LncRNA-MIAT activates hepatic stellate cells via regulating Hippo pathway and epithelial-to-mesenchymal transition

Abstract

Long non-coding RNA-myocardial infarction-associated transcript (lncRNA-MIAT) has been reported to play an important role in the development of multiple cancers. However, the biological roles of MIAT in liver fibrosis are still unknown. In this study, the expression of MIAT is up-regulated during liver fibrosis. Silencing MIAT leads to the suppression of hepatic stellate cell (HSC) proliferation and collagen expression. Double immunofluorescence analysis additionally demonstrates that MIAT inhibition leads to the suppression of type I collagen and α-SMA in vitro. In vivo, MIAT knockdown contributes to the inhibition of fibrosis progression and collagen accumulation. MIAT is confirmed as a target of miR-3085-5p, and the co-location of MIAT and miR-3085-5p is found in HSC cytoplasm. Interestingly, there is a negative correlation between MIAT expression and miR-3085-5p level in cirrhotic patients as well as activated HSCs. In addition, the effects of MIAT inhibition on HSC inactivation are blocked down by miR-3085-5p inhibitor. YAP is a target of miR-3085-5p. Reduced YAP caused by loss of MIAT is reversed by miR-3085-5p inhibitor. Notably, YAP knockdown results in the suppression of MIAT-mediated epithelial-to-mesenchymal transition (EMT) process. In conclusion, we demonstrate that MIAT enhances the activation of HSCs, at least in part, via miR-3085-5p/YAP/EMT signaling pathway.

LncRNA FRMD6‐AS1/miR‐491‐5p/USP13 pathway attenuated ferroptosis and contributed to liver fibrosis

“…The highly expressed lncRNAs normally exert promotion functions in HSCs activation and ECM deposition to contribute to liver fibrosis 39 . LncRNA MIAT expression was elevated in liver tissues from patients with cirrhosis, MIAT downregulation repressed HSCs activation (including decreasing α‐SMA and COL1α1 expressions) 19 . LINC01711 expression was highly expressed in TGF‐β‐induced human HSCs LX‐2, LINC01711 overexpression increased α‐SMA and COL1α1 expressions in TGF‐β‐induced LX‐2 cells 39 .…”

“…Many lncRNAs, such as lncRNA MIAT, LINC00663, and lncRNA DUXAP8, inhibit ferroptosis, aggravate liver injury and accelerate liver fibrosis 19–21 . LncRNA FERM Domain Containing 6 Antisense RNA 1 (FRMD6‐AS1) is a recently discovered lncRNA that firstly found in lung cancer 22 .…”

LncRNA-SNHG5 mediates activation of hepatic stellate cells by regulating NF2 and Hippo pathway

“…However, the underlying mechanism for the roles of Hippo/YAP pathway in HSC activation is still largely unknown. Moreover, recent studies have reported that the Hippo pathway-mediated EMT process may be involved in HSC activation 43 . Li et al found that SNHG5 could induce the EMT process to promote the progression of HCC 30 .…”

Puzzling out the role of MIAT LncRNA in hepatocellular carcinoma

“…MIAT acts as a sponge for miR-3085–5p, showing a negative correlation with miR-3085–5p levels in cirrhotic patients and activated HSCs. The study underscores the role of MIAT in HSC activation through the miR-3085–5p/ YAP1 , where MIAT inhibition leads to reduced yes-associated protein 1 (YAP1) levels and subsequent suppression of the epithelial-to-mesenchymal transition (EMT) process [ 104 ]. While the detailed function of MIAT in alcoholic liver disease and chronic hepatitis has not yet been investigated, to the best of our knowledge, given its role in fibrosis and cirrhosis there is potential for a similar influential role in other forms of CLD.…”