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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. [ABSTRACT FROM AUTHOR]

Both miR675 and pyruvate kinase M2 (PKM2) contribute to malignant progression of tumor, but its functions in liver cancer stem cells remain unclear. Herein, our findings indicate that miR675 plus PKM2 strongly promotes the growth of liver cancer stem cells. Mechanistically, miR675 plus PKM2 enhances the transcriptional activity of SUV39h2. On the other hand, the excessive SUV39h2 binds to more substrate histone H3, triggering an increase of tri-methylation of histone H3 on the ninth lysine. Furthermore, the tri-methylation of histone 3 on the ninth lysine (H3K9me3)-heterochromatin protein 1 alpha (HP1α) complex is increased when the complex occupancy ability on the C-myc promoter region is raised, recruiting CREB, P300, and RNApolII to the special position that results in C-myc high abundance. Therefore, miR675 plus PKM2 triggered the upregulation of C-myc by increasing the interaction between H3K9me3 and HP1α. Understanding the signaling pathways that miR675 plus PKM2 epigenetically possesses during the malignant transformation of liver cancer stem cells will contribute to more effective liver cancer therapies. [ABSTRACT FROM AUTHOR]

Background: Long noncoding RNA HULC is highly up-regulation in human hepatocellular carcinoma (HCC). However, the functions of HULC in hepatocarcinogenesis remains unclear. Methods: RT-PCR, Western blotting, Chromatin immunoprecipitation (CHIP) assay, RNA Immunoprecipitation (RIP) and tumorignesis test in vitro and in vivo were performed. Results: HULC is negatively associated with expression of PTEN or miR15a in patients of human liver cancer. Moreover, HULC accelerates malignant progression of liver cancer cells in vitro and in vivo. Mechanistically, HULC increasesthe expression of P62 via decreasing mature miR15a. On the other hand, excessive HULC increases the expression of LC3 on the level of transcription and then activates LC3 through Sirt1 (a deacetylase). Notably, HULC enhanced the interplay between LC3 and ATG3. Furthermore, HULC also increases the expression of becline-1(autophagy related gene). Therefore, HULC increases the cellular autophagy by increasing LC3II dependent on Sirt1.Noteworthy, excessive HULC reduces the expression of PTEN, β-catenin and enhances the expression of SAPK/JUNK, PKM2, CDK2, NOTCH1, C-Jun in liver cancer cells. Of significance, our observations also revealed that HULC inhibited PTEN through ubiquitin–proteasome system mediated by autophagy-P62.Ultimately,HULC activates AKT-PI3K-mTOR pathway through inhibiting PTEN in human liver cancer cells. Conclusions: This study elucidates a novel mechanism that lncRNA HULC produces a vital function during hepatocarcinogenesis. [ABSTRACT FROM AUTHOR]