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Liver-specific deletion of miR-181ab1 reduces liver tumour progression via upregulation of CBX7.

ABSTRACT: MiR-181 expression levels increased in hepatocellular carcinoma (HCC) compared to non-cancerous tissues. MiR-181 has been widely reported as a possible driver of tumourigenesis but also acts as a tumour suppressor. In addition, the miR-181 family regulates the development and function of immune and vascular cells, which play vital roles in the progression of tumours. More complicatedly, many genes have been identified as miR-181 targets to mediate the effects of miR-181. However, the role of miR-181 in the development of primary tumours remains largely unexplored. We aimed to examine the function of miR-181 and its vital mediators in the progression of diethylnitrosamine-induced primary liver cancers in mice. The size of liver tumours was significantly reduced by 90% in global (GKO) or liver-specific (LKO) 181ab1 knockout mice but not in hematopoietic and endothelial lineage-specific knockout mice, compared to WT mice. In addition, the number of tumours was significantly reduced by 50% in GKO mice. Whole-genome RNA-seq analysis and immunohistochemistry showed that epithelial-mesenchymal transition was partially reversed in GKO tumours compared to WT tumours. The expression of CBX7, a confirmed miR-181 target, was up-regulated in GKO compared to WT tumours. Stable CBX7 expression was achieved with an AAV/Transposase Hybrid-Vector System and up-regulated CBX7 expression inhibited liver tumour progression in WT mice. Hepatic CBX7 deletion restored the progression of LKO liver tumours. MiR-181a expression was the lowest and CBX7 expression the highest in iClust2 and 3 subclasses of human HCC compared to iClust1. Gene expression profiles of GKO tumours overlapped with low-proliferative peri-portal-type HCCs. Liver-specific loss of miR-181ab1 inhibited primary liver tumour progression via up-regulating CBX7 expression, but tumour induction requires both hepatic and non-hepatic miR-181. Also, miR-181ab1-deficient liver tumours may resemble low-proliferative periportal-type human HCC. miR-181 was increased with liver tumour growth. More miR-181, darker colour and higher shape. CBX7 was very low in pericentral hepatocytes, increased in early liver tumours, but reduced in advanced liver tumours. Its levels were maintained in miR-181 KO liver tumours. In tumours (T), brown (darker is more) represents miR-181, the blue circle (thicker is more) represents CBX7.

SUBMITTER: Chen J

PROVIDER: S-EPMC9307539 | biostudies-literature | 2022 Jul

REPOSITORIES: biostudies-literature

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Liver-specific deletion of miR-181ab1 reduces liver tumour progression via upregulation of CBX7.

Chen Jinbiao J Zhao Yang Y Zhang Fan F Li Jia J Boland Jade A JA Cheng Ngan Ching NC Liu Ken K Tiffen Jessamy C JC Bertolino Patrick P Bowen David G DG Krueger Andreas A Lisowski Leszek L Alexander Ian E IE Vadas Mathew A MA El-Omar Emad E Gamble Jennifer R JR McCaughan Geoffrey W GW

Cellular and molecular life sciences : CMLS 20220722 8

MiR-181 expression levels increased in hepatocellular carcinoma (HCC) compared to non-cancerous tissues. MiR-181 has been widely reported as a possible driver of tumourigenesis but also acts as a tumour suppressor. In addition, the miR-181 family regulates the development and function of immune and vascular cells, which play vital roles in the progression of tumours. More complicatedly, many genes have been identified as miR-181 targets to mediate the effects of miR-181. However, the role of miR ...[more]

PMID: 35867177

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Project description:Purpose: miR-181 is upregulated in human liver cancer. The cancer genome atlas (TCGA) liver cancer data show that the iCluster1 subclass of hepatocellular carcinoma (HCC) has a higher expression of miR-181 than either the iCluster2 or iCluster3 subclass, suggesting it may be a driver of oncogenesis. However, the miR-181 family has also been reported to inhibit tumour progression. Thus, we aim to examine the function of miR-181 and its vital mediators in hepatocarcinogenesis. Methods: Primary liver tumours were induced with diethylnitrosamine (DEN) in global (miR-181ab1GKO), liver-specific (miR-181ab1LKO) and hematopoietic & endothelial lineage-specific (miR-181ab1vavKO) miR-181ab1 deletion mice. The molecular and cellular characterization was carried out using immunohistochemistry and whole-genome transcriptome analysis. Liver-specific miR-181a and CBX7 double knockout mice were used to investigate the role of CBX7 in mediating miR-181 effects on liver tumour progression. An AAV/Transposase Hybrid-Vector System used in this study gave a reliable long-term expression of CBX7 in vivo. Relevant gene expression profiles and patient outcomes were downloaded from TCGA database, and their correlations were analysed. The mRNA profiles of miR-181ab1 wild-type (WT) and knockout (KO) mice were generated by deep sequencing, in triplicate, using Illumina HiSeq. After quality control procedures, short reads were mapped to mouse genome assembly (mm10) by STAR version 2.7.3a. Mapped reads were quantified by featureCounts version 2.0.0 from Subread package. Ward’s hierarchical clustering method was applied to group the samples based on the gene expression matrix. Differential gene expression analysis was then conducted using R package Limma. Gene set enrichment analysis was subsequently performed with R package clusterProfiler. Overlaps between differential expressed gene sets and gene sets in MSigDB were computed with Gene Set Enrichment Analysis (GSEA). Results: The number and size of liver tumours in 181ab1GKO mice were significantly reduced by 50% and 90%, respectively, compared to WT mice at 34-week post-DEN injection. The number of tumours in 181ab1LKO mice was no different from that of control mice, but the size of liver tumours was significantly reduced by 90%. The number and size of tumours were similar in miR-181ab1vavKO and WT mice. Consistent with the roles of miR-181 in the promotion of epithelial to mesenchymal transition (EMT), the TGF-beta signalling pathway was inhibited in 181ab1GKO tumours compared with WT tumours, and expression of E-Cadherin, an EMT marker, was significantly increased in miR-181ab1 KO tumours compared to WT tumours. CBX7 was reduced in WT liver tumours compared to non-tumours, and restored CBX7 expression inhibited the progression of liver tumours in WT mice. At the same time, CBX7 was upregulated in miR-181ab1 KO tumours compared to WT tumours, and CBX7 deletion turned the reduced progression of miR-181ab1 KO liver tumours back to WT liver tumours. MiR-181a expression was the lowest and CBX7 expression the highest in iCluster 2 & 3 subclasses of human HCC compared to iCluster 1. Gene expression profiles were significantly overlapped between human low proliferative periportal-type HCCs and miR-181ab1 KO tumours. Conclusions: Primary liver tumour progression is inhibited by loss of miR-181ab1 via up-regulation of CBX7 expression at the level of the liver cancer cells themselves, but tumour induction requires both hepatic and non-hepatic expression. Tumours in miR-181ab1 KO mice resemble low-proliferative periportal-type human HCC and could represent a new model to study therapies for such difficult-to-treat tumours.

Dataset Information

Liver-specific deletion of miR-181ab1 reduces liver tumour progression via upregulation of CBX7.

Publications

Liver-specific deletion of miR-181ab1 reduces liver tumour progression via upregulation of CBX7.

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