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. Graphical abstract

The role of microRNAs in hepatocellular carcinoma: Therapeutic targeting of tumor suppressor and oncogenic genes

“…Cancer-suppressing miR-146a, which controls TLR and cytokine signaling, inhibits TRAF6 and IRAK1 genes [ 98 ]. Essential immune system regulators miR-150, miR-17/92 clusters, and miR-181 may have a role in cell survival and migration [ 99 , 100 ].…”

miR-9 and miR-181a Target Gab2 to Inhibit the Proliferation and Migration of Hepatocellular Carcinoma HepG2 Cells

“…In liver cancer, miR-181a has been found to play a central role in the malignant transformation of tumors. miR-181a promotes the development of hepatocellular carcinoma by regulating PTEN, CBX7, WIF1, and HOXB5 [ 38 , 39 , 40 , 41 ]. However, other reports have indicated that miR-181a is downregulated in HCC and plays a tumor suppressor role targeting cMet, Egr1, and TGF-β [ 42 , 43 , 44 ].…”

Novel miRNA-based drug CD5-2 reduces liver tumor growth in diethylnitrosamine-treated mice by normalizing tumor vasculature and altering immune infiltrate

“…Survival data and expression profiles of microRNAs and mRNAs in The Cancer Genome Atlas (TCGA) HCC dataset were downloaded and analyzed from the OncoLnc website ( http://www.oncolnc.org/ ) or cBioPortal according to the guidelines for citing or using TCGA ( https://www.cancer.gov/about-nci/organization/ccg/research/structural-genomics/tcga/using-tcga/citing-tcga ) ( 14 – 16 ). The TIMER2.0 ( http://timer.cistrome.org/ ) database was accessed to evaluate correlations between the abundance of immune cell infiltrates and VE-Cadherin expression ( 17 ).…”