scholarly journals miR-650 Promotes the Metastasis and Epithelial–Mesenchymal Transition of Hepatocellular Carcinoma by Directly Inhibiting LATS2 Expression

2018 ◽  
Vol 51 (3) ◽  
pp. 1179-1192 ◽  
Author(s):  
Li Li Han ◽  
Xiao Ran Yin ◽  
Shu Qun Zhang
Keyword(s):  
Hepatocellular Carcinoma ◽  
Tumor Suppressor ◽  
Epithelial Mesenchymal Transition ◽  
Luciferase Assay ◽  
Large Tumor ◽  
Mesenchymal Transition ◽  
Expression Levels ◽  
Direct Target ◽  
Large Tumor Suppressor ◽  
Hcc Cells

Background/Aims: Previous studies have confirmed that microRNAs are involved in the metastasis and epithelial–mesenchymal transition (EMT) of malignancies. In this study, we examined whether miR-650 promotes the migration, invasion, and EMT of hepatocellular carcinoma (HCC) cells by targeting the large tumor suppressor kinase 2 gene (LATS2). Methods: qRT-PCR was used to detect expression of miR-650 in HCC tissues and paired normal tissues. MTT and Transwell assay were used to observe the effect of miR-650 on proliferation, migration and invasion of HCC cells. Western blot assay and Immunohistochemistry were performed to demonstrate association between miR-650 expression level and epithelial-mesenchymal transition (EMT) related protein. Mechanistically, Reporter luciferase assay was performed to reveal whether large tumor suppressor kinase 2 (LATS2) was a direct target of miR-650 in HCC cells. Results: We observed that miR-650 levels were largely up-regulated in HCC tissues, and that the increased expression was closely associated with the adverse clinical features of HCC patients. Additionally, the expression of LATS2, which was identified as a direct target of miR-650, can counteract the effects of miR-650 in HCC. Furthermore, we demonstrated that high miR-650 expression levels and low LATS2 expression levels in tumors may indicate a poor prognosis for HCC patients. Conclusion: In conclusion, the miR-650/LATS2 pathway may serve as a novel prognostic biomarker and an attractive therapeutic target for HCC patients.

scholarly journals Epithelial–Mesenchymal Transition (EMT) Induced by TGF-β in Hepatocellular Carcinoma Cells Reprograms Lipid Metabolism

2021 ◽  
Vol 22 (11) ◽  
pp. 5543
Author(s):  
Jitka Soukupova ◽  
Andrea Malfettone ◽  
Esther Bertran ◽  
María Isabel Hernández-Alvarez ◽  
Irene Peñuelas-Haro ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Lipid Metabolism ◽  
Transforming Growth Factor ◽  
Epithelial Mesenchymal Transition ◽  
Aerobic Glycolysis ◽  
Metabolic Reprogramming ◽  
Migration And Invasion ◽  
Metabolic Switch ◽  
Mesenchymal Transition ◽  
Hcc Cells

(1) Background: The transforming growth factor (TGF)-β plays a dual role in liver carcinogenesis. At early stages, it inhibits cell growth and induces apoptosis. However, TGF-β expression is high in advanced stages of hepatocellular carcinoma (HCC) and cells become resistant to TGF-β induced suppressor effects, responding to this cytokine undergoing epithelial–mesenchymal transition (EMT), which contributes to cell migration and invasion. Metabolic reprogramming has been established as a key hallmark of cancer. However, to consider metabolism as a therapeutic target in HCC, it is necessary to obtain a better understanding of how reprogramming occurs, which are the factors that regulate it, and how to identify the situation in a patient. Accordingly, in this work we aimed to analyze whether a process of full EMT induced by TGF-β in HCC cells induces metabolic reprogramming. (2) Methods: In vitro analysis in HCC cell lines, metabolomics and transcriptomics. (3) Results: Our findings indicate a differential metabolic switch in response to TGF-β when the HCC cells undergo a full EMT, which would favor lipolysis, increased transport and utilization of free fatty acids (FFA), decreased aerobic glycolysis and an increase in mitochondrial oxidative metabolism. (4) Conclusions: EMT induced by TGF-β in HCC cells reprograms lipid metabolism to facilitate the utilization of FFA and the entry of acetyl-CoA into the TCA cycle, to sustain the elevated requirements of energy linked to this process.

scholarly journals MicroRNA-3163 targets ADAM-17 and enhances the sensitivity of hepatocellular carcinoma cells to molecular targeted agents

