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Identification of exosomal miRNAs associated with the anthracycline-induced liver injury in postoperative breast cancer patients by small RNA sequencing.

ABSTRACT: Background:Anthracycline-induced liver injury (AILI) is one of the serious complications of anthracycline-based adjuvant chemotherapy for postoperative breast cancer patients. Exosomal miRNAs, as signaling molecules in intercellular communication, play the essential roles in drug-induced liver injury (DILI). However, the expression profiles of them in patients with AILI remains unknown. Methods:Seven post-chemotherapy patients were recruited in this study. After isolated plasma-derived exosomes, small RNA sequencing revealed exosomal miRNA profiles and differentially expressed miRNAs (DE-miRNAs) were identified between the liver injury group and non-liver injury group. miRTarBase and miRDB were used to predict the potential target genes of DE-miRNAs. DILI-related genes were downloaded from the CTD Database. The intersection of predicted genes and DILI-related genes were identified as the AILI-related target genes of the DE-miRNAs. GO annotation and KEGG pathway enrichment analysis were performed by the DAVID database. Furthermore, the protein-protein interaction (PPI) network was established by the STRING database and essential exosomal miRNAs were identified via Cytoscape software. Results:A total of 30 DE-miRNAs and 79 AILI-related target genes were identified. AILI-related target genes of the DE-miRNAs are significantly enriched in NOD-like receptor signaling pathway, the HIF-1 signaling pathway, and the FoxO signaling pathway. Then, the hub genes were screened and we discovered that IL-6 and SOD2 are the most critical genes that may be involved in the development of AILI through the activation of immune response and the occurrence of oxidative stress, respectively. In addition, we found that miR-1-3p could potentially regulate most of the hub genes in the miRNA-hub gene network. Conclusion:We explored the potential functions of DE-miRNAs and suggested exosomal miR-1-3p might be the essential exosomal miRNA in the pathogenesis of AILI. Moreover, our study provided an experimental basis for experimental verification to reveal the actual function and mechanism of miRNAs in AILI.

SUBMITTER: Zhang Y

PROVIDER: S-EPMC7185038 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Identification of exosomal miRNAs associated with the anthracycline-induced liver injury in postoperative breast cancer patients by small RNA sequencing.

Zhang Yue Y Wang Di D Shen Di D Luo Yang Y Che Yi-Qun YQ

PeerJ 20200424

<h4>Background</h4>Anthracycline-induced liver injury (AILI) is one of the serious complications of anthracycline-based adjuvant chemotherapy for postoperative breast cancer patients. Exosomal miRNAs, as signaling molecules in intercellular communication, play the essential roles in drug-induced liver injury (DILI). However, the expression profiles of them in patients with AILI remains unknown.<h4>Methods</h4>Seven post-chemotherapy patients were recruited in this study. After isolated plasma-de ...[more]

PMID: 32355577

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Project description:Cholestatic liver injury is an important clinical problem with limited understanding of disease pathologies. Exosomes are small extracellular vesicles released by a variety of cells, including cholangiocytes. Exosome-mediated cell-cell communication can modulate various cellular functions by transferring a variety of intracellular components to target cells. Our recent studies indicate that the long noncoding RNA (lncRNA), H19, is mainly expressed in cholangiocytes, and its aberrant expression is associated with significant down-regulation of small heterodimer partner (SHP) in hepatocytes and cholestatic liver injury in multidrug resistance 2 knockout (Mdr2-/- ) mice. However, how cholangiocyte-derived H19 suppresses SHP in hepatocytes remains unknown. Here, we report that cholangiocyte-derived exosomes mediate transfer of H19 into hepatocytes and promote cholestatic injury. Hepatic H19 level is correlated with severity of cholestatic injury in both fibrotic mouse models, including Mdr2-/- mice, a well-characterized model of primary sclerosing cholangitis (PSC), or CCl4 -induced cholestatic liver injury mouse models, and human PSC patients. Moreover, serum exosomal-H19 level is gradually up-regulated during disease progression in Mdr2-/- mice and patients with cirrhosis. H19-carrying exosomes from the primary cholangiocytes of wild-type (WT) mice suppress SHP expression in hepatocytes, but not the exosomes from the cholangiocytes of H19-/- mice. Furthermore, overexpression of H19 significantly suppressed SHP expression at both transcriptional and posttranscriptional levels. Importantly, transplant of H19-carrying serum exosomes of old fibrotic Mdr2-/- mice significantly promoted liver fibrosis (LF) in young Mdr2-/- mice. CONCLUSION:Cholangiocyte-derived exosomal-H19 plays a critical role in cholestatic liver injury. Serum exosomal H19 represents a noninvasive biomarker and potential therapeutic target for cholestatic diseases. (Hepatology 2018).

Dataset Information

Identification of exosomal miRNAs associated with the anthracycline-induced liver injury in postoperative breast cancer patients by small RNA sequencing.

Publications

Identification of exosomal miRNAs associated with the anthracycline-induced liver injury in postoperative breast cancer patients by small RNA sequencing.

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