scholarly journals TXNDC12 promotes EMT and metastasis of hepatocellular carcinoma cells via activation of β-catenin

2019 ◽  
Vol 27 (4) ◽  
pp. 1355-1368 ◽  
Author(s):  
Kefei Yuan ◽  
Kunlin Xie ◽  
Tian Lan ◽  
Lin Xu ◽  
Xiangzheng Chen ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Nuclear Translocation ◽  
Epithelial Mesenchymal Transition ◽  
Disease Free Survival ◽  
Underlying Mechanism ◽  
Carcinoma Cells ◽  
Mesenchymal Transition ◽  
Protein Protein Interaction

Abstract Metastasis is one of the main contributors to the poor prognosis of hepatocellular carcinoma (HCC). However, the underlying mechanism of HCC metastasis remains largely unknown. Here, we showed that TXNDC12, a thioredoxin-like protein, was upregulated in highly metastatic HCC cell lines as well as in portal vein tumor thrombus and lung metastasis tissues of HCC patients. We found that the enforced expression of TXNDC12 promoted metastasis both in vitro and in vivo. Subsequent mechanistic investigations revealed that TXNDC12 promoted metastasis through upregulation of the ZEB1-mediated epithelial–mesenchymal transition (EMT) process. We subsequently showed that TXNDC12 overexpression stimulated the nuclear translocation and activation of β-catenin, a positive transcriptional regulator of ZEB1. Accordingly, we found that TXNDC12 interacted with β-catenin and that the thioredoxin-like domain of TXNDC12 was essential for the interaction between TXNDC12 and β-catenin as well as for TXNDC12-mediated β-catenin activation. Moreover, high levels of TXNDC12 in clinical HCC tissues correlated with elevated nuclear β-catenin levels and predicted worse overall and disease-free survival. In summary, our study demonstrated that TXNDC12 could activate β-catenin via protein–protein interaction and promote ZEB1-mediated EMT and HCC metastasis.

HEG1 indicates poor prognosis and promotes hepatocellular carcinoma invasion, metastasis, and EMT by activating Wnt/β-catenin signaling

2019 ◽  
Vol 133 (14) ◽  
pp. 1645-1662 ◽  
Author(s):  
Yan-rong Zhao ◽  
Ji-long Wang ◽  
Cong Xu ◽  
Yi-ming Li ◽  
Bo Sun ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Heart Development ◽  
Poor Prognosis ◽  
Nuclear Translocation ◽  
Epithelial Mesenchymal Transition ◽  
Disease Free Survival ◽  
Intrahepatic Metastasis ◽  
Mesenchymal Transition

Abstract Heart development protein with EGF-like domains 1 (HEG1) plays critical roles in embryo development and angiogenesis, which are closely related to tumor progression. However, the role of HEG1 in hepatocellular carcinoma (HCC) remains unknown. In the present study, we explored the clinical significance, biological function and regulatory mechanisms of HEG1 in HCC and found that HEG1 is significantly up-regulated in HCC cell lines and primary tumor samples. Additionally, high HEG1 expression is correlated with aggressive clinicopathological features. Patients with high HEG1 expression had shorter overall survival (OS) and disease-free survival (DFS) than those with low HEG1 expression, which indicated that HEG1 is an independent factor for poor prognosis. Lentivirus-mediated HEG1 overexpression significantly promotes HCC cell migration, invasion and epithelial–mesenchymal transition (EMT) in vitro and promotes intrahepatic metastasis, lung metastasis and EMT in vivo. Opposing results are observed when HEG1 is silenced. Mechanistically, HEG1 promotes β-catenin expression and maintains its stability, leading to intracellular β-catenin accumulation, β-catenin nuclear translocation and Wnt signaling activation. Loss- and gain-of-function assays further confirmed that β-catenin is essential for HEG1-mediated promotion of HCC invasion, metastasis and EMT. In conclusion, HEG1 indicates poor prognosis; plays important roles in HCC invasion, metastasis and EMT by activating Wnt/β-catenin signaling; and can serve as a potentially valuable prognostic biomarker and therapeutic target for HCC.