2019 ◽  
Vol 10 (10) ◽  
Author(s):  
Bin Yang ◽  
Chunping Wang ◽  
Hui Xie ◽  
Yiwu Wang ◽  
Jiagan Huang ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Notch Signaling ◽  
Signaling Pathway ◽  
Epithelial Mesenchymal Transition ◽  
Notch Signaling Pathway ◽  
Advanced Hepatocellular Carcinoma ◽  
Targeted Agents ◽  
Mesenchymal Transition ◽  
Molecular Targeted Agents ◽  
Hcc Cells

Abstract Molecular targeted agents, such as sorafenib, remain the only choice of an antitumor drug for the treatment of advanced hepatocellular carcinoma (HCC). The Notch signaling pathway plays central roles in regulating the cellular injury/stress response, anti-apoptosis, or epithelial–mesenchymal transition process in HCC cells, and is a promising target for enhancing the sensitivity of HCC cells to antitumor agents. The ADAM metalloprotease domain-17 (ADAM-17) mediates the cleavage and activation of Notch protein. In the present study, microRNA-3163 (miR-3163), which binds to the 3′-untranslated region of ADAM-17, was screened using online methods. miRDB and pre-miR-3163 sequences were prepared into lentivirus particles to infect HCC cells. miR-3163 targeted ADAM-17 and inhibited the activation of the Notch signaling pathway. Infection of HCC cells with miR-3163 enhanced their sensitivity to molecular targeted agents, such as sorafenib. Therefore, miR-3163 may contribute to the development of more effective strategies for the treatment of advanced HCC.

scholarly journals Chromatin remodeling factor ARID2 suppresses hepatocellular carcinoma metastasis via DNMT1-Snail axis

2020 ◽  
Vol 117 (9) ◽  
pp. 4770-4780 ◽  
Author(s):  
Hao Jiang ◽  
Hui-Jun Cao ◽  
Ning Ma ◽  
Wen-Dai Bao ◽  
Jing-Jing Wang ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Chromatin Remodeling ◽  
Epithelial Mesenchymal Transition ◽  
Positive Association ◽  
Mechanistic Study ◽  
Migration And Invasion ◽  
Metastasis Suppressor ◽  
Mesenchymal Transition ◽  
Hcc Cells

Recurrence and metastasis remain the major obstacles to successful treatment of hepatocellular carcinoma (HCC). Chromatin remodeling factor ARID2 is commonly mutated in HCC, indicating its important role in cancer development. However, its role in HCC metastasis is largely elusive. In this study, we find that ARID2 expression is significantly decreased in metastatic HCC tissues, showing negative correlation with pathological grade, organ metastasis and positive association with survival of HCC patients. ARID2 inhibits migration and invasion of HCC cells in vitro and metastasis in vivo. Moreover, ARID2 knockout promotes pulmonary metastasis in different HCC mouse models. Mechanistic study reveals that ARID2 represses epithelial–mesenchymal transition (EMT) of HCC cells by recruiting DNMT1 to Snail promoter, which increases promoter methylation and inhibits Snail transcription. In addition, we discover that ARID2 mutants with disrupted C2H2 domain lose the metastasis suppressor function, exhibiting a positive association with HCC metastasis and poor prognosis. In conclusion, our study reveals the metastasis suppressor role as well as the underlying mechanism of ARID2 in HCC and provides a potential therapeutic target for ARID2-deficient HCC.

scholarly journals Epigenetic silencing of CDKN1A and CDKN2B by SNHG1 promotes the cell cycle, migration and epithelial-mesenchymal transition progression of hepatocellular carcinoma

2020 ◽  
Vol 11 (10) ◽  
Author(s):  
Bei Li ◽  
Ang Li ◽  
Zhen You ◽  
Jingchang Xu ◽  
Sha Zhu
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Cycle ◽  
Epithelial Mesenchymal Transition ◽  
Critical Role ◽  
Luciferase Assay ◽  
Bioinformatics Analyses ◽  
Mesenchymal Transition ◽  
Rna Immunoprecipitation

