-containing protein-3 (JMJD3). JMJD3 is a histone demethylase that specifically removes methyl groups. Previous studies have suggested that JMJD3 has a dual role in cancer cells. JMJD3 stimulates the expression of proliferative-related genes and increases tumor cell growth, propagation, and migration in various cancers, including neural, prostate, ovary, skin, esophagus, leukemia, hepatic, head and neck, renal, lymphoma, and lung. In contrast, JMJD3 can suppress the propagation of tumor cells, and enhance their apoptosis in colorectal, breast, and pancreatic cancers. In this review, we summarized the recent advances of JMJD3 function in cancer cells.
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Lisina , Neoplasias , Apoptose , Feminino , Histonas/genética , Histonas/metabolismo , Humanos , Histona Desmetilases com o Domínio Jumonji/genética , Histona Desmetilases com o Domínio Jumonji/metabolismo , Lisina/metabolismo , Masculino , Metilação , Neoplasias/genéticaRESUMO
Breast cancer (BC) is the most common cancer and the prevalent type of malignancy among women. Multiple risk factors, including genetic changes, biological age, dense breast tissue, and obesity are associated with BC. The mitogen-activated protein kinases (MAPK) signaling pathway has a pivotal role in regulating biological functions such as cell proliferation, differentiation, apoptosis, and survival. It has become evident that the MAPK pathway is associated with tumorigenesis and may promote breast cancer development. The MAPK/RAS/RAF cascade is closely associated with breast cancer. RAS signaling can enhance BC cell growth and progression. B-Raf is an important kinase and a potent RAF isoform involved in breast tumor initiation and differentiation. Depending on the reasons for cancer, there are different strategies for treatment of women with BC. Till now, several FDA-approved treatments have been investigated that inhibit the MAPK pathway and reduce metastatic progression in breast cancer. The most common breast cancer drugs that regulate or inhibit the MAPK pathway may include Farnesyltransferase inhibitors (FTIs), Sorafenib, Vemurafenib, PLX8394, Dabrafenib, Ulixertinib, Simvastatin, Alisertib, and Teriflunomide. In this review, we will discuss the roles of the MAPK/RAS/RAF/MEK/ERK pathway in BC and summarize the FDA-approved prescription drugs that target the MAPK signaling pathway in women with BC.