RESUMEN
Growing evidence indicates that deubiquitinase ubiquitin-specific protease 11 (USP11) plays an important role in cellular function by regulating the stability of its substrates. USP11 is dysregulated in many types of cancer and involved in tumor development and progression. We previously showed that USP11 was upregulated in hepatocellular carcinoma (HCC) and promoted HCC cell invasion and metastasis potency. However, the mechanism underlying the role of USP11 in HCC cell metastasis and its function in cell proliferation remain unknown. Here, CCK-8, soft agar assays and nude mouse models showed that USP11 was essential for HCC cells survival and proliferation in vitro and in vivo. Results form mass spectrometry, co-immunoprecipitation, and ubiquitination assays demonstrated that USP11 interacted with nuclear factor 90 (NF90) and promoted its deubiquitination, thereby stabilizing it in HCC cells. Moreover, the effect of USP11 on promoting HCC cells proliferation and metastasis was dependent on NF90, and USP11 expression was positively correlated with NF90 expression in human HCC tissues, as demonstrated via immunohistochemistry. Collectively, the present findings indicated that USP11 binded to and deubiquitinated NF90, thereby stabilizing the protein expression level and promoting HCC cell proliferation and metastasis. NF90 was identified as an important downstream target of USP11. Dysregulated signaling of this novel USP11/NF90 axis might promote HCC proliferation and metastasis, and the axis could be a potential therapeutic target in HCC.
RESUMEN
miRNAs are small noncoding RNAs that act as critical epigenetic regulators in tumor carcinogenesis. In this study, our data showed that miR-137 was significantly downregulated in 58 pairs of human pancreatic cancer (PanCa) tissues and PanCa cell lines. Furthermore, the deregulated miR-137 was correlated with increased tumor size, higher TNM stage, and worse prognosis in pancreatic cancer. Functional studies demonstrated that overexpression of miR-137 dramatically suppressed cell proliferation and induced cell apoptosis in vitro. Meanwhile, upregulated miR-137 remarkably inhibited migration and invasion of pancreatic cancer cells. Further studies indicated that MRGBP was identified as the direct downstream target gene of miR-137. In addition, MRGBP expression is significantly downregulated in miR-137-transfected cells. Our previous study revealed that silencing of MRGBP suppressed the growth of PanCa cells in vitro and in vivo and also promoted apoptosis, and inhibited migration and invasion of PanCa cells, which are consistent with the effects of miR-137 overexpression. Taken together, our findings suggest that miR-137 may function as a novel tumor promoter through directly targeting MRGBP in PanCa.
Asunto(s)
Proteínas Portadoras/metabolismo , Genes Supresores de Tumor , MicroARNs/metabolismo , Proteínas de Neoplasias/metabolismo , Neoplasias Pancreáticas/metabolismo , ARN Neoplásico/metabolismo , Anciano , Apoptosis/genética , Proteínas Portadoras/genética , Línea Celular Tumoral , Femenino , Histona Acetiltransferasas , Humanos , Masculino , MicroARNs/genética , Persona de Mediana Edad , Proteínas de Neoplasias/genética , Proteínas Nucleares , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patología , ARN Neoplásico/genéticaRESUMEN
MORF4-related gene-binding protein (MRGBP), which is also known as chromosome 20 open reading frame 20 (C20orf20), is commonly highly expressed in several types of malignant tumors and tumor progression. However, the expression pattern and underlying mechanism of MRGBP in pancreatic ductal adenocarcinoma (PDAC) remain unknown. In the study, we found that MRGBP was frequently upregulated in PDAC tissues and cell lines. In addition, the upregulation of MRGBP was positively associated with TNM stage, T classification, and poor prognosis. Knockdown of MRGBP in the PDAC cell lines ASPC-1 and Mia PaCa-2 by transiently transfected with small interfering RNA (siRNA) drastically attenuated the proliferation, migration, and invasion of those cells, whereas ectopic MRGBP overexpression in BxPC-3 cells produced exactly the opposite effect. Furthermore, we also found that overexpression of MRGBP remarkably led to cell morphological changes and induced an increased expression of mesenchymal marker Vimentin, whereas a decreased expression of epithelial marker E-cadherin. Taken together, this study indicates that MRGBP acts as a tumor oncogene in PDAC and is a promising target of carcinogenesis.
RESUMEN
BACKGROUND AND AIM: Berberine, an herbal alkaloid, has been reported to have promotion potential of apoptosis and anticancer effect on a variety of human tumor cells. To obtain more specific understanding of those consequences of berberine on hepatocellular carcinoma (HCC) and the tumor microenvironment, we conducted in vitro experiments to investigate the inhibitory effect of berberine on tumor-induced angiogenesis using HCC cells and human umbilical vein endothelial cells (HUVECs). METHODS: Human umbilical vein endothelial cell growth was quantified with the CCK-8 cell proliferation assay; cell migration was observed with a Boyden chamber (Transwell, Corning, Lowell, MA, USA), and angiogenesis was assessed by endothelial tube formation in Matrigel in vitro. In addition, VEGF level was determined by ELISA and VEGF mRNA expression by RT-PCR. RESULTS: Berberine inhibited the capacity of HCC to stimulate HUVEC's proliferation, migration and endothelial tube formation, suggesting that berberine could influence the cross-talk between the HCC cell and vascular endothelial cells. These results demonstrate berberine's antiangiogenesis property and its clinical potential as an inhibitor of tumor angiogenesis. Subsequently analyses reveal that berberine prevents secretion of VEGF from HCC and down-regulates VEGF mRNA expression. CONCLUSION: These findings strongly suggest that berberine is a potential antiangiogenic agent and a promising antitumor drug for HCC.