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Pan M, Luo M, Liu L, Chen Y, Cheng Z, Wang K, Huang L, Tang N, Qiu J, Huang A, Xia J. EGR1 suppresses HCC growth and aerobic glycolysis by transcriptionally downregulating PFKL. J Exp Clin Cancer Res 2024; 43:35. [PMID: 38287371 PMCID: PMC10823730 DOI: 10.1186/s13046-024-02957-5] [Citation(s) in RCA: 12] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2023] [Accepted: 01/14/2024] [Indexed: 01/31/2024] Open
Abstract
BACKGROUND Hepatocellular Carcinoma (HCC) is a matter of great global public health importance; however, its current therapeutic effectiveness is deemed inadequate, and the range of therapeutic targets is limited. The aim of this study was to identify early growth response 1 (EGR1) as a transcription factor target in HCC and to explore its role and assess the potential of gene therapy utilizing EGR1 for the management of HCC. METHODS In this study, both in vitro and in vivo assays were employed to examine the impact of EGR1 on the growth of HCC. The mouse HCC model and human organoid assay were utilized to assess the potential of EGR1 as a gene therapy for HCC. Additionally, the molecular mechanism underlying the regulation of gene expression and the suppression of HCC growth by EGR1 was investigated. RESULTS The results of our investigation revealed a notable decrease in the expression of EGR1 in HCC. The decrease in EGR1 expression promoted the multiplication of HCC cells and the growth of xenografted tumors. On the other hand, the excessive expression of EGR1 hindered the proliferation of HCC cells and repressed the development of xenografted tumors. Furthermore, the efficacy of EGR1 gene therapy was validated using in vivo mouse HCC models and in vitro human hepatoma organoid models, thereby providing additional substantiation for the anti-cancer role of EGR1 in HCC. The mechanistic analysis demonstrated that EGR1 interacted with the promoter region of phosphofructokinase-1, liver type (PFKL), leading to the repression of PFKL gene expression and consequent inhibition of PFKL-mediated aerobic glycolysis. Moreover, the sensitivity of HCC cells and xenografted tumors to sorafenib was found to be increased by EGR1. CONCLUSION Our findings suggest that EGR1 possesses therapeutic potential as a tumor suppressor gene in HCC, and that EGR1 gene therapy may offer benefits for HCC patients.
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Affiliation(s)
- Mingang Pan
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Chongqing Medical University, Chongqing, 400016, China
| | - Muyu Luo
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Chongqing Medical University, Chongqing, 400016, China
| | - Lele Liu
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Chongqing Medical University, Chongqing, 400016, China
| | - Yunmeng Chen
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Chongqing Medical University, Chongqing, 400016, China
| | - Ziyi Cheng
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Chongqing Medical University, Chongqing, 400016, China
| | - Kai Wang
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Chongqing Medical University, Chongqing, 400016, China
| | - Luyi Huang
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Chongqing Medical University, Chongqing, 400016, China
| | - Ni Tang
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Chongqing Medical University, Chongqing, 400016, China
| | - Jianguo Qiu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital, Chongqing Medical University, Chongqing, 400016, China.
| | - Ailong Huang
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Chongqing Medical University, Chongqing, 400016, China.
| | - Jie Xia
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Chongqing Medical University, Chongqing, 400016, China.
