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

Juan Carlos Hernandez; Chia-Lin Chen; Tatsuya Machida; Dinesh Babu Uthaya Kumar; Stanley M. Tahara; Jared Montana; Linda Sher; Jake Liang; Jae U. Jung; Hidekazu Tsukamoto; Keigo Machida

iScience (Mar 2023)

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

Juan Carlos Hernandez,
Chia-Lin Chen,
Tatsuya Machida,
Dinesh Babu Uthaya Kumar,
Stanley M. Tahara,
Jared Montana,
Linda Sher,
Jake Liang,
Jae U. Jung,
Hidekazu Tsukamoto,
Keigo Machida

Affiliations

Juan Carlos Hernandez: 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
Chia-Lin Chen: Departments of Molecular Microbiology and Immunology, University of Southern California, Los Angeles, CA 90033, USA
Tatsuya Machida: Departments of Molecular Microbiology and Immunology, University of Southern California, Los Angeles, CA 90033, USA
Dinesh Babu Uthaya Kumar: Departments of Molecular Microbiology and Immunology, University of Southern California, Los Angeles, CA 90033, USA
Stanley M. Tahara: Departments of Molecular Microbiology and Immunology, University of Southern California, Los Angeles, CA 90033, USA
Jared Montana: Departments of Molecular Microbiology and Immunology, University of Southern California, Los Angeles, CA 90033, USA
Linda Sher: Department of Surgery, University of Southern California, Los Angeles, CA 90033, USA
Jake Liang: NIDDK, Bethesda, DC, USA
Jae U. Jung: Departments of Molecular Microbiology and Immunology, University of Southern California, Los Angeles, CA 90033, USA
Hidekazu Tsukamoto: 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
Keigo Machida: 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; Corresponding author

Journal volume & issue: Vol. 26, no. 3
p. 106254

Abstract

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Summary: 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.

Published in iScience

ISSN: 2589-0042 (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Science
Website: http://www.cell.com/iscience/home

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