Abstract Enhanced SNHG1 (small nucleolar RNA host gene 1) expression has been found to play a critical role in the initiation and progression of hepatocellular carcinoma (HCC) with its detailed mechanism largely unknown. In this study, we show that SNHG1 promotes the HCC progression through epigenetically silencing CDKN1A and CDKN2B in the nucleus, and competing with CDK4 mRNA for binding miR-140-5p in the cytoplasm. Using bioinformatics analyses, we found hepatocarcinogenesis is particularly associated with dysregulated expression of SNHG1 and activation of the cell cycle pathway. SNHG1 was upregulated in HCC tissues and cells, and its knockdown significantly inhibited HCC cell cycle, growth, metastasis, and epithelial–mesenchymal transition (EMT) both in vitro and in vivo. Chromatin immunoprecipitation and RNA immunoprecipitation assays demonstrate that SNHG1 inhibit the transcription of CDKN1A and CDKN2B through enhancing EZH2 mediated-H3K27me3 in the promoter of CDKN1A and CDKN2B, thus resulting in the de-repression of the cell cycle. Dual-luciferase assay and RNA pulldown revealed that SNHG1 promotes the expression of CDK4 by competitively binding to miR-140-5p. In conclusion, we propose that SNHG1 formed a regulatory network to confer an oncogenic function in HCC and SNHG1 may serve as a potential target for HCC diagnosis and treatment.

scholarly journals HDAC9 Is Preferentially Expressed in Dedifferentiated Hepatocellular Carcinoma Cells and Is Involved in an Anchorage-Independent Growth

Cancers ◽  
2020 ◽  
Vol 12 (10) ◽  
pp. 2734
Author(s):  
Keita Kanki ◽  
Ryota Watanabe ◽  
Le Nguyen Thai ◽  
Chun-Hao Zhao ◽  
Kyoko Naito
Keyword(s):  
Hepatocellular Carcinoma ◽  
Histone Deacetylases ◽  
Epithelial Mesenchymal Transition ◽  
Cell Transformation ◽  
The Cancer Genome Atlas ◽  
Hepatic Differentiation ◽  
Differentiation Markers ◽  
Mesenchymal Transition ◽  
Cancer Genome Atlas ◽  
Hcc Cells

Aberrant activation of histone deacetylases (HDACs) is one of the causes of tumor cell transformation in many types of cancer, however, the critical HDAC responsible for the malignant transformation remain unclear. To identify the HDAC related to the dedifferentiation of hepatocellular carcinoma (HCC) cells, we investigated the expression profile of HDACs in differentiated and undifferentiated hepatoma cells. We found that HDAC9, a member of the class II HDAC, is preferentially expressed in undifferentiated HCC cells. Analysis of 373 HCC patients in The Cancer Genome Atlas (TCGA) database revealed that the expression of HDAC9 mRNA positively correlated with the markers of mesenchymal phenotype and stemness, and conversely, negatively correlated with hepatic differentiation markers. HDAC9 was transcriptionally upregulated in epithelial–mesenchymal transition (EMT)-induced HCC cells treated with TGF-β. Genetic and pharmacological inhibition of HDAC9 in undifferentiated HCC cells showed decreased sphere-forming activity, which indicates an ability of anchorage-independent cell growth and self-renewal. We also showed that aldehyde dehydrogenase 1A3 (ALDH1A3) was downregulated in HDAC9-suppressing cells, and ALDH inhibitor disulfiram significantly decreased the sphere formation of undifferentiated HCC cells. Together, our data provide useful information for the development of HDAC9-specific inhibitors for the treatment of HCC progression.

scholarly journals Silencing of the TROP2 gene suppresses proliferation and invasion of hepatocellular carcinoma HepG2 cells

2019 ◽  
Vol 47 (3) ◽  
pp. 1319-1329 ◽  
Author(s):  
Jian Zhang ◽  
Hai Ma ◽  
Liu Yang ◽  
Hongchun Yang ◽  
Zhenxing He
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Proliferation ◽  
Protein Expression ◽  
Cell Lines ◽  
Epithelial Mesenchymal Transition ◽  
Migration And Invasion ◽  
Human Trophoblast ◽  
Mesenchymal Transition ◽  
Expression Levels ◽  
Proliferation And Invasion

Objectives Overexpression of human trophoblast cell surface antigen 2 (Trop2) has been observed in many cancers; however, its roles in proliferation, apoptosis, migration, and invasion of hepatocellular carcinoma (HCC) remain unclear. Thus, this study aimed to characterize the function of Trop2 in HCC. Methods Trop2 protein expression was detected by immunohistochemistry in HCC tissues. Cell proliferation, apoptosis, and invasion were respectively measured by CCK-8, flow cytometry, Transwell, and wound healing assays. Expression levels of epithelial–mesenchymal transition-related proteins and Trop2 protein in HCC cell lines were detected by western blotting after silencing of the TROP2 gene. Results Trop2 protein was highly expressed in HCC tissues and HCC cell lines. Trop2 mRNA and protein expression levels decreased in HepG2 and HCCLM3 cells after transfection with Trop2 siRNA. Silencing of the TROP2 gene in HepG2 and HCCLM3 cells strongly inhibited cell proliferation and migration, while enhancing cell apoptosis. Investigation of the molecular mechanism revealed that silencing of the TROP2 gene suppressed epithelial–mesenchymal transition of HepG2 and HCCLM3 cells. Conclusions The results of the present study may improve understanding of the role of Trop2 in regulation of cell proliferation and invasion, and may aid in development of novel therapy for HCC.