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DU K, Wu X, Ji X, Liang N, Li Z. Early growth response 1 promoted the invasion of glioblastoma multiforme by elevating HMGB1. J Neurosurg Sci 2023; 67:422-430. [PMID: 33297605 DOI: 10.23736/s0390-5616.20.05107-3] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
BACKGROUND Glioblastoma multiforme (GBM) is the most common and deadly glioma subtype. Early growth response 1 (EGR1) participates in the progression of several cancer types, but the expression and function of EGR1 in GBM was rarely investigated. METHODS The expressions of EGR1 in GBM were detected with qRT-PCR and immunohistochemistry in 12 pairs of fresh GBM tissues and 116 paraffin-embedded specimens. The patients were divided into high and low EGR1 groups according to the IHC score of EGR1, and the prognostic significances of different groups were evaluated with univariate and multivariate analyses. With in-vitro experiments, we assessed the role of EGR1 in the proliferation and invasion of GBM cells. RESULTS In our study, EGR1 was up-regulated in GBM tissues compared with tumor-adjacent normal tissues. High expression of EGR1 or HMGB1 were unfavorable prognostic biomarkers of GBM. Coexpression of EGR1 and HMGB1 could predict the prognosis of GBM more sensitively. EGR1 facilitated the proliferation and invasion of GBM cells. Moreover, EGR1 promoted the invasion, instead of proliferation, of GBM cells by elevating the expression of HMGB1. CONCLUSIONS ERG1 was a prognostic biomarker of GBM, and ERG1 and HMGB1 synergistically could predict the GBM prognosis more precisely. ERG1 could promote GBM cell invasion by inducing HMGB1 expression.
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Affiliation(s)
- Kai DU
- Department of Neurosurgery, Yidu Central Hospital of Weifang, Weifang, China
| | - Xiaoyou Wu
- Department of Pediatrics, Yidu Central Hospital of Weifang, Weifang, China
| | - Xiaofei Ji
- Department of Pediatrics, Yidu Central Hospital of Weifang, Weifang, China
| | - Nan Liang
- Department of Neurosurgery, the Second Hospital of Shandong First Medical University, Taian, China
| | - Zheng Li
- Department of Neurosurgery, the Second Hospital of Shandong First Medical University, Taian, China -
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Junjie L, Cheng G, Kangkang L, Yu L, Zhiyao Y, Xudong W, Xianmei Z, Xiaomin L. Citrus alkaline extracts improve LPS-induced pulmonary fibrosis via epithelial mesenchymal transition signals. Chin Med 2023; 18:62. [PMID: 37248506 DOI: 10.1186/s13020-023-00766-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2023] [Accepted: 05/11/2023] [Indexed: 05/31/2023] Open
Abstract
BACKGROUND Acute respiratory distress syndrome (ARDS) is a serious life threatening clinical critical illness. ARDS-related pulmonary fibrosis is a common complication of ARDS. The occurrence of early pulmonary fibrosis indicates a higher incidence and mortality of multiple organ failure. LPS-induced ARDS-related pulmonary fibrosis model in mice was established in this study. And we have explored the anti-pulmonary fibrosis effects and molecular mechanisms of the Citrus Alkaline Extracts (CAE) in vivo and in vitro. METHODS Pulmonary fibrosis mouse model and lung epithelial cell injury model were established in this study. H&E, Masson and Sirius Red staining were used to estimate lung tissue damage. Immunohistochemistry and western blotting were used to analyze proteins expression. Protein-protein interaction was observed by Co-Immunoprecipitation. Systemic impact of CAE on signaling pathway was examined by RNA-seq. RESULTS Through H&E, Masson and Sirius Red staining, it was convincingly indicated that therapeutic administration of CAE alleviated lung injury and fibrosis, while pretreated administration of CAE showed weak improvement. In vitro experiments showed that CAE had dual regulation to E-cadherin and N-cadherin, the important indicators of epithelial-mesenchymal transition (EMT). And it was further demonstrated that CAE reversed TGF-β1-induced EMT mainly through Wnt/β-catenin, Stat3/6 and COX2/PGE2 signals. Through RNA-Seq, we discovered important mechanisms by which CAE exerts its therapeutic effect. And network pharmacology analysis demonstrated core potential targets of CAE in EMT. CONCLUSION Thus, this study provides new therapeutic effects of CAE in anti-fibrosis, and offers potential mechanisms for CAE in LPS-induced pulmonary fibrosis.