Cripto-1 promotes tumor invasion and predicts poor outcomes in hepatocellular carcinoma

2019 ◽  
Vol 41 (5) ◽  
pp. 571-581
Author(s):  
Tao Huang ◽  
Yi-Zhan Guo ◽  
Xiao Yue ◽  
Guo-Pei Zhang ◽  
Yi Zhang ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Epithelial Mesenchymal Transition ◽  
Survival Rates ◽  
Disease Free Survival ◽  
Migration And Invasion ◽  
Invasion And Metastasis ◽  
Mesenchymal Transition ◽  
Poor Outcomes

Abstract Cripto-1 (CR1), an oncofetal protein, had been implied to reactivate in some cancers. However, the relationship between CR1 expression and patient outcomes and the tumor biological function of CR1 contributing to invasion and metastasis in hepatocellular carcinoma (HCC) is poorly defined. In this study, we demonstrated that CR1 was expressed in over 80% of HCCs in a training cohort (n = 242) and a validation cohort (n = 159). High CR1 expression was significantly correlated with aggressive HCC phenotypes (i.e. portal vein tumor thrombus, microscopic vascular invasion, multiple tumors and poor tumor differentiation). In both the training and validation cohorts, patients with high CR1 expression had remarkably shorter disease-free survival and overall survival rates than those with low CR1 expression. A series in vitro and in vivo assays showed that CR1 substantially promoted HCC cell migration, invasion and metastasis. Mechanistically, we demonstrated that CR1 induced HCC cells to undergo epithelial–mesenchymal transition through activating the Akt/NFκB/p65 signaling. Chromatin immunoprecipitation assay showed that NFκB/p65 enhanced CR1 expression by binding its promoter. Thus, CR1 and NFκB/p65 form a positive feedback loop that sustained the process of migration and invasion of HCC. Therefore, CR1 plays an important role in HCC invasion and metastasis and may be an effective and reliable prognostic biomarker for HCC recurrence after resection. Targeting CR1 may be a promising treatment for HCC.

scholarly journals Sirt1 deacetylates and stabilizes p62 to promote hepato-carcinogenesis

2021 ◽  
Vol 12 (4) ◽  
Author(s):  
Lifeng Feng ◽  
Miaoqin Chen ◽  
Yiling Li ◽  
Muchun Li ◽  
Shiman Hu ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Overall Survival ◽  
Cell Growth ◽  
Knockout Mice ◽  
Liver Tumors ◽  
Underlying Mechanism ◽  
Carcinoma Cells ◽  
Conditional Knockout

Abstractp62/SQSTM1 is frequently up-regulated in many cancers including hepatocellular carcinoma. Highly expressed p62 promotes hepato-carcinogenesis by activating many signaling pathways including Nrf2, mTORC1, and NFκB signaling. However, the underlying mechanism for p62 up-regulation in hepatocellular carcinoma remains largely unclear. Herein, we confirmed that p62 was up-regulated in hepatocellular carcinoma and its higher expression was associated with shorter overall survival in patients. The knockdown of p62 in hepatocellular carcinoma cells decreased cell growth in vitro and in vivo. Intriguingly, p62 protein stability could be reduced by its acetylation at lysine 295, which was regulated by deacetylase Sirt1 and acetyltransferase GCN5. Acetylated p62 increased its association with the E3 ligase Keap1, which facilitated its poly-ubiquitination-dependent proteasomal degradation. Moreover, Sirt1 was up-regulated to deacetylate and stabilize p62 in hepatocellular carcinoma. Additionally, Hepatocyte Sirt1 conditional knockout mice developed much fewer liver tumors after Diethynitrosamine treatment, which could be reversed by the re-introduction of exogenous p62. Taken together, Sirt1 deacetylates p62 at lysine 295 to disturb Keap1-mediated p62 poly-ubiquitination, thus up-regulating p62 expression to promote hepato-carcinogenesis. Therefore, targeting Sirt1 or p62 is a reasonable strategy for the treatment of hepatocellular carcinoma.

scholarly journals Scorpion inhibits epithelial–mesenchymal transition and metastasis of hepatocellular carcinoma

2018 ◽  
Vol 243 (7) ◽  
pp. 645-654 ◽  
Author(s):  
Yi-Quan Yan ◽  
Juan Xie ◽  
Jing-Fu Wang ◽  
Zhao-Feng Shi ◽  
Xiang Zhang ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Poor Prognosis ◽  
Epithelial Mesenchymal Transition ◽  
Migration And Invasion ◽  
Mesenchymal Transition ◽  
Unfavorable Clinical Outcome ◽  
Metastasis Models ◽  
Tumor Growth And Metastasis

