The lncrna h19-derived microrna-675 promotes liver necroptosis by targeting fadd

Rona Harari-Steinfeld, Maytal Gefen, Alina Simerzin, Elina Zorde-Khvalevsky, Mila Rivkin, Ezra Ella, Tomer Friehmann, Mordechay Gerlic, Jessica Zucman-Rossi, Stefano Caruso, Mélissa Leveille, Jennifer L. Estall, Daniel S. Goldenberg, Hilla Giladi, Eithan Galun, Zohar Bromberg

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Article number411
Pages (from-to)1-17
Number of pages17
JournalCancers
Volume13
Issue number3
DOIs
StatePublished - 1 Feb 2021

Keywords

  • Apoptosis
  • Hepatocellular carcinoma
  • Liver inflammation
  • Necrosis

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