Mesenchymal stem cell-derived exosomes protect against liver fibrosis via delivering miR-148a to target KLF6/STAT3 pathway in macrophages.

BACKGROUND: Despite emerging evidence on the therapeutic potential of mesenchymal stem cells (MSCs) for liver fibrosis, the underlying mechanisms remain unclear. At present, MSC-derived exosomes (MSC-EXOs) are widely accepted as crucial messengers for intercellular communication. This study aimed to explore the therapeutic effects of MSC-EXOs on liver fibrosis and identify the mechanisms underlying the action of MSC-EXOs. METHODS: Carbon tetrachloride was used to induce a liver fibrosis model, which was intravenously administered with MSCs or MSC-EXOs to assess treatment efficacy. The resulting histopathology, fibrosis degree, inflammation and macrophage polarization were analyzed. RAW264.7 and BMDM cells were used to explore the regulatory effects of MSC-EXOs on macrophage polarization. Then, the critical miRNA mediating the therapeutic effects of MSC-EXOs was screened via RNA sequencing and validated experimentally. Furthermore, the target mRNA and downstream signaling pathways were elucidated by luciferase reporter assay, bioinformatics analysis and western blot. RESULTS: MSCs alleviated liver fibrosis largely depended on their secreted exosomes, which were visualized to circulate into liver after transplantation. In addition, MSC-EXOs were found to modulate macrophage phenotype to regulate inflammatory microenvironment in liver and repair the injury. Mechanically, RNA-sequencing illustrates that miR-148a, enriched in the MSC-EXOs, targets Kruppel-like factor 6 (KLF6) to suppress pro-inflammatory macrophages and promote anti-inflammatory macrophages by inhibiting the STAT3 pathway. Administration of miR-148a-enriched MSC-EXOs or miR-148a agomir shows potent ameliorative effects on liver fibrosis. CONCLUSIONS: These findings suggest that MSC-EXOs protect against liver fibrosis via delivering miR-148a that regulates intrahepatic macrophage functions through KLF6/STAT3 signaling and provide a potential therapeutic target for liver fibrosis.

A novel immune checkpoint-related gene signature for hepatocellular carcinoma to predict clinical outcomes and therapeutic response.

Immune checkpoint genes (ICGs) have recently been proven to perform instrumental functions in the maintenance of immune homeostasis and represent a promising therapeutic strategy; however, their expression patterns and prognostic values are not fully elucidated in hepatocellular carcinoma (HCC). In this investigation, we focused on establishing and validating a prognostic gene signature to facilitate decision-making in clinical practice. Clinical information, as well as transcriptome data, was obtained from the Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) database. Univariate Cox regression and least absolute shrinkage and selection operator (LASSO) Cox method were employed to build a multi-gene signature in the TCGA database, while the ICGC database was used for validation. Subsequently, utilizing the six-gene signature, we were able to categorize patients into high- and low-risk groups. In two cohorts, survival analysis findings revealed a dismal outlook for the high-risk group. The receiver operating characteristic curves were utilized to estimate the gene signature's prediction ability. Moreover, correlation analysis showed high-risk group was linked to advanced pathological stage, infiltration of immune cells and therapeutic response. In summary, this unique gene profile might serve not only as a useful prognostic indicator but also as a marker of therapy responsiveness in HCC.

MicroRNAs Are Key Molecules Involved in the Gene Regulation Network of Colorectal Cancer.

Colorectal cancer (CRC) is one of the most common types of cancer and one of the leading causes of mortality worldwide. MicroRNAs (miRNAs) play central roles in normal cell maintenance, development, and other physiological processes. Growing evidence has illustrated that dysregulated miRNAs can participate in the initiation, progression, metastasis, and therapeutic resistance that confer miRNAs to serve as clinical biomarkers and therapeutic targets for CRC. Through binding to the 3'-untranslated region (3'-UTR) of target genes, miRNAs can lead to target mRNA degradation or inhibition at a post-transcriptional level. During the last decade, studies have found numerous miRNAs and their potential targets, but the complex network of miRNA/Targets in CRC remains unclear. In this review, we sought to summarize the complicated roles of the miRNA-target regulation network (Wnt, TGF-ß, PI3K-AKT, MAPK, and EMT related pathways) in CRC with up-to-date, high-quality published data. In particular, we aimed to discuss the downstream miRNAs of specific pathways. We hope these data can be a potent supplement for the canonical miRNA-target regulation network.