scholarly journals Metadherin–PRMT5 complex enhances the metastasis of hepatocellular carcinoma through the WNT–β-catenin signaling pathway

2019 ◽  
Vol 41 (2) ◽  
pp. 130-138 ◽  
Author(s):  
Kai Zhu ◽  
Yuanfei Peng ◽  
Jinwu Hu ◽  
Hao Zhan ◽  
Liuxiao Yang ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Hepatocellular Carcinoma ◽  
Signaling Pathway ◽  
Epithelial Mesenchymal Transition ◽  
Arginine Methyltransferase ◽  
Mesenchymal Transition ◽  
Functional Assays ◽  
In Vivo Experiments ◽  
Hcc Cells

Abstract Accumulating data suggest that metadherin (MTDH) may function as an oncogene. Our previous study showed that MTDH promotes hepatocellular carcinoma (HCC) metastasis via the epithelial-mesenchymal transition. In this study, we aim to further elucidate how MTDH promotes HCC metastasis. Using Co-immunoprecipitation (co-IP) and mass spectrometry, we found that MTDH can specifically bind to protein arginine methyltransferase 5 (PRMT5). Further functional assays revealed that PRMT5 overexpression promoted the proliferation and motility of HCC cells and that knockout of PRMT5 impeded the effect of MTDH. The immunohistochemistry assay/tissue microarray results showed that when MTDH was overexpressed in HCC cells, PRMT5 translocated from the nucleus to the cytoplasm, with the subsequent translocation of β-catenin from the cytoplasm to the nucleus and upregulation of the WNT–β-catenin signaling pathway. Further in vivo experiments suggested that PRMT5 and β-catenin played a pivotal role in MTDH-mediated HCC metastasis. We therefore concluded that the MTDH–PRMT5 complex promotes HCC metastasis by regulating the WNT–β-catenin signaling pathway.

scholarly journals HIF-1α Promotes Hepatocellular Carcinoma Metastasis by Regulating Angiogenesis and Epithelial-Mesenchymal Transition

2020 ◽  
Author(s):  
Min Yao ◽  
Li Wang ◽  
Xiyu Chen ◽  
Ying Chen ◽  
Jie Yang ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Malignant Transformation ◽  
Epithelial Mesenchymal Transition ◽  
Hypoxia Inducible Factor ◽  
Medical Society ◽  
Mesenchymal Transition ◽  
Positive Correlations ◽  
Angiopoietin 2 ◽  
Endothelial Growth Factor ◽  
Hcc Cells

Abstract Background: Invasion and metastasis of hepatocellular carcinoma (HCC) still remain to be hard in medical society. However, little knowledge is known regarding the hypoxia impact in HCC with angiogenesis and epithelial-mesenchymal transition (EMT). The aims of this study were to explore the regulating roles of hypoxia-inducible factor-1α (HIF-1α) in angiogenesis and EMT of HCC. Method: The levels of HIF-1α, angiopoietin-2 (Ang-2), and vascular endothelial growth factor (VEGF) expression in a cohort of chronic liver diseases were detected by enzyme- linked immunosorbent assays, and their dynamic up-regulations were confirmed in model of rat hepatocyte malignant transformation. After HIF-1α gene transfected with specific miRNA, biological behaviors of HCC cells were analyzed by transwell or invasion assay; angiogenesis and EMT were analyzed at protein level by Western blot or at mRNA by quantitative real-time PCR. Results: The levels of circulating HIF-1α, VEGF, and Ang-2 in the HCC group (145.6 ± 32.6 μg/L, 458.9 ± 125.3 μg/L, and 42.9 ± 5.1μg/L) were significantly higher (P < 0.001) than those in the LC (79.5 ± 8.4 μg/L, 206.8 ± 56.8 μg/L, and 26.2 ± 6.1 μg/L) or the CH (60.1 ± 18.8 μg/L, 178.1 ± 85.4 μg/L, and 21.8 ± 6.9 μg/L) group, respectively. Dynamic up-regulations of HIF-1α and angiogenic factors have been confirmed by rat model with hepatocyte malignant transformation. There were closely positive correlations (P < 0.001) between them of HIF-1α and VEGF or Ang-2. After HCC cells transfected with specific HIF-1α-miRNA, the levels of HIF-1α, VEGF and Ang-2 expression were significantly down-regulated, with inhibiting infiltration or migration, blockading EMT with increasing E-cadherin and decreasing of snail, twist and vimentin. Conclusions: HIF-1α over-expression could promote the metastasis or invasion of HCC via regulating neovascularization and EMT formation.

