TY - JOUR
T1 - The lncrna h19-derived microrna-675 promotes liver necroptosis by targeting fadd
AU - Harari-Steinfeld, Rona
AU - Gefen, Maytal
AU - Simerzin, Alina
AU - Zorde-Khvalevsky, Elina
AU - Rivkin, Mila
AU - Ella, Ezra
AU - Friehmann, Tomer
AU - Gerlic, Mordechay
AU - Zucman-Rossi, Jessica
AU - Caruso, Stefano
AU - Leveille, Mélissa
AU - Estall, Jennifer L.
AU - Goldenberg, Daniel S.
AU - Giladi, Hilla
AU - Galun, Eithan
AU - Bromberg, Zohar
N1 - Publisher Copyright:
© 2021 by the authors. Licensee MDPI, Basel, Switzerland.
PY - 2021/2/1
Y1 - 2021/2/1
N2 - The H19-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 (p = 0.014) as well as in human samples (p = 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.
AB - The H19-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 (p = 0.014) as well as in human samples (p = 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.
KW - Apoptosis
KW - Hepatocellular carcinoma
KW - Liver inflammation
KW - Necrosis
UR - http://www.scopus.com/inward/record.url?scp=85099691536&partnerID=8YFLogxK
U2 - 10.3390/cancers13030411
DO - 10.3390/cancers13030411
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C2 - 33499244
AN - SCOPUS:85099691536
SN - 2072-6694
VL - 13
SP - 1
EP - 17
JO - Cancers
JF - Cancers
IS - 3
M1 - 411
ER -