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Affiliation(s)
- Li Junjie
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, 163 Xianlin Avenue, Nanjing, 210023, China
| | - Gu Cheng
- Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, 155 Hanzhong Road, Nanjing, 210004, China
| | - Luo Kangkang
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, 163 Xianlin Avenue, Nanjing, 210023, China
| | - Li Yu
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, 163 Xianlin Avenue, Nanjing, 210023, China
| | - Yuan Zhiyao
- Nanjing Stomatological Hospital, Medical School of Nanjing University, Nanjing, 210008, China
| | - Wu Xudong
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, 163 Xianlin Avenue, Nanjing, 210023, China.
| | - Zhou Xianmei
- Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, 155 Hanzhong Road, Nanjing, 210004, China.
| | - Lu Xiaomin
- Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, 155 Hanzhong Road, Nanjing, 210004, China.
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4
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Zou Q, Du B, Zhang Q, Wang H, Zhang M, Yang X, Wang Q, Wang K. Investigation on protein dimerization and evaluation of medicine effects by single molecule force spectroscopy. Anal Chim Acta 2023; 1252:341043. [PMID: 36935149 DOI: 10.1016/j.aca.2023.341043] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2022] [Revised: 02/28/2023] [Accepted: 03/02/2023] [Indexed: 03/09/2023]
Abstract
Monitoring the dimerization state of the mesenchymal-epithelial transition factor (Met) was essential for in-depth understanding of the tumor signal transduction network. At present, the dimerization activation pathway of Met protein was mainly studied at the macro level, while the research at the single molecule level was far from comprehensive. Herein, the dimerization activation of Met protein's extracellular domain induced by ligand hepatocyte growth factor (HGF) was dynamically studied by single-molecule force spectroscopy. Met protein was immobilized on a biomimetic lipid membrane for ensuring its physiological environment, and then the Met dimers were recognized by bivalent probe which was formed by two Met-binding aptamers. Then the dimeric state of Met protein could be distinguished from monomeric state of Met protein through some parameters, (such as unimodal ratio, bimodal ratio and separation work). The unimodal indicates the occurrence of single molecule binding event, and the bimodal represents the occurrence of double binding event (also represents the presence of Met dimer). Before HGF treatment, most of the Met protein on the lipid membrane was still in the form of monomer, so the unimodal ratio in the force curve was larger (78.8 ± 5.2%), and the bimodal ratio was smaller (17.0 ± 4.1%). After HGF treatment, the unimodal ratio decreased to 54.0 ± 7.4%, and the bimodal ratio increased to 43.2 ± 7.3%. It was due to the formation of dimers after the binding of Met protein on the fluidity lipid membrane with HGF. In addition, the average separation work increased to about 2 times after HGF treatment. Given that studies of Met protein dimerization inhibitors have contributed to the development of more potent and safe inhibitors to significantly inhibit tumor metastasis, the effects of different medicines (including anticoagulant medicines, different antibiotics and anti-cancer medicines) on the dimerization activation of Met protein were then explored by the platform described above. The results showed that anticoagulant medicines heparin and its analogs can significantly inhibit HGF-mediated Met protein activation, while different antibiotics and anticancer medicines had no significant effect on the dimerization of Met protein. This work provided a platform for studying protein dimerization as well as for screening Met protein dimerization inhibitors at the single-molecule level.
