LIN28 and histone H3K4 methylase induce TLR4 to generate tumor-initiating stem-like cells.

Autor:	Hernandez JC; Departments of Molecular Microbiology and Immunology, University of Southern California, Los Angeles, CA 90033, USA.; MS Biotechnology Program, California State University Channel Islands, Camarillo, CA 93012, USA., Chen CL; Departments of Molecular Microbiology and Immunology, University of Southern California, Los Angeles, CA 90033, USA.; Department of Life Sciences & Institute of Genome Sciences, National Yang Ming Chiao Tung University, Taipei 110, Taiwan., Machida T; Departments of Molecular Microbiology and Immunology, University of Southern California, Los Angeles, CA 90033, USA., Uthaya Kumar DB; Departments of Molecular Microbiology and Immunology, University of Southern California, Los Angeles, CA 90033, USA., Tahara SM; Departments of Molecular Microbiology and Immunology, University of Southern California, Los Angeles, CA 90033, USA., Montana J; Departments of Molecular Microbiology and Immunology, University of Southern California, Los Angeles, CA 90033, USA., Sher L; Department of Surgery, University of Southern California, Los Angeles, CA 90033, USA., Liang J; NIDDK, Bethesda, DC, USA., Jung JU; Departments of Molecular Microbiology and Immunology, University of Southern California, Los Angeles, CA 90033, USA., Tsukamoto H; Department of Pathology, University of Southern California, Los Angeles, CA 90033, USA.; Southern California Research Center for ALPD and Cirrhosis, Los Angeles, CA, USA.; Department of Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, CA, USA., Machida K; Departments of Molecular Microbiology and Immunology, University of Southern California, Los Angeles, CA 90033, USA.; Southern California Research Center for ALPD and Cirrhosis, Los Angeles, CA, USA.
Jazyk:	angličtina
Zdroj:	IScience [iScience] 2023 Feb 22; Vol. 26 (3), pp. 106254. Date of Electronic Publication: 2023 Feb 22 (Print Publication: 2023).
DOI:	10.1016/j.isci.2023.106254
Abstrakt:	Chemoresistance and plasticity of tumor-initiating stem-like cells (TICs) promote tumor recurrence and metastasis. The gut-originating endotoxin-TLR4-NANOG oncogenic axis is responsible for the genesis of TICs. This study investigated mechanisms as to how TICs arise through transcriptional, epigenetic, and post-transcriptional activation of oncogenic TLR4 pathways. Here, we expressed constitutively active TLR4 ( caTLR4 ) in mice carrying pLAP-tTA or pAlb-tTA, under a tetracycline withdrawal-inducible system. Liver progenitor cell induction accelerated liver tumor development in caTLR4-expressing mice. Lentiviral shRNA library screening identified histone H3K4 methylase SETD7 as central to activation of TLR4. SETD7 combined with hypoxia induced TLR4 through HIF2 and NOTCH. LIN28 post-transcriptionally stabilized TLR4 mRNA via de-repression of let-7 microRNA. These results supported a LIN28-TLR4 pathway for the development of HCCs in a hypoxic microenvironment. These findings not only advance our understanding of molecular mechanisms responsible for TIC generation in HCC, but also represent new therapeutic targets for the treatment of HCC. Competing Interests: There is no conflict of interest. (© 2023 The Author(s).)
Databáze:	MEDLINE
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