Exosomal circRNAs: Emerging Players in Tumor Metastasis.
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ABSTRACT:
SUBMITTER: Zhou H
PROVIDER: S-EPMC8692866 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Exosomes are multifunctional regulators of intercellular communication by carrying various messages under both physiological and pathological status of cancer patients. Accumulating studies have identified the presence of circular RNAs (circRNAs) in exosomes with crucial regulatory roles in diverse pathophysiological processes. Exosomal circRNAs derived from donor cells can modulate crosstalk with recipient cells locally or remotely to enhance cancer development and propagation, and play crucial roles in the tumor microenvironment (TME), leading to significant enhancement of tumor immunity, metabolism, angiogenesis, drug resistance, epithelial mesenchymal transition (EMT), invasion and metastasis. In this review, we describe the advances of exosomal circRNAs and their roles in modulating cancer hallmarks, especially those in the TME. Moreover, clinical application potential of exosomal circRNAs in cancer diagnosis and therapy are highlighted, bridging the gap between basic knowledge and clinical practice.
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Project description:Exosomes are crucial vehicles in intercellular communication. Circular RNAs (circRNAs), novel endogenous noncoding RNAs, play diverse roles in ischemic stroke. Recently, the abundance and stability of circRNAs in exosomes have been identified. However, a comprehensive analysis of exosomal circRNAs in large artery atherosclerotic (LAA) stroke has not yet been reported. We performed RNA sequencing (RNA-Seq) to comprehensively identify differentially expressed (DE) exosomal circRNAs in five paired LAA and normal controls. Further, quantitative real-time PCR (qRT-PCR) was used to verify the RNA-Seq results in a cohort of stroke patients (32 versus 32). RNA-Seq identified a total of 462 circRNAs in peripheral exosomes; there were 25 DE circRNAs among them. Additionally, circRNA competing endogenous RNA (ceRNA) network and translatable analysis revealed the potential functions of the exosomal circRNAs in LAA progression. Two ceRNA pathways involving 5 circRNAs, 2 miRNAs, and 3 mRNAs were confirmed by qRT-PCR. In the validation cohort, receiver operating characteristic (ROC) curve analysis identified two circRNAs as possible novel biomarkers, and a logistic model combining two and four circRNAs increased the area under the curve compared with the individual circRNAs. Here, we show for the first time the comprehensive expression of exosomal circRNAs, which displayed the potential diagnostic and biological function in LAA stroke.
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Project description:Apical periodontitis is an inflammatory disorder of periradicular tissues developed from endodontic infections. Understanding its pathophysiology and the underlying molecular mechanisms is key to the advancement of endodontics. MicroRNAs (miRNAs), a group of evolutionarily conserved small non-coding RNAs, may be phenotypically and functionally associated with the pathogenesis of apical periodontitis. Several studies have focused on the role of miRNAs in the pulp and periradicular biology, and they have demonstrated their essential functions, such as initiating odontogenic differentiation and promoting pro- or anti-inflammatory responses in pulpitis. Up to date, over 2,000 miRNAs have been discovered in humans; however, only few have been reported to associate with apical periodontitis. Therefore, identifying miRNAs involved in diseased apical tissues and conducting functional studies are important in expanding our current knowledge of pulp and periradicular biology and exploring novel therapeutic avenues. In this review, we revisit current models of apical periodontitis and miRNA biogenesis, analyze existing evidence of the involvement of miRNAs in diseased apical tissues, and discuss their diverse functions and potential values. Based on their sheer abundance, prolonged stability in biofluid, and relative ease of sampling, miRNAs may be a useful tool to be developed as diagnostic biomarkers for apical periodontitis. Furthermore, it can be used as therapeutic targets in conjunction with conventional endodontic therapies.
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Project description:Large artery atherosclerotic (LAA) stroke is closely associated with atherosclerosis, characterized by the accumulation of immune cells. Early recognition of LAA stroke is crucial. Circulating exosomal circRNAs profiling represents a promising, noninvasive approach for the detection of LAA stroke. Exosomal circRNA sequencing was used to identify differentially expressed circRNAs between LAA stroke and normal controls. From a further validation stage, the results were validated using RT-qPCR. We then built logistic regression models of exosomal circRNAs based on a large replication stage, and receiver operating characteristic (ROC) curves were constructed to assess the diagnostic efficacy. Using exosomal circRNA sequencing, large sample validation, and diagnostic model construction revealed that exosomal circ_0043837 and circ_ 0001801were independent predictive factors for LAA stroke, and had better diagnostic efficacy than plasma circRNAs. In the atherosclerotic group (AS), we developed a nomogram for clinical use that integrated the two-circRNA-based risk factors to predict which patients might have the risk of plaque rupture. Circulating exosomal circRNAs profiling identifies novel predictive biomarkers for the LAA stroke and plaque rupture, with superior diagnostic value than plasma circRNAs. It might facilitate the prevention and better management of this disease.
