The lncRNA H19-Derived MicroRNA-675 Promotes Liver Necroptosis by Targeting FADD

The -derived microRNA-675 (miR-675) has been implicated as both tumor promoter and tumor suppressor and also plays a role in liver inflammation. We found that miR-675 promotes cell death in human hepatocellular carcinoma (HCC) cell lines. We show that Fas-associated protein with death domain (FADD),...

Full description

Saved in:
Bibliographic Details
Published in:Cancers 2021-01, Vol.13 (3), p.411
Main Authors: Harari-Steinfeld, Rona, Gefen, Maytal, Simerzin, Alina, Zorde-Khvalevsky, Elina, Rivkin, Mila, Ella, Ezra, Friehmann, Tomer, Gerlic, Mordechay, Zucman-Rossi, Jessica, Caruso, Stefano, Leveille, Mélissa, Estall, Jennifer L, Goldenberg, Daniel S, Giladi, Hilla, Galun, Eithan, Bromberg, Zohar
Format: Article
Language:English
Subjects:
Animal models
Apoptosis
Cell death
Cell growth
FADD protein
Fas-associated protein
Genes
Hepatocellular carcinoma
Hypoxia
Inflammation
Kinases
Life Sciences
Liver cancer
MAP kinase
MicroRNAs
miRNA
Necroptosis
Proteins
Tumor cell lines
Tumor suppressor genes
Tumors
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:The -derived microRNA-675 (miR-675) has been implicated as both tumor promoter and tumor suppressor and also plays a role in liver inflammation. We found that miR-675 promotes cell death in human hepatocellular carcinoma (HCC) cell lines. We show that Fas-associated protein with death domain (FADD), a mediator of apoptotic cell death signaling, is downregulated by miR-675 and a negative correlation exists between miR-675 and FADD expression in mouse models of HCC ( = 0.014) as well as in human samples ( = 0.017). We demonstrate in a mouse model of liver inflammation that overexpression of miR-675 promotes necroptosis, which can be inhibited by the necroptosis-specific inhibitor Nec-1/Nec-1s. miR-675 induces the level of both p-MLKL (Mixed Lineage Kinase Domain-Like Pseudokinase) and RIP3 (receptor-interacting protein 3), which are key signaling molecules in necroptosis, and enhances MLKL binding to RIP3. miR-675 also inhibits the levels of cleaved caspases 8 and 3, suggesting that miR-675 induces a shift from apoptosis to a necroptotic cellular pathway. In conclusion, downregulation of FADD by miR-675 promotes liver necroptosis in response to inflammatory signals. We propose that this regulation cascade can stimulate and enhance the inflammatory response in the liver, making miR-675 an important regulator in liver inflammation and potentially also in HCC.
ISSN:2072-6694
2072-6694
DOI:10.3390/cancers13030411