Silencing of IL13RA2 promotes partial epithelial-mesenchymal transition in hepatocellular carcinoma via ERK signaling pathway activation.
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ABSTRACT:
SUBMITTER: Wang M
PROVIDER: S-EPMC6996351 | biostudies-literature | 2019 Dec
REPOSITORIES: biostudies-literature
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Project description:BackgroundResidual tumor progression after insufficient radiofrequency ablation (RFA) has been recently reported. However, whether epithelial-mesenchymal transition (EMT), which is a key process that drives cancer metastasis, is involved in the tumor progression after insufficient RFA is not well understood.MethodsHuman hepatocellular carcinoma (HCC) cell lines SMMC7721 and Huh7 were used. Insufficient RFA was simulated using a water bath (47°C 5 min, 10 min, 15 min, 20 min and 25 min gradually). MTT assay was used to evaluate the proliferation of HCC cells in vitro. Migration and invasion of HCC cells were determined by transwell assay. The molecular changes in HCC cells after insufficient RFA were evaluated by western blot. LY294002 and PD98059 were used to treat HCC cells. An ectopic nude mice model and a tail vein metastatic assay were used to evaluate the growth and metastatic potential of SMMC7721 cells in vivo after insufficient RFA.ResultsSMMC7721 and Huh7 cells after insufficient RFA (named as SMMC7721-H and Huh7-H respectively) exhibited enhanced proliferation, migration and invasion (6.4% and 23.6%, 33.2% and 66.1%, and 44.1% and 57.4% increase respectively) in vitro. Molecular changes of EMT were observed in SMMC7721-H and Huh7-H cells. LY294002 and PD98059 inhibited the EMT of SMMC7721-H and Huh7-H cells. SMMC7721-H cells also exhibited larger tumor size (1440.8±250.3 mm3 versus 1048.56±227.6 mm3) and more lung metastasis (97.4% increase) than SMMC7721 cells in vivo. Higher expression of PCNA, N-cadherin and MMP-2 and MMP-9, was also observed in SMMC7721-H tumors.ConclusionsInsufficient RFA could directly promote the invasiveness and metastasis of HCC cells. Insufficient RFA may promote the EMT of HCC cells through Akt and ERK signaling pathways.
| S-EPMC3842745 | biostudies-literature
Project description:Increasing evidence has revealed that cancer cells undergoing an intermediate state, partial epithelial mesenchymal transition (p-EMT), tend to metastasize rather than complete EMT. We performed a comprehensive analysis of E-cadherin and 25 p-EMT-related genes in HCC to explore the roles and regulatory mechanisms of them in HCC. We analysed E-cadherin and 25 p-EMT-related genes in HCC and constructed an mRNA-miRNA-lncRNA ceRNA subnetwork containing p-EMT-related genes by bioinformatic approaches. IHC was used to identify the protein expression of key p-EMT-related genes, P4HA2, ITGA5, MMP9, MT1X and SPP1. Complete EMT is not necessary for HCC progression. Overexpression of P4HA2, ITGA5, MMP9, SPP1 and down-regulation of MT1X were found in HCC tissues, which were significantly associated with poor prognosis of HCC patients. By means of stepwise reverse prediction and validation from mRNA to lncRNA, an mRNA-miRNA-lncRNA ceRNA subnetwork correlated with HCC prognosis was identified by expression and survival analysis. This study implied that key p-EMT-related genes P4HA2, ITGA5, MMP9, MT1X, SPP1 could be prognostic biomarkers and potential targets of therapy for HCC patients. We constructed an mRNA-miRNA-lncRNA subnetwork containing p-EMT-related genes successfully, among which each component might be utilized as a prognostic biomarker of HCC.
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Project description:BackgroundOur recent study identified that human chemokine-like factor (CKLF)-like MARVEL transmembrane domain-containing family member 2 (CMTM2) was deregulated in hepatocellular carcinoma (HCC) tissues and posed as a potential tumor suppressor. However, the mechanism of CMTM2 in HCC occurrence and development has not been well elaborated.Materials and methodsThe expression of CMTM2 was knocked-down by RNA interruption in Huh-7 and SMMC7721 cells. Cell proliferation ability was detected by CCK8 test and colony formation assay. The cell invasion and migration were measured by wound healing and Transwell assay.ResultsWe found that the cell proliferation was significantly increased by interruption of CMTM2 expression, both in Huh-7 and SMMC7721 cells. Moreover, down-regulated CMTM2 could promote the invasion and migration ability of HCC cells through inducing the epithelial-mesenchymal transition (EMT) process. We further discovered that both the expression of CMTM2 and the EMT-associated marker E-cadherin were decreased in the same thirty cases of HCC tissues compared with the corresponding adjacent non-tumor tissues. Pearson correlation test showed that there was a significantly positive correlation between CMTM2 and E-cadherin in HCC tissues (P<0.05).ConclusionBased on the results of cell model and HCC tissues, our study suggests that down-regulated CMTM2 promotes HCC metastasis through inducing the EMT process.