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Project description:Numerous reports have elucidated the important participation of exosomes in the communication between tumor cells and other cancer-related cells including tumor-associated macrophages (TAMs) in microenvironment. However, the interchange of exosomes between tumor cells and TAMs in the progression of lung adenocarcinoma (LUAD) remains largely enigmatic. Herein, we discovered that LUAD cells induced the M2 polarization of TAMs and the M2-polarized macrophages facilitated LUAD cell invasion and migration and tumor metastasis in vivo. In detail, LUAD cells secreted exosomes to transport miR-19b-3p into TAMs so that miR-19b-3p targeted PTPRD and inhibited the PTPRD-mediated dephosphorylation of STAT3 in TAMs, leading to STAT3 activation and M2 polarization. Also, the activated STAT3 transcriptionally induced LINC00273 in M2 macrophages and exosomal LINC00273 was transferred into LUAD cells. In LUAD cells, LINC00273 recruited NEDD4 to facilitate LATS2 ubiquitination and degradation, so that the Hippo pathway was inactivated and YAP induced the transcription of RBMX. RBMX bound to miR-19b-3p to facilitate the packaging of miR-19b-3p into LUAD cell-derived exosomes. Collectively, our results revealed the mechanism underlying the interactive communication between LUAD cells and TAMs through elucidating the exchange of exosomal miR-19b-3p and LINC00273 and proved the prometastatic effect of the interchange between two cells. These discoveries opened a new vision for developing LUAD treatment.
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Project description:Extracellular vesicles (EVs) are lipid membranous vesicles that are released from every type of cell. It has become clear that EVs are involved in a variety of biological phenomena, including cancer progression, and play critical roles in intracellular communication through the horizontal transfer of cellular cargoes such as proteins, DNA fragments, RNAs including mRNA and non-coding RNAs (microRNA, piRNA, and long non-coding RNA) and lipids. The most common cause of death associated with cancer is metastasis. Recent investigations have revealed that EVs are deeply associated with metastasis. Bone is a preferred site of metastasis, and bone metastasis is generally incurable and dramatically affects patient quality of life. Bone metastasis can cause devastating complications, including hypercalcemia, pathological fractures, spinal compression, and bone pain, which result in a poor prognosis. Although the mechanisms underlying bone metastasis have yet to be fully elucidated, increasing evidence suggests that EVs in the bone microenvironment significantly contribute to cancer progression and cancer bone tropism. Emerging evidence on EV functions in bone metastasis will facilitate the discovery of novel treatments. In this review, we will discuss the remarkable effects of EVs, especially on the tumor microenvironment in bone.
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Project description:BackgroundMounting evidence has demonstrated the vital importance of tumor-associated macrophages (TAMs) and exosomes in the formation of the premetastatic niche. However, the molecular mechanisms by which tumor-derived exosomal miRNAs interact with TAMs underlying premetastatic niche formation and colorectal cancer liver metastasis (CRLM) remain largely unknown.MethodsTransmission electron microscopy and differential ultracentrifugation were used to verify the existence of exosomes. In vivo and in vitro assays were used to identify roles of exosomal miR-934. RNA pull-down assay, dual-luciferase reporter assay, etc. were applied to clarify the mechanism of exosomal miR-934 regulated the crosstalk between CRC cells and M2 macrophages.ResultsIn the present study, we first demonstrated the aberrant overexpression of miR-934 in colorectal cancer (CRC), especially in CRLM, and its correlation with the poor prognosis of CRC patients. Then, we verified that CRC cell-derived exosomal miR-934 induced M2 macrophage polarization by downregulating PTEN expression and activating the PI3K/AKT signaling pathway. Moreover, we revealed that hnRNPA2B1 mediated miR-934 packaging into exosomes of CRC cells and then transferred exosomal miR-934 into macrophages. Interestingly, polarized M2 macrophages could induce premetastatic niche formation and promote CRLM by secreting CXCL13, which activated a CXCL13/CXCR5/NF?B/p65/miR-934 positive feedback loop in CRC cells.ConclusionsThese findings indicate that tumor-derived exosomal miR-934 can promote CRLM by regulating the crosstalk between CRC cells and TAMs. These findings reveal a tumor and TAM interaction in the metastatic microenvironment mediated by tumor-derived exosomes that affects CRLM. The present study also provides a theoretical basis for secondary liver cancer.
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