MLKL Inhibits Intestinal Tumorigenesis by Suppressing STAT3 Signaling Pathway

Overview

Journal Int J Biol Sci

Specialty Biology

Date 2021 Mar 26

PMID 33767595

Citations 8

Authors

Qun Zhao

Xinran Cheng

Jian Guo

Yun Bi

Li Kuang

Jianhua Ren

Jing Zhong

Longrui Pan

Xudong Zhang

Yang Guo

Yongqiang Liu

Shu Jin

Yan Tan

Xianjun Yu

Affiliations

Soon will be listed here.

Abstract

Mixed lineage kinase domain-like protein (MLKL) plays an important role in necroptosis, but the role and mechanism of MLKL in intestinal tumorigenesis remain unclear. Here, we found that hematopoietic- and nonhematopoietic-derived MLKL affected intestinal inflammation, but nonhematopoietic-derived MLKL primarily inhibited intestinal tumorigenesis. Loss of MLKL enhanced intestinal regeneration and the susceptibility to intestinal tumorigenesis in mice by hyperactivating the Janus kinase 2 (JAK2)/ signal transducer and activator of transcription 3 (STAT3) axis. Furthermore, MLKL deficiency increased interleukin-6 (IL-6) production in dendritic cells. Administration of anti-IL-6R antibody therapy reduced intestinal tumorigenesis in mice. Notably, low MLKL expression in human colorectal tumors, which enhanced STAT3 activation, was associated with decreased overall survival. Together, our results reveal that MLKL exhibits a suppressive effect during intestinal tumorigenesis by suppressing the IL-6/JAK2/STAT3 signals.

Citing Articles

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Transcriptomic comparison of two selective retinal cell ablation paradigms in zebrafish reveals shared and cell-specific regenerative responses.

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The Many Faces of MLKL, the Executor of Necroptosis.

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The Induction Mechanism of Ferroptosis, Necroptosis, and Pyroptosis in Inflammatory Bowel Disease, Colorectal Cancer, and Intestinal Injury.

Zhou P, Zhang S, Wang M, Zhou J Biomolecules. 2023; 13(5).

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