miR-181a Promotes Multiple Protumorigenic Functions by Targeting TGFβR3

Chitsazzadeh, Vida; Nguyen, Tran; Pulido, Alvaro de Mingo; Bittencourt, Bruna B.; Du, Lili; Adelmann, Charles H.; Rivera, Ivannie Ortiz; Nguyen, Khanh Thi-Thuy; Guerra, Leah; Davis, Andrew John; Napoli, Marco; Ma, Wencai; Davis, R. Eric; Rajapakshe, Kimal; Coarfa, Cristian; Flores, Elsa R.; Tsai, Kenneth Y.

doi:10.1016/j.jid.2021.09.040

Cited by 3 publications

(1 citation statement)

References 35 publications

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“…The current study showed that miR-181ab1 loss altered the expression levels of TGF-beta signature genes, suggesting miR-181 might also regulate the TGF-beta pathway. This notion has been confirmed in squamous cell carcinoma [ 69 ]. However, further investigations are needed to examine detailed aspects of molecular regulations between miR-181, the TGF-beta pathway, and EMT.…”

Section: Discussionmentioning

confidence: 71%

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

Chen

Zhao

Zhang

et al. 2022

Cell. Mol. Life Sci.

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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

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Section: Discussionmentioning

confidence: 71%