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Affiliation(s)
- Qingqing Zou
- State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Chemistry and Chemical Engineering, Key Laboratory for Bio-Nanotechnology and Molecular Engineering of Hunan Province, Hunan University, Changsha, 410082, PR China
| | - Bin Du
- State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Chemistry and Chemical Engineering, Key Laboratory for Bio-Nanotechnology and Molecular Engineering of Hunan Province, Hunan University, Changsha, 410082, PR China
| | - Qianqian Zhang
- State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Chemistry and Chemical Engineering, Key Laboratory for Bio-Nanotechnology and Molecular Engineering of Hunan Province, Hunan University, Changsha, 410082, PR China
| | - Hongqiang Wang
- State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Chemistry and Chemical Engineering, Key Laboratory for Bio-Nanotechnology and Molecular Engineering of Hunan Province, Hunan University, Changsha, 410082, PR China
| | - Mingwan Zhang
- State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Chemistry and Chemical Engineering, Key Laboratory for Bio-Nanotechnology and Molecular Engineering of Hunan Province, Hunan University, Changsha, 410082, PR China
| | - Xiaohai Yang
- State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Chemistry and Chemical Engineering, Key Laboratory for Bio-Nanotechnology and Molecular Engineering of Hunan Province, Hunan University, Changsha, 410082, PR China
| | - Qing Wang
- State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Chemistry and Chemical Engineering, Key Laboratory for Bio-Nanotechnology and Molecular Engineering of Hunan Province, Hunan University, Changsha, 410082, PR China.
| | - Kemin Wang
- State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Chemistry and Chemical Engineering, Key Laboratory for Bio-Nanotechnology and Molecular Engineering of Hunan Province, Hunan University, Changsha, 410082, PR China.
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Hereditary Tyrosinemia Type 1 Mice under Continuous Nitisinone Treatment Display Remnants of an Uncorrected Liver Disease Phenotype. Genes (Basel) 2023; 14:genes14030693. [PMID: 36980965 PMCID: PMC10047938 DOI: 10.3390/genes14030693] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2023] [Revised: 03/02/2023] [Accepted: 03/08/2023] [Indexed: 03/18/2023] Open
Abstract
Hereditary tyrosinemia type 1 (HT1) is a genetic disorder of the tyrosine degradation pathway (TIMD) with unmet therapeutic needs. HT1 patients are unable to fully break down the amino acid tyrosine due to a deficient fumarylacetoacetate hydrolase (FAH) enzyme and, therefore, accumulate toxic tyrosine intermediates. If left untreated, they experience hepatic failure with comorbidities involving the renal and neurological system and the development of hepatocellular carcinoma (HCC). Nitisinone (NTBC), a potent inhibitor of the 4-hydroxyphenylpyruvate dioxygenase (HPD) enzyme, rescues HT1 patients from severe illness and death. However, despite its demonstrated benefits, HT1 patients under continuous NTBC therapy are at risk to develop HCC and adverse reactions in the eye, blood and lymphatic system, the mechanism of which is poorly understood. Moreover, NTBC does not restore the enzymatic defects inflicted by the disease nor does it cure HT1. Here, the changes in molecular pathways associated to the development and progression of HT1-driven liver disease that remains uncorrected under NTBC therapy were investigated using whole transcriptome analyses on the livers of Fah- and Hgd-deficient mice under continuous NTBC therapy and after seven days of NTBC therapy discontinuation. Alkaptonuria (AKU) was used as a tyrosine-inherited metabolic disorder reference disease with non-hepatic manifestations. The differentially expressed genes were enriched in toxicological gene classes related to liver disease, liver damage, liver regeneration and liver cancer, in particular HCC. Most importantly, a set of 25 genes related to liver disease and HCC development was identified that was differentially regulated in HT1 vs. AKU mouse livers under NTBC therapy. Some of those were further modulated upon NTBC therapy discontinuation in HT1 but not in AKU livers. Altogether, our data indicate that NTBC therapy does not completely resolves HT1-driven liver disease and supports the sustained risk to develop HCC over time as different HCC markers, including Moxd1, Saa, Mt, Dbp and Cxcl1, were significantly increased under NTBC.