Hepatocellular carcinoma (HCC) is one of the most malignant diseases worldwide. The unfavorable clinical outcome and poor prognosis are due to high rates of recurrence and metastasis after treatments. Some scholars of traditional Chinese medicine suggested that endogenous wind-evil had played an important role in metastasis of malignant tumor. Therefore, the drug of dispelling wind-evil could be used to prevent cancer metastasis and improve the poor prognosis. So we wondered whether Scorpion, one of the most important wind calming drugs, has antitumor effect especially in epithelial–mesenchymal transition (EMT) and metastasis of HCC in this research. We found that Scorpion-medicated serum could inhibit proliferation, induce apoptosis, and decrease migration and invasion capacity of Hepa1-6 cells in vitro. Meanwhile, we observed that water decoction of Scorpion restrained tumor growth and metastasis in nude mouse of HCC metastasis models. Further experiments showed that Scorpion could suppress EMT, which is characterized by increased epithelial marker E-cadherin expression and decreased mesenchymal markers N-cadherin and Snail expression following Scorpion treatment both in vitro and in vivo. These results suggested that the Scorpion could inhibit Hepa1-6 cells’ invasion and metastasis in part by reversing EMT and providing a possible potential approach for preventing HCC metastasis. Impact statement The unfavorable clinical outcome and poor prognosis of hepatocellular carcinoma (HCC) are due to high rates of recurrence and metastasis after treatments. Here we found Scorpion, one of the most important wind calming drugs, has antitumor effect. Scorpion-medicated serum inhibited the proliferation, induced apoptosis, and decreased migration and invasion capacity of Hepa1-6 cells in vitro. Water decoction of Scorpion restrained tumor growth and metastasis in nude mouse of HCC metastasis models. Further experiments showed that Scorpion could suppress EMT of HCC both in vitro and in vivo. Our results suggested that the Scorpion could inhibit Hepa1-6 cells’ invasion and metastasis in part by reversing EMT and providing a possible potential approach for preventing HCC metastasis.

Effects of GLS1 on the epithelial-mesenchymal transition of hepatocellular carcinoma in vitro and in vivo

2018 ◽  
Vol 7 (1) ◽  
pp. 97-108 ◽  
Author(s):  
Yajuan Cao ◽  
Binghua Li ◽  
Xianbiao Shi ◽  
Hongyan Wu ◽  
Chen Yan ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Epithelial Mesenchymal Transition ◽  
Mesenchymal Transition

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 Armadillo Repeat-Containing Protein 8 (ARMC8) Silencing Inhibits Proliferation and Invasion in Osteosarcoma Cells

2016 ◽  
Vol 24 (5) ◽  
pp. 381-389 ◽  
Author(s):  
Feng Jiang ◽  
Yan Shi ◽  
Hong Lu ◽  
Guojun Li
Keyword(s):  
Epithelial Mesenchymal Transition ◽  
Underlying Mechanism ◽  
Migration And Invasion ◽  
Osteosarcoma Cell ◽  
Osteosarcoma Cells ◽  
Mesenchymal Transition ◽  
Armadillo Repeat ◽  
Proliferation And Invasion

Armadillo repeat-containing protein 8 (ARMC8) plays an important role in regulating cell migration, proliferation, tissue maintenance, signal transduction, and tumorigenesis. However, the expression pattern and role of ARMC8 in osteosarcoma are still unclear. In this study, our aims were to examine the effects of ARMC8 on osteosarcoma and to explore its underlying mechanism. Our results demonstrated that ARMC8 was overexpressed in osteosarcoma cell lines. Knockdown of ARMC8 significantly inhibited osteosarcoma cell proliferation in vitro and markedly inhibited xenograft tumor growth in vivo. ARMC8 silencing also suppressed the epithelial‐mesenchymal transition (EMT) phenotype, as well as inhibited the migration and invasion of osteosarcoma cells. Furthermore, knockdown of ARMC8 obviously inhibited the expression of β-catenin, c-Myc, and cyclin D1 in MG-63 cells. In conclusion, this report demonstrates that ARMC8 silencing inhibits proliferation and invasion of osteosarcoma cells. Therefore, ARMC8 may play an important role in the development and progression of human osteosarcoma and may represent a novel therapeutic target in the treatment of osteosarcoma.

scholarly journals HCK promotes glioblastoma progression by TGFβ signaling

2020 ◽  
Vol 40 (6) ◽  
Author(s):  
Zhenlin Wang ◽  
Chenting Ying ◽  
Anke Zhang ◽  
Houshi Xu ◽  
Yang Jiang ◽  
...  
Keyword(s):  
Tyrosine Kinases ◽  
B Lymphocyte ◽  
Epithelial Mesenchymal Transition ◽  
Enrichment Analysis ◽  
Underlying Mechanism ◽  
Gene Set Enrichment Analysis ◽  
Tgfβ Signaling ◽  
Mesenchymal Transition

