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

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

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Item Type: Article
Status: Published
Date: 22 July 2022
Divisions: Liver Immunology
Liver Injury and Cancer
Melanoma Epigenetics Laboratory
Vascular Biology
Depositing User: General Admin
Date Deposited: 13 Sep 2022 04:34
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.

Creators:
Creators
Email
Chen, Jinbiao
UNSPECIFIED
Zhao, Yang
UNSPECIFIED
Zhang, Fan
UNSPECIFIED
Li, Jia
UNSPECIFIED
Boland, Jade A.
UNSPECIFIED
Cheng, Ngan Ching
UNSPECIFIED
Liu, Ken
UNSPECIFIED
Tiffen, Jessamy C.
UNSPECIFIED
Bertolino, Patrick
UNSPECIFIED
Bowen, David G.
UNSPECIFIED
Krueger, Andreas
UNSPECIFIED
Lisowski, Leszek
UNSPECIFIED
Alexander, Ian E.
UNSPECIFIED
Vadas, Mathew A.
UNSPECIFIED
El-Omar, Emad
UNSPECIFIED
Gamble, Jennifer R.
UNSPECIFIED
McCaughan, Geoffrey W.
UNSPECIFIED
Last Modified: 25 Sep 2022 23:53
URI: https://eprints.centenary.org.au/id/eprint/1269

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