The RNA-binding protein, Epithelial Splicing Regulatory Protein 1 (ESRP1) can promote or suppress tumorigenesis depending on the cell type and disease context. In colorectal cancer, we have previously shown that aberrantly high ESRP1 expression can drive tumor progression. In order to unveil the mechanisms by which ESRP1 can modulate cancer traits, we searched for proteins affected by modulation of Esrp1 in two human colorectal cancer cell lines, HCA24 and COLO320DM, by proteomics analysis. Proteins hosted by endogenous ESRP1 ribonucleoprotein complex in HCA24 cells were also analyzed following RNA-immunoprecipitation. Proteomics data were complemented with bioinformatics approach to exploit publicly available data on protein-protein interaction (PPI). Gene Ontology was analysed to identify a common molecular signature possibly explaining the pro-tumorigenic role of ESRP1. Interestingly, proteins identified herein support a role for ESRP1 in response to external stimulus, regulation of cell cycle and hypoxia. Our data provide further insights into factors affected by and entwined with ESRP1 in colorectal cancer.
Severe corneal damage leads to complete vision loss, thereby affecting life quality and impinging heavily on the healthcare system. Current clinical approaches to manage corneal wounds suffer from severe drawbacks, thus requiring the development of alternative strategies. Of late, mesenchymal stromal/stem cell (MSC)-derived extracellular vesicles (EVs) have become a promising tool in the ophthalmic field. In the present study, we topically delivered bone-marrow-derived MSC-EVs (BMSC-EVs), embedded in methylcellulose, in a murine model of alkali-burn-induced corneal damage in order to evaluate their role in corneal repair through histological and molecular analyses, with the support of magnetic resonance imaging. Our data show that BMSC-EVs, used for the first time in this specific formulation on the damaged cornea, modulate cell death, inflammation and angiogenetic programs in the injured tissue, thus leading to a faster recovery of corneal damage. These results were confirmed on cadaveric donor-derived human corneal epithelial cells in vitro. Thus, BMSC-EVs modulate corneal repair dynamics and are promising as a new cell-free approach for intervening on burn wounds, especially in the avascularized region of the eye.
Aims: Biliary diseases represent around 10% of all chronic liver diseases and affect both adults and children. Currently available biochemical tests detect cholestasis but not early liver fibrosis. Circulating extracellular vesicles (EVs) provide a noninvasive, real-time molecular snapshot of the injured organ. We thus aimed at searching for a panel of EV-based biomarkers for cholestasis-induced early liver fibrosis using mouse models. Results: Progressive and detectable histological evidence of collagen deposition and liver fibrosis was observed from day 8 after bile duct ligation (BDL) in mice. Whole transcriptome and small RNA sequencing analyses of circulating EVs revealed differentially enriched RNA species after BDL versus sham controls. Unsupervised hierarchical clustering identified a signature that allowed for discrimination between BDL and controls. In particular, 151 microRNAs (miRNAs) enriched in BDL-derived EVs were identified, of which 66 were conserved in humans. The liver was an important source of circulating EVs in BDL animals as evidenced by the enrichment of several hepatic mRNAs, such as Albumin and Haptoglobin . Interestingly, among experimentally validated miRNAs, miR192-5p, miR194-5p, miR22-3p, and miR29a-3p showed similar enrichment patterns also in EVs derived from 3,5-diethoxycarboncyl-1,4-dihydrocollidine-treated (drug-induced severe cholestasis) but not in mice with mild phenotype or non-cholestatic liver fibrosis. Innovation: A panel of mRNAs and miRNAs contained in circulating EVs, when combined, indicates hepatic damage and fibrosis in mice and represents promising biomarkers for human severe cholestasis-induced liver fibrosis. Conclusion: Analysis of EV-based miRNAs, in combination with hepatic injury RNA markers, can detect early cholestatic liver injury and fibrosis in mice. Antioxid. Redox Signal. 36, 480–504.
Significance Liver fibrosis results from different etiologies and represents one of the most serious health issues worldwide. Fibrosis is the outcome of chronic insults on the liver and is associated with several factors, including abnormal iron metabolism. Recent AdvancesMultiple mechanisms underlying the pro-fibrogenic role of iron have been proposed. The pivotal role of Liver Sinusoidal Endothelial Cells (LSECs) in iron level regulation, as well as their morphological and molecular de-differentiation occurring in liver fibrosis, have encouraged research on LSECs as prime regulators of very early fibrotic events.Importantly, normal differentiated LSECs may act as gatekeepers of fibrogenesis by maintaining the quiescence of Hepatic Stellate Cells (HSCs), while LSECs capillarization precedes the onset of liver fibrosis. Critical IssuesIn the present review, the morphological and molecular alterations occurring in LSECs following liver injury are addressed in an attempt to highlight how vascular dysfunction promotes fibrogenesis. In particular, we discuss in depth how a vicious loop can be established in which iron-dysregulation and LSEC de-differentiation synergize to exacerbate and promote the progression of liver fibrosis.Future Directions LSECs, due to their pivotal role in early liver fibrosis and iron homeostasis, show great promises as a therapeutic target. In particular, new strategies can be devised for restoring LSECs differentiation and thus their role as regulators of iron homeostasis, hence preventing the progression of liver fibrosis or, even better, promoting its regression.
RNA binding proteins are well recognized as critical regulators of tumorigenic processes through their capacity to modulate RNA biogenesis, including alternative splicing, RNA stability and mRNA translation. The RNA binding protein Epithelial Splicing Regulatory Protein 1 (ESRP1) can act as a tumor suppressor or promoter in a cell type- and disease context-dependent manner. We have previously shown that elevated expression of ESRP1 in colorectal cancer cells can drive tumor progression. To gain further insights into the pro-tumorigenic mechanism of action of ESRP1, we performed cDNA microarray analysis on two colorectal cells lines modulated for ESRP1 expression. Intriguingly, RAC1b was highly expressed, both at mRNA and protein levels, in ESRP1-overexpressing cells, while the opposite trend was observed in ESRP1-silenced CRC cells. Moreover, RAC1 and RAC1b mRNA co-immunoprecipitate with ESRP1 protein. Silencing of RAC1b expression significantly reduced the number of soft agar colonies formed by ESRP1-overexpressing cells, suggesting that ESRP1 acted, at least partially, through RAC1b in its tumor-promoting activities in CRC cells. Thus, our data provide molecular cues on targetable candidates in CRC cases with high ESRP1 expression.
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