| First Author | Hernandez JC | Year | 2023 |
| Journal | iScience | Volume | 26 |
| Issue | 3 | Pages | 106254 |
| PubMed ID | 36949755 | Mgi Jnum | J:334295 |
| Mgi Id | MGI:7447995 | Doi | 10.1016/j.isci.2023.106254 |
| Citation | Hernandez JC, et al. (2023) LIN28 and histone H3K4 methylase induce TLR4 to generate tumor-initiating stem-like cells. iScience 26(3):106254 |
| abstractText | 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. |
