Abstract
Inflammatory cytokines and lncRNAs are closely associated with tumorigenesis. Herein, we reveal inflammatory cytokines IL6 cooperates with long noncoding RNA CUDR to trigger the malignant transformation of human embryonic stem cells-derived hepatocyte-like stem cells. Mechanistically, IL6 cooperates with CUDR to cause MELLT3 to interact with SUV39h1 mRNA3′UTR and promote SUV39h1 expression. Moreover, the excessive SUV39h1 also increases tri-methylation of histone H3 on nineth lysine (H3K9me3). Intriguingly, under inflammatory conditions, H3K9me3 promotes the excessive expression and phosphorylation of NF-κB, and in turn, phorsphorylated NF-κB promotes the expression and phosphorylation of Stat3. Furthermore, that the phosphorylated Stat3 loads onto the promoter region of miRs and lncRNAs. Ultimately, the abnormal expression of miRs and lncRNAs increased telomerase activity, telomere length and microsatellite instability (MSI), leading to malignant transformation of hepatocyte-like stem cells.
Highlights
Inflammatory cytokines and Long non-coding RNAs (lncRNAs) are closely associated with tumorigenesis
We demonstrate that interplay between CUDR with inflammatory cytokines prompts the malignant transformation of hepatocyte-like cells induced by human embryonic stem cells
To explore whether excessive CUDR prompts malignant transformation of human embryonic stem cells derived-hepatocyte-like stem cells in the injury liver inflammation microenvironment induced with Carbon tetrachloride (CCl4), induced hepatotoxicity and trigger liver injury[28,29], we performed liver multiple transfection in vivo with CUDR overexpression or knockdown plasmids
Summary
CUDR prompts malignant transformation of human embryonic stem cells derived-hepatocyte-like stem cells in mouse injury liver inflammation microenvironment. Western blotting showed CUDR overexpression promoted and CUDR knockdown inhibited the expression and its phosphorylation of NFκB in these IL6 treated hepatocyte-like stem cells (Fig. 4f). To address whether CUDR altered the expression and its phosphorylation of Stat[3] through NFκB, we first performed the Chromatin Immunoprecipitation (CHIP) assay in hepatocyte-like stem cells treated with IL6 and transfected with pCMV6-A-GFP, pCMV6-A-GFP-CUDR, pGFP-V-RS, pGFP-V-RS-CUDR. This action was abrogated in control group Both excessive CUDR and CUDR knockdown did significantly alter the telomerase length in hepatocyte-like stem cells without IL6 treatment (Fig. 8d). CUDR enhances telomerase activity, elongates telomere length and increases microsatellite instability(MSI) in the inflammatory environment through miRs or lncRNAs. IL6 cooperates with CUDR to aggravate hepatocyte-like stem cells malignant transformation through NF-κB signaling. Taken Together, these observations suggest that IL6 cooperates with CUDR to aggravate malignant transformation of hepatocyte-like stem cells through NF-κBsignaling
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