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Project description:Hepatocellular carcinoma (HCC) is one of the most common malignant cancers and currently the third leading cause of cancer-related deaths, worldwide. Epithelial-mesenchymal transition (EMT) plays a major role in HCC progression. In this study, we first found that the expression of E74-like ETS transcription factor 3 (ELF3), a member of the E-twenty-six family of transcription factors, was increased in HCC tissues, and that ELF3 overexpression was associated with poor prognoses for HCC patients. Gain-of-function and loss-of-function studies revealed that increased ELF3 expression promoted HCC cell proliferation, migration, and invasion, while these processes were inhibited when ELF3 was silenced. Additionally, ELF3 was found to promote EMT, which we demonstrated through decreased E-cadherin expression and increased N-cadherin and fibronectin expression. ELF3 knockdown reversed EMT via repressing ZEB1 expression through miR-141-3p upregulation. Chromatin immunoprecipitation assays revealed that ELF3 bound to the miR-141-3p promoter, suppressing miR-141-3p expression. Taken together, our data show that ELF3 repressed E-cadherin and promoted EMT in HCC cells by suppressing miR-141-3p, thereby activating ZEB1. Thus, ELF3 may be a potential prognostic biomarker and/or therapeutic target for HCC.
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Project description:Rationale: The role of SLUG in epithelial-mesenchymal transition during tumor progression has been thoroughly studied, but its precise regulation remains poorly explored. Methods: The affinity purification, mass spectrometry and CO-IP were performed to identify the interaction between SLUG and ubiquitin-specific protease 5 (USP5). Cycloheximide chase assays and deubiquitination assays confirmed that the effect of USP5 on the deubiquitin of SLUG. The dual-luciferase reporter and chromatin immunoprecipitation assays were employed to observe the direct transcriptional regulation of E-cadherin by SLUG effected by USP5. EMT related markers was detected by western blotting and immunofluorescence. Molecular docking, SPR sensor (biacore) and co-location were detected to prove Formononetin targets USP5. Bioinformatics analysis was used to study the relation of USP5 and SLUG to malignancy degree of HCC. Cell migration, invasion in HCC cells and xenografts model in nude mouse were conducted to detect the promotion of USP5 and the inhibition of Formononetin on EMT. Results: USP5 interacts with and stabilizes SLUG to regulate its abundance through USP5 deubiquitination activities in epithelial-mesenchymal transition (EMT) of hepatocellular carcinoma (HCC). USP5 is highly expressed and positively correlated with SLUG expression in HCC with high malignancy. Knockdown of USP5 inhibits SLUG deubiquitination and inhibits HCC cells proliferation, metastasis, and invasion, while overexpression of USP5 promotes SLUG stability and EMT in vitro and in vivo. Through virtual screening, we found that Formononetin exhibits excellent binding to USP5. Moreover, Formononetin inhibits deubiquitinating activities of USP5 to SLUG and consequently impedes the EMT and malignant progression of HCC. Conclusion: Our findings reveal that USP5 serve as a potential target for tumor intervention and provide a preliminary antitumor therapy for inhibit EMT by targeting USP5 or its interaction with SLUG in HCC.
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Project description:Our previous studies have found that osteopontin (OPN) is a promoter for hepatocellular carcinoma (HCC) progression. However, the molecular mechanism by which OPN enhances HCC metastasis remains elusive. Epithelial-mesenchymal transition (EMT) of cancer cells plays a pivotal role in promoting metastatic process. In this study, we demonstrated that OPN promotes HCC metastasis by inducing an EMT-like, more aggressive cellular phenotype in vitro and in vivo. Furthermore, OPN was identified to interact with vimentin by reciprocal OPN and vimentin immunoprecipitation as well as co-immunofluorescence examination. By using deletion mutants, we found that the residues between 246 and 406 in vimentin are required for binding to OPN. Importantly, OPN significantly increased vimentin stability through inhibition of its protein degradation. Knockdown of vimentin neutralized the EMT induced by OPN both in vitro and in vivo. Moreover, a significant correlation between OPN and vimentin levels was found in clinical HCC specimens and their combination had a worse prognosis with shorter overall survival (OS) and time to recurrence (TTR). In multivariate analysis, OPN and their combination were demonstrated to be independent prognostic indicators for OS and TTR of HCC patients. Collectively, this study indicates that OPN can induce EMT of HCC cells through increasing vimentin stability, which provides more in-depth understanding about the molecular mechanisms of OPN in promoting HCC metastasis and opens tantalizing therapeutic possibilities in HCC.
