Inflammatory cytokine IL6 cooperates with CUDR to aggravate hepatocyte-like stem cells malignant transformation through NF-κB signaling

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.

Non-coding RNA in hepatocellular carcinoma: Mechanisms, biomarkers and therapeutic targets

“…76 Furthermore, a positive feedback loop links IL6 and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-jB). 77 Several lncRNAs either activate 9,78 or inhibit 20,22 STAT3 signaling in liver cancer (Fig. 4).…”

“…UCA1 induces also the malignant transformation of hepatocyte-like-stem cells in an experimental mouse model. 78 Moreover, UCA1 contributes to the proliferation of HCC cells via regulation of CDKN1B. 79 UCA1 is also linked to the development of drug resistances in human cancer cells.…”

Emerging roles of long non-coding RNAs in tumor metabolism

“…As indicated by recent studies, UCA1 activates mTOR by upregulating HK2 and increases glycolysis through both the activation of STAT3 and the repression of miR-143, thereby revealing a novel glucose metabolism regulatory pathway, UCA1-mTOR-STAT3/miR-143/HK2, in bladder cancer cells [ 131 , 132 ]. Interestingly, mTOR can also be activated by CUDR, thus regulating HK2 expression through the activation of STAT3 and the repression of miR-143 [ 133 ].…”

Long non‑coding RNA BCAR4 promotes liver cancer progression by regulating proliferation, migration and invasion

“…Several canonical signaling pathways have been indicated to mediate lncRNA-regulated behaviors in LC, such as Wnt signaling (24,25) and STAT3 signaling (26)(27)(28)(29). In addition, Table III.…”