scholarly journals HSD17B6 downregulation predicts poor prognosis and drives tumor progression via activating Akt signaling pathway in lung adenocarcinoma

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Tian Tian ◽  
Fu Hong ◽  
Zhiwen Wang ◽  
Jiaru Hu ◽  
Ni Chen ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Lung Adenocarcinoma ◽  
Poor Prognosis ◽  
Epithelial Mesenchymal Transition ◽  
Tumor Grade ◽  
Tumor Stage ◽  
Advanced Tumor Stage ◽  
Large Tumor ◽  
Mesenchymal Transition ◽  
Advanced Tumor

AbstractLung adenocarcinoma is one of the most frequent tumor subtypes, involving changes in a variety of oncogenes and tumor suppressor genes. Hydroxysteroid 17-Beta Dehydrogenase 6 (HSD17B6) could synthetize dihydrotestosterone, abnormal levels of which are associated with progression of multiple tumors. Previously, we showed that HSD17B6 inhibits malignant progression of hepatocellular carcinoma. However, the mechanisms underlying inhibiting tumor development by HSD17B6 are not clear. Moreover, its role in lung adenocarcinoma (LUAD) is yet unknown. Here, we investigated its expression profile and biological functions in LUAD. Analysis of data from the LUAD datasets of TCGA, CPTAC, Oncomine, and GEO revealed that HSD17B6 mRNA and protein expression was frequently lower in LUAD than in non-neoplastic lung tissues, and its low expression correlated significantly with advanced tumor stage, large tumor size, poor tumor differentiation, high tumor grade, smoking, and poor prognosis in LUAD. In addition, its expression was negatively regulated by miR-31-5p in LUAD. HSD17B6 suppressed LUAD cell proliferation, migration, invasion, epithelial–mesenchymal transition (EMT), and radioresistance. Furthermore, HSD17B6 overexpression in LUAD cell lines enhanced PTEN expression and inhibited AKT phosphorylation, inactivating downstream oncogenes like GSK3β, β-catenin, and Cyclin-D independent of dihydrotestosterone, revealing an underlying antitumor mechanism of HSD17B6 in LUAD. Our findings indicate that HSD17B6 may function as a tumor suppressor in LUAD and could be a promising prognostic indicator for LUAD patients, especially for those receiving radiotherapy.

scholarly journals Epigenetic silencing of ZIC4 contributes to cancer progression in hepatocellular carcinoma

2020 ◽  
Vol 11 (10) ◽  
Author(s):  
Wenbiao Chen ◽  
Donge Tang ◽  
Dongxin Tang ◽  
Yong Dai
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cancer Progression ◽  
Promoter Region ◽  
Developmental Process ◽  
Epithelial Mesenchymal Transition ◽  
Epigenetic Silencing ◽  
The Cancer Genome Atlas ◽  
Mesenchymal Transition ◽  
Hcc Cells

Abstract Inactivation of tumor suppressor gene played critical roles in the development and progression of human hepatocellular carcinoma (HCC). Zic family member 4 (ZIC4) is transcription factor and plays an important role in the developmental process. However, the expression and biological role of ZIC4 in HCC is poorly understood. Here, bioinformatics analysis based on The Cancer Genome Atlas (TCGA) database revealed an aberrant hypermethylation of ZIC4 in HCC. ZIC4 is frequently hypermethylated in promoter region and down expressed in HCC cells and tissues. Functionally, ZIC4 inhibition facilitated the proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT) in vitro and in vivo. Conversely, ZIC4 overexpression reduced proliferation and invasiveness of HCC cells. In addition, ZIC4 inhibition rescued the antitumor effect induced by enhancer of zeste homolog 2 (EZH2) knockdown or EZH2 inhibitor. Mechanistically, EZH2 knockdown or EZH2 inhibitor reduced the enrichment of EZH2 and H3K27me3 in ZIC4 promoter region and leading to the upregulation of ZIC4. Altogether, these data indicate that epigenetic silencing of ZIC4 by EZH2 mediated H3K27me3 is an important mechanism in HCC and provide a new therapeutic target for the treatment of hepatocellular carcinoma disease.

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