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Zhou L, Li J, Liu X, Tang Y, Li T, Deng H, Chen J, Yin X, Hu K, Ouyang W. Dexmedetomidine promotes apoptosis and suppresses proliferation of hepatocellular carcinoma cells via microRNA-130a/EGR1 axis. Cell Death Dis 2022; 8:31. [PMID: 35046398 PMCID: PMC8770558 DOI: 10.1038/s41420-021-00805-5] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2021] [Revised: 09/03/2021] [Accepted: 10/20/2021] [Indexed: 11/09/2022]
Abstract
Accumulating evidence has revealed the role of microRNAs (miRs) in hepatocellular carcinoma (HCC). Dexmedetomidine, a highly selective α2-adrenergic agonist, is widely used in perioperative settings for analgesia and sedation. Herein, we aimed to determine whether dexmedetomidine might directly regulate miR-130a/early growth response 1 (EGR1) axis in HCC and explore the related mechanisms. miR-130a and EGR1 expression were determined in HCC tissues and their correlation was evaluated. Human HCC cell line HCCLM3 was selected. Upon the determination of the optimal concentration of dexmedetomidine, HCCLM3 cells were treated with dexmedetomidine, miR-130a- or EGR1-related oligonucleotides or plasmids were transfected into cells to explore their functions in cell biological behaviors. miR-130a and EGR1 levels in cells were tested. The targeting relationship between miR-130a and EGR1 was verified. miR-130a was inhibited while EGR1 was elevated in HCC tissues and they were negatively correlated. EGR1 was targeted by miR-130a. With the increase of dexmedetomidine concentration, HCCLM3 cell viability was correspondingly inhibited, miR-130a expression was elevated and EGR1 expression was decreased. Dexmedetomidine, upregulating miR-130a or downregulating EGR1 inhibited proliferation, invasion and migration, and promoted apoptosis of HCCLM3 cells. MiR-130a upregulation/downregulation enhanced/impaired the effect of dexmedetomidine on cell biological behaviors. Our study provides evidence that raising miR-130a enhances the inhibitory effects of dexmedetomidine on HCC cellular growth via inhibiting EGR1. Thus, miR-130a may be a potential candidate for the treatment of HCC.
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7
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Topel H, Bağırsakçı E, Yılmaz Y, Güneş A, Bağcı G, Çömez D, Kahraman E, Korhan P, Atabey N. High glucose induced c-Met activation promotes aggressive phenotype and regulates expression of glucose metabolism genes in HCC cells. Sci Rep 2021; 11:11376. [PMID: 34059694 PMCID: PMC8166976 DOI: 10.1038/s41598-021-89765-5] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2020] [Accepted: 04/26/2021] [Indexed: 02/08/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is strongly associated with metabolic dysregulations/deregulations and hyperglycemia is a common metabolic disturbance in metabolic diseases. Hyperglycemia is defined to promote epithelial to mesenchymal transition (EMT) of cancer cells in various cancers but its molecular contribution to HCC progression and aggressiveness is relatively unclear. In this study, we analyzed the molecular mechanisms behind the hyperglycemia-induced EMT in HCC cell lines. Here, we report that high glucose promotes EMT through activating c-Met receptor tyrosine kinase via promoting its ligand-independent homodimerization. c-Met activation is critical for high glucose induced acquisition of mesenchymal phenotype, survival under high glucose stress and reprogramming of cellular metabolism by modulating glucose metabolism gene expression to promote aggressiveness in HCC cells. The crucial role of c-Met in high glucose induced EMT and aggressiveness may be the potential link between metabolic syndrome-related hepatocarcinogenesis and/or HCC progression. Considering c-Met inhibition in hyperglycemic patients would be an important complementary strategy for therapy that favors sensitization of HCC cells to therapeutics.
