a b s t r a c tIn liver cancer, miR-155 up-regulation can regulate cancer-cell invasion. However, whether miR-155 expression is associated with liver cancer stem cells (CSCs) remains unknown. Here, we show that miR-155 expression is up-regulated in tumor spheres. Knock-down of miR-155 resulted in suppression of tumor sphere formation, through a decrease in the proportion of CD90 + and CD133 + CSCs and in the expression of Oct4, whereas miR-155 overexpression had the opposite effect. TP53INP1 was determined to be involved in the CSCs-like properties that were regulated by miR-155. Thus, miR-155 may play an important role in promoting the generation of stem cell-like cells and their selfrenewal by targeting the gene TP53INP1.
Oncogenic mutations in PIK3CA, the gene encoding the catalytic subunit of phosphoinositide 3-kinase (PI3K), occur with high frequency in hepatocellular carcinoma (HCC). The protein kinase Akt is considered to be the primary effector of PI3K, but there is evidence to suggest that serum and glucocorticoid kinase 3 (SGK3) acts in an Akt-independent manner downstream of PI3K. In this report, we found that SGK3 promotes epithelial-mesenchymal transition (EMT) and reduces phosphorylation-dependent degradation of β-catenin in HCC cells. We determined that miR-155, previously shown to promote EMT, stimulates the expression of SGK3 by targeting and repressing P85α, thereby removing its inhibitory effect on PI3K-AKT signaling. These findings suggest that miR-155 promotes EMT and metastatic properties in HCC cells through activation of PI3K/SGK3/β-catenin signaling pathways.
The phosphoinositide 3-kinase pathway is one of the most commonly altered pathways in human cancers. The serum/glucocorticoid-regulated kinase (SGK) family of serine/threonine kinases consists of three isoforms, SGK1, SGK2, and SGK3. This family of kinases is highly homologous to the AKT kinase family, sharing similar upstream activators and downstream targets. Few studies have investigated the role of SGK2 in hepatocellular carcinoma. Here, we report that SGK2 expression levels were upregulated in hepatocellular carcinoma tissues and human hepatoma cell lines compared to the adjacent normal liver tissues and a normal hepatocyte line, respectively. We found that downregulated SGK2 inhibits cell migration and invasive potential of hepatocellular carcinoma cell lines (SMMC-7721 and Huh-7).We also found that downregulated SGK2 suppressed the expression level of unphosphorylated (activated) glycogen synthase kinase 3 beta. In addition, SGK2 downregulation decreased the dephosphorylation (activation) of β-catenin by preventing its proteasomal degradation in the hepatocellular carcinoma cell lines. These findings suggest that SGK2 promotes hepatocellular carcinoma progression and mediates glycogen synthase kinase 3 beta/β-catenin signaling in hepatocellular carcinoma cells.
Programmed death ligand 1 (PD‐L1) plays an important role in the occurrence of hepatocellular carcinoma (HCC). The present study indicated that epithelial–mesenchymal transition (EMT) and induction of cancer stem cell (CSC)‐like properties contribute to metastasis of cancers. However, the molecular mechanisms underlying PD‐L1 and EMT and CSC phenotypes in HCC remain to be elucidated. Here, we report that PD‐L1 regulates not only EMT but also the stem‐like transition in liver cancer cells. We observed high PD‐L1 expression in CD133+ liver CSCs and CSC‐enriched tumor spheres. Altering PD‐L1 expression promoted liver CSC phenotypes by increasing the expression of stemness genes, the CD133+ cell population sizes, and the ability to form tumor spheres. Programmed death ligand 1 enhanced HCC cell tumorigenicity and invasion in nude mice. Additionally, PD‐L1 overexpression in cells significantly increased cell motility and invasion, as well as the EMT process. Conversely, suppression of PD‐L1 in cells had an opposite effect. Prolonged treatment of HCC cells with Akt inhibitor prefosine leads to activation of serum and glucocorticoid kinase 2 (SGK2) and rescued downregulation of PD‐L1. Mechanistically, PD‐L1 directly interacted with SGK2. Programmed death ligand 1 upregulated SGK2 and activated the SGK2/β‐catenin signaling pathway, and promoted EMT and CSC expansion in liver cancer cells, highlighting the role of SGK2 in PD‐L1‐mediated EMT and CSC phenotypes in liver cancer cells. In conclusion, our findings suggest that PD‐L1 activated the SGK2/β‐catenin signaling pathway, to induce EMT and acquisition of a stem cell phenotype.
SummaryTransforming growth factorb1 (TGFb1) is considered to be the principal contributor to liver fibrosis. So in this study the ribozymes against TGFb1 were designed. The in vitro cleavage activities of the ribozymes were assayed through incubation of 32 p-labeled target RNAs and 32 p-labeled ribozymes in different conditions. HSC-T6 cells were transfected with the eukaryotic constructs encoding ribozyme and disable ribozyme, then the stable cell clones were used to evaluate its antifibrotic characteristic through the effect of ribozyme on biological character of activated hepatic stellate cells (HSCs). The results demonstrated that two ribozymes (Rz803 and Rz1395) could cleave target RNAs into expected products effectively, Rz803 possessed better cleavage activity in vitro. Stable transfection of Rz803 into activated HSCs reduced TGFb1 expression in mRNA and protein level efficiently. The further studies demonstrated that Rz803 reduced deposition of collagen I, suppressed HSC proliferation, but had no effect on HSC activation in transfected HSC-T6 cells. Therefore, it indicated that Rz803 could reverse the character of activated HSCs by downregulating TGFb1 expression efficiently and diminishing TGFb1 signaling underlying activation of hepatic stellate cells. As the consequence, it would provide a potential therapeutic approach for liver fibrosis. IUBMB Life, 57: 31-39, 2005 Keywords RNA, catalytic; transforming growth factorb1, hepatic stellate cell; Character Introduction:
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