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MiR-22 gene therapy as a novel option for HCC treatment in part via augmentation of retinoic acid but silencing IL17 signaling in orthotopic murine models

ABSTRACT: miR-22 expression is reduced in hepatocellular carcinoma (HCC), a deadly cancer with very limited treatment options. Our published data showed that retinoic acid (RA) via its receptor RARβ induces miR-22. Moreover, miR-22 increase the expression of RARβ, which signifies the significance of RA signaling in tumor suppression. Using orthotopic HCC mice models including β-catenin positive HCC, we studied the anti-HCC effect of miR-22 for the first time focusing on the potential roles of RA signaling in regulating tumor immunity based on transcriptomic profiling data found in both mouse and human HCC. Our data showed that miR-22 treated HCC without toxicity, with improved survival compared with Lenvatinib. Reduced RA signaling and increased IL17 signaling found in mouse HCC as well as isolated T cells were consistently found in miR-22 low human HCC, whereas miR-22 treatment of mouse HCC reversed both pathways verified in β-catenin positive HCC. Moreover, in isolated T cells, miR-22 silenced the Il17a gene, which lead to Th17 cell reduction, by reducing the recruitment of HIFα to the Rorc gene as well as the RORγT, HIF1α, and STAT3 to the Il17a gene. Further, IL23-driven IL17 signaling expansion attenuated the anti-HCC effects of miR-22. Additionally, CD8 blockade diminished the therapeutic effects of miR-22. Together, via regulating tumor immunity, miR-22 can be a novel option for HCC treatment.

ORGANISM(S): Mus musculus

PROVIDER: GSE215753 | GEO | 2023/08/21

REPOSITORIES: GEO

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Project description:Microarray analysis reveals up-regulation of retinoic acid and hepatocyte growth factor related signaling pathways by pro-insulin C-peptide in kidney proximal tubular cells: Antagonism of the pro-fibrotic effects of TGF-b1 Novel signaling roles for C-peptide have recently been discovered with evidence that it can ameliorate complications of type 1 diabetes. Here we sought to identify new pathways regulated by C-peptide of relevance to the pathophysiology of diabetic nephropathy. Microarray analysis was performed to identify genes regulated by either C-peptide and/or transforming growth factor beta 1 (TGF-β1) in a human proximal tubular cell line, HK-2. Expression of retinoic acid receptor β (RARβ), hepatcoyte growth factor (HGF), cellular retinoic acid binding protein II (CRABPII), vimentin, E-cadherin, Snail and β-catenin was assessed by immunoblotting. The cellular localisation of vimentin and β-catenin was determined by immunocytochemistry. Changes in cell morphology were assessed by phase contrast microscopy. Gene expression profiling demonstrated differential expression of 953 and 1,458 genes after C-peptide exposure for 18h or 48h respectively. From these, members of the anti-fibrotic retinoic acid (RA) and HGF signaling pathways were selected. Immunoblotting demonstrated that C-peptide increased RARβ, CRABPII and HGF. We confirmed a role for RA in reversal of TGF-β1-induced changes associated with epithelial-mesenchymal transition (EMT), including expression changes in Snail, E-cadherin, vimetin and redistribution of β-catenin. Importantly, these TGF-β1-induced changes were inhibited by C-peptide. Further, effects of TGF-β1 on Snail and E-cadherin expression were blocked by HGF and inhibitory effects of C-peptide were removed by blockade of HGF activity. This study identifies a novel role for HGF as an effector of C-peptide, possibly via an RA signaling pathway, highlighting C-peptide as a potential therapy for diabetic nephropathy.

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MiR-22 gene therapy as a novel option for HCC treatment in part via augmentation of retinoic acid but silencing IL17 signaling in orthotopic murine models

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