Abstract:Primary liver tumours have a high incidence and mortality. The most important forms are hepatocellular carcinoma and intrahepatic cholangiocarcinoma, both can occur together in the mixed phenotype hepatocellular-cholangiocarcinoma. Liver progenitor cells (LPCs) are bipotential stem cells activated in case of severe liver damage and are capable of forming both cholangiocytes and hepatocytes. Possibly, alterations in Wnt, transforming growth factor-β, Notch and hypoxia pathways in these LPCs can cause them to gi… Show more
“…1a and b). In addition, HFHs have features similar to hepatic progenitor cells, which possess self-renewal capacity and migratory potential 26 . Thus, compared with these cancer cells, the relative increase in the migratory and invasive abilities of HFHs is thought to be due to these reported characteristics.Figure 1Downregulation of UHRF1 enhances the migratory and invasive properties of hepatocellular carcinoma cells.…”
UHRF1 (ubiquitin-like, with PHD and RING finger domains 1) plays a crucial role in DNA methylation, chromatin remodeling and gene expression and is aberrantly upregulated in various types of human cancers. However, the precise role of UHRF1 in cancer remains controversial. In this study, we observed that hypoxia-induced downregulation of UHRF1 contributes to the induction of the epithelial-mesenchymal transition (EMT) in hepatocellular carcinoma cells. By negatively modulating UHRF1 expression, we further showed that UHRF1 deficiency in itself is sufficient to increase the migratory and invasive properties of cells via inducing EMT, increasing the tumorigenic capacity of cells and leading to the expansion of cancer stem-like cells. Epigenetic changes caused by UHRF1 deficiency triggered the upregulation of CXCR4, thereby activating AKT and JNK to increase the expression and secretion of IL-6. In addition, IL-6 readily activated the JAK/STAT3/Snail signaling axis, which subsequently contributed to UHRF1 deficiency-induced EMT. Our results collectively demonstrate that UHRF1 deficiency may play a pivotal role in the malignant alteration of cancer cells.
“…1a and b). In addition, HFHs have features similar to hepatic progenitor cells, which possess self-renewal capacity and migratory potential 26 . Thus, compared with these cancer cells, the relative increase in the migratory and invasive abilities of HFHs is thought to be due to these reported characteristics.Figure 1Downregulation of UHRF1 enhances the migratory and invasive properties of hepatocellular carcinoma cells.…”
UHRF1 (ubiquitin-like, with PHD and RING finger domains 1) plays a crucial role in DNA methylation, chromatin remodeling and gene expression and is aberrantly upregulated in various types of human cancers. However, the precise role of UHRF1 in cancer remains controversial. In this study, we observed that hypoxia-induced downregulation of UHRF1 contributes to the induction of the epithelial-mesenchymal transition (EMT) in hepatocellular carcinoma cells. By negatively modulating UHRF1 expression, we further showed that UHRF1 deficiency in itself is sufficient to increase the migratory and invasive properties of cells via inducing EMT, increasing the tumorigenic capacity of cells and leading to the expansion of cancer stem-like cells. Epigenetic changes caused by UHRF1 deficiency triggered the upregulation of CXCR4, thereby activating AKT and JNK to increase the expression and secretion of IL-6. In addition, IL-6 readily activated the JAK/STAT3/Snail signaling axis, which subsequently contributed to UHRF1 deficiency-induced EMT. Our results collectively demonstrate that UHRF1 deficiency may play a pivotal role in the malignant alteration of cancer cells.
“…They promote adaptation of tumor cells to hypoxic stress by regulating the expression of genes involved in metabolism, angiogenesis, cell proliferation and apoptosis21222324. Both in vitro and in vivo experiments have demonstrated the existence of a crosstalk between the Wnt/β-catenin and HIF pathways25. An interaction was found between β-catenin and HIF-1α, implying an underlying competition for β-catenin between HIF-1α and T-cell factor-426.…”
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confidence: 99%
“…An interaction was found between β-catenin and HIF-1α, implying an underlying competition for β-catenin between HIF-1α and T-cell factor-426. Given the complex mechanism underlying this crosstalk, further efforts should be made to investigate the network of Wnt/β-catenin and hypoxia signaling pathways24252627.…”
The Wnt/β-catenin signaling is abnormally activated in the progression of hepatocellular carcinoma (HCC). BCL9 is an essential co-activator in the Wnt/β-catenin signaling. Importantly, BCL9 is absent from tumors originating from normal cellular counterparts and overexpressed in many cancers including HCC. But the mechanism for BCL9 overexpression remains unknown. Ample evidence indicates that hypoxia inducible factors (HIFs) play a role in the development of HCC. It was found in our study that BCL9 was overexpressed in both primary HCC and bone metastasis specimens; loss of BCL9 inhibited the proliferation, migration and angiogenesis of HCC; and that that hypoxia mechanically induced the expression of BCL9. BCL9 induction under the hypoxic condition was predominantly mediated by HIF-1α but not HIF2α. In vitro evidence from xenograft models indicated that BCL9 promoter/gene knockout inhibited HCC tumor growth and angiogenesis. Notably, we found that BCL9 and HIF-1α were coordinately regulated in human HCC specimen. The above findings suggest that hypoxia may promote the expression of BCL9 and associate with the development of HCC. Specific regulation of BCL9 expression by HIF-1α may prove to be an underlying crosstalk between Wnt/β-catenin signaling and hypoxia signaling pathways.
“…The Wnt pathway is involved in the carcinogenesis in HCC (5). Without stimulation, Axin, Dishevelled (DVL), and glycogen synthase kinase-3 β form a complex and degrade β-catenin (6).…”
Abstract. Short-hairpin RNA of frizzled-2 (shRNA-Fz2) is known to suppress the proliferation of hepatocellular carcinoma (HCC) cells; however, its effect on HCC cell motility is unknown. In this study, suppression of HCC cell motility by shRNA-Fz2 was analyzed, and introduction of shRNA-Fz2 into HCC cells was facilitated with ultrasound (US) irradiation generated from a diagnostic US device, which was enhanced by the contrast-enhanced US reagent Sonazoid. The HCC cell lines HLF and PLC/PRF/5 that were transfected with shRNA-Fz2 were plated to form monolayers, following which the cell monolayers were scratched with a sterile razor. After 48 h, the cells were stained with hematoxylin and eosin, and the distance between the growing edge of the cell layer and the scratch lines was measured. Total RNA from the cells was isolated and subjected to real-time quantitative PCR to quantify matrix metalloproteinase 9 expression at 48 h after transfection of shRNA-Fz2. Starch-iodide method was applied to analyze the generation of H 2 O 2 following US irradiation with the addition of Sonazoid in the liquid, and cell proliferation was analyzed 72 h later. The distances between the growing edge of the cell layer and the scratch lines and MMP9 expression levels were significantly decreased with transfection of shRNA-Fz2 (P<0.05). In the starch-iodide method, absorbance significantly decreased with the addition of Sonazoid (P<0.05), which suggested that US irradiation with Sonazoid generated H 2 O 2 and enhanced sonoporation. ShRNA-Fz2 suppressed cell proliferation of both cell lines at a mechanical index of 0.4. Motility of HLF cells and PLC/PRF/5 cells was suppressed by shRNA-FZ2. Sonazoid enhanced sonoporation of the cells with the diagnostic US device and the suppression of proliferation of both HCC cell lines by shRNA-Fz2.
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