Biology subjects

Vucur, M.

Publications and source records attributed to Vucur, M..

4 recordsLinked to original sources

bioRxiv2024

Phosphatase-independent suppression of mucosal inflammation and disease progression by Salmonella SopB

Salmonella enterica subsp. enterica serovar Typhimurium (S. Typhimurium) translocates effector molecules via its Salmonella pathogenicity island (SPI)1 encoded type 3 secretion system (T3SS) to induce internalization by intestinal epithelial cells and manipulate cellular responses. Among these effector molecules, the Salmonella outer protein B (SopB) was shown to possess phosphatidyl-inositol phosphatase activity and induce bacterial internalisation, promote cell survival, influence endosomal trafficking and alter host cell signalling. Using a neonatal S. Typhimurium infection model, we here show that SopB in vivo suppresses early epithelial chemokine expression, delays mucosal immune cell recruitment, reduces barrier impairment by enterocyte necroptosis, and prevents disease progression and premature death. Unexpectedly, this immunosuppressive effect was independent of the phosphatidyl-inositol phosphatase and phosphotransferase activity of SopB but required an intact N-terminal domain. Thus, SopB exerts a potent phosphatase-independent immunosuppressive effect to delay local tissue inflammation and disease progression likely to promote host transmission.

microbiology↗

bioRxiv2024

The ferroptosis mediator ACSL4 fails to prevent disease progression in mouse models of MASLD

Metabolic dysfunction-associated steatotic liver disease is an increasingly prevalent condition, representing a major risk factor for the development of progressive chronic liver damage. This can potentially give rise to the development of steatohepatitis and hepatocellular carcinoma (HCC). It is already known, that patients with metabolic dysfunction-associated steatotic liver disease (MASLD) show increased systemic and hepatic iron concentrations as well as perturbed lipid metabolism, suggesting involvement of ferroptotic cell death in the development and progression of MASLD. Consequently, inhibition of ferroptosis represents a potential therapeutic option for patients with MASLD. The aim of this study was to determine whether a liver parenchymal cell specific conditional deletion of the pro-ferroptotic gene acyl-CoA synthetase long-chain family member 4 (ACSL4LPC-KO) can ameliorate the onset and progression of MASLD in mice. To this end, ACSL4LPC-KO and floxed wild-type littermates were fed a choline-deficient high-fat diet over the course of 20 and 40 weeks to monitor the progression of metabolic liver injury as well as the development of metabolic syndrome. In contrast to the recently published studies by Duan et al. [1], our results show no significant differences between ACSL4LPC-KO and WT mice with regard to the development of MASLD or the progression of metabolic syndrome. Furthermore, no differences were observed in metabolic parameters (i.e. weight gain, glucose tolerance test, hepatic steatosis) or MASLD-associated inflammatory response. Our analyses therefore suggest that loss of ACSL4 has no effect on the progression of MASLD induced by choline-deficient high fat diet. The discrepancy between our and previously published results could be due to differences in the diets or the influence of a distinct microbiome, so the results obtained with liver parenchymal cell specific ACSL4 null mice should be taken with caution.

systems biology↗

bioRxiv2023

KIF23 regulation by miR-107 controls replicative tumor cell fitness in mouse and human hepatocellular carcinoma

Background & AimsIn hepatocellular carcinoma, there is a lack of successful translation of experimental targets identified in mouse models to human patients. In this study, we used a comprehensive transcriptomic approach in mice to identify novel potential targets for therapeutic intervention in humans. MethodsWe analysed combined genome-wide miRNA and mRNA expression data in three pathogenically distinct mouse models of liver cancer. Effects of target genes on hepatoma cell fitness were evaluated by proliferation, survival and motility assays. TCGA and GEO databases, in combination with tissue microarrays (TMA), were used to validate the mouse targets and their impact on human HCC prognosis. Finally, the functional effects of the identified targets on tumorigenesis and tumor therapy were tested in hydrodynamic tail vein injection (HDTVi)-based preclinical HCC models in vivo. ResultsThe expression of miR-107 was found to be significantly reduced in mouse models of liver tumors of various etiologies and in cohorts of human HCC patients. Overexpression of miR-107 or inhibition of its novel target Kinesin family member 23 (Kif23) significantly reduced proliferation by interfering with cytokinesis, thereby controlling survival and motility of mouse and human hepatoma cells. In humans, KIF23 expression was found to be a prognostic marker in liver cancer, with high expression associated with poor prognosis. HDTVi of vectors carrying either pre-miR- 107 or anti-Kif23 shRNA inhibited the development of highly aggressive cMyc-NRas- induced liver cancers in mice. ConclusionsDisruption of the miR-107/Kif23 axis inhibited hepatoma cell proliferation in vitro and prevented oncogene-induced liver cancer development in vivo, offering a novel potential avenue for the treatment of HCC in humans. Impact and implicationsA comprehensive analysis integrating in silico prediction, miRNA and mRNA data in three pathogenically distinct mouse models provided novel targets for the treatment of human HCC, bridging the translational gap between mouse data and human HCC. Our functional findings on the novel miR-107/Kif23 module provide important new insights into the control of mitosis in liver cancer cells. The findings that miR-107 overexpression or Kif23 inhibition had a dramatic functional effect on inhibiting the growth of liver cancer cells in vitro and in vivo suggest that the miR-107/Kif23 axis may be a promising novel target and potential adjunct to sequential systemic therapy of HCC. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=164 SRC="FIGDIR/small/565448v1_ufig1.gif" ALT="Figure 1"> View larger version (45K): org.highwire.dtl.DTLVardef@afda02org.highwire.dtl.DTLVardef@111da7borg.highwire.dtl.DTLVardef@11eeeecorg.highwire.dtl.DTLVardef@1d7d9f7_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LImiR-107 is globally downregulated in mouse liver cancers of different etiologies and represents a potential biomarker in human HCC. C_LIO_LIIntegration of in-silico-prediction, miRNA and mRNA transcriptomics identified KIF23, a mitotic spindle-associated protein, as a specific target mediating the biological effects of miR-107. C_LIO_LIThe miR-107/KIF23 module promotes replicative fitness of liver cancer cells through an essential function in cytokinesis C_LIO_LIMice receiving shRNA targeting Kif23 were completely protected from oncogene-induced liver cancer. C_LI

cancer biology↗

bioRxiv2023

Differential modulation of miR-122 transcription by TGFbeta1/BMP6: implications for nonresolving inflammation and hepatocarcinogenesis

Chronic inflammation is widely recognized as a significant factor that promotes and worsens the development of malignancies, including hepatocellular carcinoma. This study aimed to explore the potential role of microRNAs in inflammation-associated nonresolving hepatocarcinogenesis. By conducting a comprehensive analysis of altered microRNAs in animal models with liver cancer of various etiologies, we identified miR-122 as the most significantly downregulated microRNA in the liver of animals with inflammation-associated liver cancer. Although previous research has indicated the importance of miR-122 in maintaining hepatocyte function, its specific role as either the trigger or the consequence of underlying diseases remains unclear. Through extensive analysis of animals and in vitro models, we have successfully demonstrated that MIR122 transcription is differentially regulated by the immunoregulatory cytokines by the transforming growth factor-beta 1 (TGF{beta}1) and the bone morphogenetic protein- 6 (BMP6). Furthermore, we presented convincing evidence directly linking reduced MIR122 transcription to inflammation and in chronic liver diseases. The results of this study strongly suggest that prolonged activation of signaling pathways, leading to disruption of cytokine-mediated regulation of MIR122, may significantly contribute to the onset and exacerbation of chronic liver disease.

cancer biology↗