Immunoglobulin M: A Neglected Serum Biomarker in Treatment-Naive Primary Biliary Cholangitis With Normal Alkaline Phosphatase.

The diagnosis of primary biliary cholangitis (PBC) in patients with seropositive anti-mitochondrial antibody (AMA) but normal alkaline phosphatase (ALP) depends on a liver biopsy. We aimed to reveal potential serum biomarkers that could suggest the necessity of a liver biopsy in such patients. Retrospective analysis was performed. Subjects who were treatment naive with seropositive AMA but normal ALP and who underwent at least one liver biopsy between 2008 and 2020 were included in this study. Histologic biopsies were evaluated by two experienced pathologists blinded to the serum tests. A total of 115 patients who were treatment naive were included in this study. Of these, 77 patients (67%) exhibited histologic PBC features and nonspecific histologic features were found in the remaining 38 (33%) patients. Multivariate analysis suggested that baseline serum immunoglobulin M (IgM) >0.773 × upper limit of normal (ULN) (P < 0.001) and age >42 years (P = 0.002) were associated with the diagnosis of PBC through liver biopsies. A significant decrease in the median levels of gamma-glutamyl transpeptidase (GGT) and IgM was found in 54 patients with PBC who received ursodeoxycholic acid (UDCA). Conclusion: For patients who were treatment naive with seropositive AMA but normal ALP, baseline serum IgM >0.773 × ULN and age >42 years were the factors that strongly suggested a diagnosis of PBC. In these patients receiving UDCA, a dynamic monitoring of GGT and IgM might be helpful in evaluating therapeutic responses.

Systematic Construction and Validation of a Prognostic Model for Hepatocellular Carcinoma Based on Immune-Related Genes.

Hepatocellular carcinoma (HCC), a highly aggressive tumor, has high incidence and mortality rates. Recently, immunotherapies have been shown to be a promising treatment in HCC. The results of either the CheckMate-040 or IMbrave 150 trials demonstrate the importance of immunotherapy in the systemic treatment of liver cancer. Thus, in this study, we tried to establish a reliable prognostic model for liver cancer based on immune-related genes (IRGs) and to provide a new insight for immunotherapy of HCC. In this study, we used four datasets that incorporated 851 HCC samples, including 340 samples with complete clinical information from the cancer genome atlas (TCGA) database, to establish an effective model for predicting the prognosis of HCC patients based on the differential expression of IRGs and validated the prognostic model using the data from International Cancer Genome Consortium (ICGC). The top 6 characteristic IRGs identified by protein-protein interaction (PPI) network analysis, MMP9, FOS, CAT, ESR1, ANGPTL3, and KLKB1, were selected for further study. In addition, we assessed the correlations of the six characteristic IRGs with the tumor immune microenvironment, clinical stage, and sensitivity to anti-cancer drugs. We also explored whether the differential expression of the characteristic IRGs was specific to HCC or present in pan-cancer. The expression levels of the six characteristic IRGs were significantly different between most tumor tissues and adjacent normal tissues. In addition, these characteristic IRGs showed a strong association with immune cell infiltration in HCC patients. We found that MMP9 and ESR1 were independent prognostic factors for HCC, while CAT, ESR1, and KLKB1 were associated with the clinical stage. We collected HCC paraffin sections from 24 patients from Xijing hospital to identify the differential expression of the five genes (MMP9, ESR1, CAT, FOS, and KLKB1). Finally, the results of decision curve analysis (DCA) and nomogram revealed that our models provided a prognostic benefit for most HCC patients and the predicted overall survival (OS) was consistent with the actual OS. In conclusion, we systemically constructed a novel prognostic model that provides new insights into HCC.