Abstract The hematopoietic cell kinase (HCK), a member of the Src family protein-tyrosine kinases (SFKs), is primarily expressed in cells of the myeloid and B lymphocyte lineages. Nevertheless, the roles of HCK in glioblastoma (GBM) remain to be examined. Thus, we aimed to investigate the effects of HCK on GBM development both in vitro and in vivo, as well as the underlying mechanism. The present study found that HCK was highly expressed in both tumor tissues from patients with GBM and cancer cell lines. HCK enhanced cell viability, proliferation, and migration, and induced cell apoptosis in vitro. Tumor xenografts results also demonstrated that HCK knockdown significantly inhibited tumor growth. Interestingly, gene set enrichment analysis (GSEA) showed HCK was closed associated with epithelial mesenchymal transition (EMT) and TGFβ signaling in GBM. In addition, we also found that HCK accentuates TGFβ-induced EMT, suggesting silencing HCK inhibited EMT through the inactivation of Smad signaling pathway. In conclusion, our findings indicated that HCK is involved in GBM progression via mediating EMT process, and may be served as a promising therapeutic target for GBM.

scholarly journals Arctigenin Suppressed Epithelial-Mesenchymal Transition Through Wnt3a/β-Catenin Pathway in PQ-Induced Pulmonary Fibrosis

2020 ◽  
Vol 11 ◽  
Author(s):  
Fei Gao ◽  
Yun Zhang ◽  
Zhizhou Yang ◽  
Mengmeng Wang ◽  
Zhiyi Zhou ◽  
...  
Keyword(s):  
Pulmonary Fibrosis ◽  
Signaling Pathway ◽  
Lung Fibrosis ◽  
Epithelial Mesenchymal Transition ◽  
A549 Cells ◽  
Underlying Mechanism ◽  
Alveolar Type ◽  
Mesenchymal Transition

Arctigenin (ATG), a major bioactive substance of Fructus Arctii, counters renal fibrosis; however, whether it protects against paraquat (PQ)-induced lung fibrosis remains unknown. The present study was to determine the effect of ATG on PQ-induced lung fibrosis in a mouse model and the underlying mechanism. Firstly, we found that ATG suppressed PQ-induced pulmonary fibrosis by blocking the epithelial-mesenchymal transition (EMT). ATG reduced the expressions of Vimentin and α-SMA (lung fibrosis markers) induced by PQ and restored the expressions of E-cadherin and Occludin (two epithelial markers) in vivo and in vitro. Besides, the Wnt3a/β-catenin signaling pathway was significantly activated in PQ induced pulmonary fibrosis. Further analysis showed that pretreatment of ATG profoundly abrogated PQ-induced EMT-like phenotypes and behaviors in A549 cells. The Wnt3a/β-catenin signaling pathway was repressed by ATG treatment. The overexpression of Wnt3a could weaken the therapeutic effect of ATG in A549 cells. These findings suggested that ATG could serve as a new therapeutic candidate to inhibit or even reverse EMT-like changes in alveolar type II cells during PQ-induced lung fibrosis, and unraveled that the Wnt3a/β-catenin pathway might be a mechanistic tool for ATG to control pulmonary fibrosis.

miR-199a-5p suppresses epithelial- mesenchymal-transition in anaplastic thyroid carcinoma cells via targeting Snail signals

2020 ◽  
Vol 29 (3) ◽  
pp. 317-326
Author(s):  
Fengyun Hao ◽  
Ya-Nan Bi ◽  
Lei Wang ◽  
Yubing Wang ◽  
Jilei Ma ◽  
...  
Keyword(s):  
Thyroid Carcinoma ◽  
Epithelial Mesenchymal Transition ◽  
Anaplastic Thyroid Carcinoma ◽  
Carcinoma Cells ◽  
Migration And Invasion ◽  
Mesenchymal Transition ◽  
Novel Approach ◽  
Accurate Expression

MicroRNAs (miRNAs) have been validated to play prominent roles in the occurrence and development of anaplastic thyroid carcinoma (ATC). miR-199a-5p was previously reported to act as a tumor suppressor or oncomiRNA in various types of cancer. However, its accurate expression, function, and mechanism in ATC remain unclear. Here, we find that miR-199a-5p is significantly downregulated in ATC tissues compared with adjacent non-cancerous tissues. Overexpression of miR-199a-5p significantly inhibits migration and invasion of ATC cells in vitro, and lung metastasis in vivo. Importantly, miR-199a-5p suppresses epithelial-mesenchymal transition (EMT) both in vitro and in vivo by targeting Snail. Taken together, this study reveals that miR-199a-5p is critical to the EMT progression in ATC cells. Targeting the pathway described here may be a novel approach for inhibiting metastasis of ATC.

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