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Project description:The therapeutic outcome of hepatocellular carcinoma (HCC) remains unsatisfactory because of poor response and acquired drug resistance. To better elucidate the molecular mechanisms of HCC, here we used three Gene Expression Omnibus datasets to identify potential oncogenes, and thereby identified small nuclear ribonucleoprotein polypeptide C (SNRPC). We report that SNRPC is highly up-regulated in HCC tissues as determined using immunohistochemistry assays of samples from a cohort of 224 patients with HCC, and overexpression of SNRPC was correlated with multiple tumors, advanced stage, and poor outcome. Kaplan-Meier analysis confirmed that patients with high SNRPC expression exhibited shorter survival in four independent HCC cohorts (all P < 0.05). Furthermore, SNRPC mutations are significantly more frequent in HCC tissues than in normal liver tissues and are an early event in the development of HCC. Functional network analysis suggested that SNRPC is linked to the regulation of ribosome, spliceosome, and proteasome signaling. Subsequently, gain- and loss-of-function assays showed that SNRPC promotes the motility and epithelial-mesenchymal transition of HCC cells in vitro. SNRPC expression was negatively correlated with the infiltration of CD4+ T cells, macrophage cells, and neutrophil cells (all P < 0.05), as determined by analyzing the TIMER (Tumor IMmune Estimation Resource) database. In conclusion, our findings suggest that SNRPC has a potential role in epithelial-mesenchymal transition and motility in HCC.
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Project description:BACKGROUND: SIRT1 is a member of the mammalian sirtuin family with the ability to deacetylate histone and nonhistone proteins. The correlation between SIRT1 expression and tumor metastasis in several types of cancer has aroused widespread concern. This study investigated SIRT1 expression and its prognostic value in hepatocellular carcinoma (HCC). The function of SIRT1 in hepatocarcinogenesis was further investigated in cell culture and mouse models. METHODS: Western blotting and immunohistochemistry were used to explore SIRT1 expression in HCC cell lines and primary HCC clinical specimens. The functions of SIRT1 in the migration and invasion in the HCC cell line were analyzed by infecting cells with adenovirus containing full-length SIRT1 or sh-RNA. The effect of SIRT1 on tumorigenicity in nude mice was also investigated. RESULTS: SIRT1 expression was significantly overexpressed in the tumor tissues and HCC cell lines. SIRT1 significantly promoted the ability of migration and invasion in HCC cells. In addition, experiments with a mouse model revealed that SIRT1 overexpression enhanced HCC tumor metastasis in vivo. Furthermore, we demonstrated that SIRT1 significantly enhanced the invasive and metastatic potential by inducing epithelial-mesenchymal transition in HCC cells. A clinicopathological analysis showed that SIRT1 expression was significantly correlated with tumor size, tumor number, and TNM staging. Kaplan-Meier survival curves revealed that positive SIRT1 expression was associated with poor prognosis in patients with HCC. CONCLUSIONS: Our data suggest that SIRT1 may play an important role in HCC progression and could be a potential molecular therapy target for HCC.
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Project description:Serine/threonine/tyrosine kinase 1 (STYK1) is known to be involved in tumor progression. However, its molecular role and mechanism in hepatocellular carcinoma (HCC) remains unknown. We evaluated the effect of STYK1 expression in HCC tissues and investigated the underlying mechanisms associated with progression. HCC tissues expressed greater levels of STYK1 than paired non-tumor tissues. Patients with HCC expressing low levels of STYK1 showed both, greater disease-free (p?<?0.0001) and overall (p?=?0.0004) survival than those expressing high levels of STYK1. Decreased expression of STYK1 was significantly associated with decreased cell proliferation, reduced migratory capability, and reduced invasive capability. Overexpression of STYK1 was significantly associated with increased cell proliferation, migratory capability, and invasive capability in vitro, as well as increased volume of tumor, weight of tumor, and number of pulmonary metastases in vivo. Furthermore, STYK1's mechanism of promoting cancer cell mobility and epithelial-mesenchymal transition (EMT) was found to be via the MEK/ERK and PI3K/AKT pathways, resulting in increased expression of mesenchymal protein markers: snail, fibronectin, and vimentin, and decreased E-cadherin expression. Our results suggest that STYK1 acts as an oncogene by inducing cell invasion and EMT via the MEK/ERK and PI3K/AKT signaling pathways and it therefore may be a potential therapeutic target in HCC.
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Project description:Holliday Junction Recognition Protein (HJURP) is involved in various cancers including hepatocellular carcinoma (HCC). Current studies have showed that HJURP is correlated with HCC proliferation. However, the role of HJURP in HCC Epithelial-to-Mesenchymal Transition remains unclear. In this study, we found that HJURP knockdown significantly reduced the migration and invasion abilities of HCC cells both in vivo and in vitro by interacting with Sphingosine kinase1 (SPHK1). Conversely, HJURP overexpression enhanced these biological abilities. Moreover, high HJURP expression is related to poor prognosis of HCC patients. In conclusion, HJURP plays an important role in tumor metastasis by upregulating SPHK1. And high HJURP expression may predict a lower disease-free survival rate and higher possibility of microvascular invasion in HCC patients.
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