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- W2486951054 abstract "Hepatocellular carcinoma (HCC), the second-leading cause of cancer-related death world-wide, displays overexpression of the pro-inflammatory cytokine interleukin6 (IL6) and inhibition of transforming growth factor β (TGF-β) in its early phase. We aimed to identify the dynamics of liver immune cells under inflammatory conditions and to characterize early-phase tumor-initiating cells to comprehend aberrant molecular pathway(s) in HCC progression in a TGF-β disrupted murine model (β2SP+/-). Methods: Chronic inflammation was induced in wild-type (WT) and β2SP+/- mice by hydrodynamic injection of IL6 (pIL6) encoding Sleeping Beauty transposons twice per month for 3 months. Liver stem cells were isolated by using CD133 antibody at the end of third month and cultured with suitable supplements. Results: Culturing of stem cells enriched from WT and β2SP+/- mice treated with pIL6 showed that the stem cells derived from β2SP+/- mice were highly tumorigenic and metastatic in immune-deficient mice. Staining of these cells with EMT markers Twist and Slug were found in the nucleus. Immunophenotyping suggested that pIL6 treatment induced significant expansion and pro-inflammatory phenotypes of liver NKT and suppressed MDSCs in the β2SP+/- mice compared with WT to generate tumorigenic stem cells. By using numerous pharmacological inhibitors to identify aberrant molecular signaling event(s), we discovered constitutively activated nuclear factor κB (NF-κB) in these cancer stem cells (CSCs). Upon stable knockdown of NF-κB in the CSCs, both EMT phenotype and metastatic ability decreased significantly both in vitro and in vivo. Furthermore, screening of putative kinase(s) that could phosphorylate NF-κB identified that TGF-β activated kinase-1 (TAK-1) directly phosphorylated NF-κB. Staining of HCC tissue specimens showed that CD133+ liver stem cells expressed constitutively activated NF-κB. Conclusions: Collectively, our data suggest that IL6, highly expressed in 40% HCC patients, can be considered an initiation driver to develop metastatic CSCs by constitutively activated TAK1-NFκB pathway at pre-HCC stage. Citation Format: Abhisek Mitra, Xueqing Xia, Lopa Mishra, Shulin Li. IL6 mediated inflammatory loop reprograms normal to highly metastatic cancer stem cells at pre-HCC liver in β2SP+/- mice. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1569." @default.
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- W2486951054 date "2016-07-15" @default.
- W2486951054 modified "2023-09-27" @default.
- W2486951054 title "Abstract 1569: IL6 mediated inflammatory loop reprograms normal to highly metastatic cancer stem cells at pre-HCC liver in β2SP+/- mice" @default.
- W2486951054 doi "https://doi.org/10.1158/1538-7445.am2016-1569" @default.
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