Exosomes play a role as mediators of cell-to-cell communication, thus exhibiting pleiotropic activities to homeostasis regulation. Exosomal non-coding RNAs (ncRNAs), mainly microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), are closely related to a variety of biological and functional aspects of human health. When the exosomal ncRNAs undergo tissue-specific changes due to diverse internal or external disorders, they can cause tissue dysfunction, aging, and diseases. In this review, we comprehensively discuss the underlying regulatory mechanisms of exosomes in human diseases. In addition, we explore the current knowledge on the roles of exosomal miRNAs, lncRNAs, and circRNAs in human health and diseases, including cancers, metabolic diseases, neurodegenerative diseases, cardiovascular diseases, autoimmune diseases, and infectious diseases, to determine their potential implication in biomarker identification and therapeutic exploration.

Roles and mechanisms of exosomal non-coding RNAs in human health and diseases.

Exosomes are very small extracellular vesicles secreted by multiple cell types and are extensively distributed in various biological fluids. Recent research indicated that exosomes can participate in regulating the tumor microenvironment and impacting tumor proliferation and progression. Due to the extensive enrollment in cancer development, exosomes have become a focus of the search for a new therapeutic method for cancer. Exosomes can be utilized for the therapeutic delivery of small molecules, proteins and RNAs to target cancer cells with a high efficiency. Exosome-carried proteins, lipids and nucleic acids are being tested as promising biomarkers for cancer diagnosis and prognosis, even as potential treatment targets for cancer. Moreover, different sources of exosomes exhibit multiple performances in cancer applications. In this review, we elaborate on the specific mechanism by which exosomes affect the communication between tumors and the microenvironment and state the therapeutic and diagnostic applications of exosomes in cancers.

The Role of Exosomes and Their Applications in Cancer

miR-425-5p as an exosomal biomarker for metastatic prostate cancer

BACKGROUNDS Liver hepatocellular carcinoma (HCC) is one of the most malignant tumors, of which prognosis is unsatisfactory in most cases and metastatic of HCC often results in poor prognosis. In this study, we aimed to construct a metastasis- related mRNAs prognostic model to increase the accuracy of prediction of HCC prognosis. METHODS Three hundred seventy-four HCC samples and 50 normal samples were downloaded from The Cancer Genome Atlas (TCGA) database, involving transcriptomic and clinical data. Metastatic-related genes were acquired from HCMBD website at the same time. Two hundred thirty-three samples were randomly divided into train dataset and test dataset with a proportion of 1:1 by using caret package in R. Kaplan-Meier method and univariate Cox regression analysis and lasso regression analysis were performed to obtain metastasis-related mRNAs which played significant roles in prognosis. Then, using multivariate Cox regression analysis, a prognostic prediction model was established. Transcriptome and clinical data were combined to construct a prognostic model and a nomogram for OS evaluation. Functional enrichment in high- and low-risk groups were also analyzed by GSEA. An entire set based on The International Cancer Genome Consortium(ICGC) database was also applied to verify the model. The expression levels of SLC2A1, CDCA8, ATG10 and HOXD9 are higher in tumor samples and lower in normal tissue samples. The expression of TPM1 in clinical sample tissues is just the opposite. RESULTS One thousand eight hundred ninety-five metastasis-related mRNAs were screened and 6 mRNAs were associated with prognosis. The overall survival (OS)-related prognostic model based on 5 MRGs (TPM1,SLC2A1, CDCA8, ATG10 and HOXD9) was significantly stratified HCC patients into high- and low-risk groups. The AUC values of the 5-gene prognostic signature at 1 year, 2 years, and 3 years were 0.786,0.786 and 0.777. A risk score based on the signature was a significantly independent prognostic factor (HR = 1.434; 95%CI = 1.275-1.612; P < 0.001) for HCC patients. A nomogram which incorporated the 5-gene signature and clinical features was also built for prognostic prediction. GSEA results that low- and high-risk group had an obviously difference in part of pathways. The value of this model was validated in test dataset and ICGC database. CONCLUSION Metastasis-related mRNAs prognostic model was verified that it had a predictable value on the prognosis of HCC, which could be helpful for gene targeted therapy.

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Five metastasis-related mRNAs signature predicting the survival of patients with liver hepatocellular carcinoma.

Prostate cancer is a major health problem worldwide. MiR-183 is an oncomiR and a candidate biomarker in prostate cancer, affecting various pathways responsible for disease initiation and progression. We sought to discover the most relevant processes controlled by miR-183 through an unbiased transcriptomic approach using prostate cell lines and patient tissues to identify miR-183 responsive genes and pathways. Gain of function experiments, reporter gene assays, and transcript and protein measurements were conducted to validate predicted functional effects and protein mediators. A total of 135 candidate miR-183 target genes overrepresenting cell adhesion terms were inferred from the integrated transcriptomic analysis. Cell attachment, spreading assays and focal adhesion quantification of miR-183-overexpressing cells confirmed the predicted reduction in cell adhesion. ITGB1 was validated as a major target of repression by miR-183 as well as a mediator of cell adhesion in response to miR-183. The reporter gene assay and PAR-CLIP read mapping suggest that ITGB1 may be a direct target of miR-183. The negative correlation between miR-183 and ITGB1 expression in prostate cancer cohorts supports their interaction in the clinical set. Overall, cell adhesion was uncovered as a major pathway controlled by miR-183 in prostate cancer, and ITGB1 was identified as a relevant mediator of this effect.

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Hsa-miR-183-5p Modulates Cell Adhesion by Repression of ITGB1 Expression in Prostate Cancer

Emerging evidence continues to highlight the significant role of microRNAs (miRNAs) in the regulation of cancer growth and metastasis. Herein, the current study aimed to elucidate the role of exosomal miR-183 in prostate cancer development. Initially, public microarray-based gene expression profiling of prostate cancer was employed to identify differentially expressed miRNAs. The putative target gene TPM1 of miR-183 was subsequently predicted, followed by the application of a luciferase reporter assay and examination of the expression patterns in prostate cancer patients and cell lines. The effects of miR-183 and TPM1 on processes such as cell proliferation, invasion and migration were evaluated using in vitro gain- and loss-of-function experiments. The effect of PC3 cells-derived exosomal miR-183 was validated in LNCaP cells. In vivo experiments were also performed to examine the effect of miR-183 on prostate tumor growth. High expression of miR-183 accompanied with low expression of TPM1 was detected in prostate cancer. Our data indicated that miR-183 could target and downregulate TPM1, with the overexpression of miR-183 and exosomal miR-183 found to promote cell proliferation, migration, and invasion in prostate cancer. Furthermore, the tumor-promoting effect of exosome-mediated delivery of miR-183 was subsequently confirmed in a tumor xenograft model. Taken together, the key findings of our study demonstrate that prostate cancer cell-derived exosomal miR-183 enhance prostate cancer cell proliferation, invasion and migration via the downregulation of TPM1, highlighting a promising therapeutic target against prostate cancer.

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Yanping Dai

Papers

Inhibition of cancer cell-derived exosomal microRNA-183 suppresses cell growth and metastasis in prostate cancer by upregulating TPM1