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Affiliation(s)
- Hande Topel
- Izmir Biomedicine and Genome Center (IBG), Balcova, 35340, Izmir, Turkey.,Department of Medical Biology and Genetics, Graduate School of Health Sciences, Dokuz Eylul University, Balcova, 35340, Izmir, Turkey
| | - Ezgi Bağırsakçı
- Izmir Biomedicine and Genome Center (IBG), Balcova, 35340, Izmir, Turkey.,Department of Molecular Biology and Genetics, Izmir International Biomedicine and Genome Institute, Dokuz Eylul University, Balcova, 35340, Izmir, Turkey
| | - Yeliz Yılmaz
- Izmir Biomedicine and Genome Center (IBG), Balcova, 35340, Izmir, Turkey.,Department of Medical Biology and Genetics, Graduate School of Health Sciences, Dokuz Eylul University, Balcova, 35340, Izmir, Turkey
| | - Ayşim Güneş
- Izmir Biomedicine and Genome Center (IBG), Balcova, 35340, Izmir, Turkey
| | - Gülsün Bağcı
- Izmir Biomedicine and Genome Center (IBG), Balcova, 35340, Izmir, Turkey.,Department of Molecular Biology and Genetics, Izmir International Biomedicine and Genome Institute, Dokuz Eylul University, Balcova, 35340, Izmir, Turkey
| | - Dehan Çömez
- Izmir Biomedicine and Genome Center (IBG), Balcova, 35340, Izmir, Turkey.,Department of Molecular Biology and Genetics, Izmir International Biomedicine and Genome Institute, Dokuz Eylul University, Balcova, 35340, Izmir, Turkey
| | - Erkan Kahraman
- Izmir Biomedicine and Genome Center (IBG), Balcova, 35340, Izmir, Turkey.,Department of Medical Biology and Genetics, Graduate School of Health Sciences, Dokuz Eylul University, Balcova, 35340, Izmir, Turkey
| | - Peyda Korhan
- Izmir Biomedicine and Genome Center (IBG), Balcova, 35340, Izmir, Turkey
| | - Neşe Atabey
- Izmir Biomedicine and Genome Center (IBG), Balcova, 35340, Izmir, Turkey.
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Yılmaz Y, Batur T, Korhan P, Öztürk M, Atabey N. Targeting c-Met and AXL Crosstalk for the Treatment of Hepatocellular Carcinoma. LIVER CANCER IN THE MIDDLE EAST 2021:333-364. [DOI: 10.1007/978-3-030-78737-0_21] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Wei F, Jing H, Wei M, Liu L, Wu J, Wang M, Han D, Yang F, Yang B, Jiao D, Zheng G, Zhang L, Xi W, Guo Z, Yang AG, Qin W, Zhou Y, Wen W. Ring finger protein 2 promotes colorectal cancer progression by suppressing early growth response 1. Aging (Albany NY) 2020; 12:26199-26220. [PMID: 33346749 PMCID: PMC7803491 DOI: 10.18632/aging.202396] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2019] [Accepted: 11/11/2020] [Indexed: 12/15/2022]
Abstract
Ring finger protein 2 (RNF2) is an important component of polycomb repressive complex 1. RNF2 is upregulated in many kinds of tumors, and elevated RNF2 expression is associated with a poor prognosis in certain cancers. To assess the function of RNF2 in colorectal cancer, we examined RNF2 protein levels in 313 paired colorectal cancer tissues and adjacent normal tissues. We then analyzed the association of RNF2 expression with the patients’ clinicopathologic features and prognoses. RNF2 expression was upregulated in colorectal cancer tissues and was associated with the tumor differentiation status, tumor stage and prognosis. In colorectal cancer cell lines, downregulation of RNF2 inhibited cell proliferation and induced apoptosis. Gene microarray analysis revealed that early growth response 1 (EGR1) was upregulated in RNF2-knockdown cells. Knocking down EGR1 partially reversed the inhibition of cell proliferation and the induction of apoptosis in RNF2-knockdown cells. RNF2 was enriched at the EGR1 promoter, where it mono-ubiquitinated histone H2A, thereby inhibiting EGR1 expression. These results indicate that RNF2 is oncogenic in colorectal cancer and may promote disease progression by inhibiting EGR1 expression. RNF2 is thus a potential prognostic marker and therapeutic target in colorectal cancer.
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Affiliation(s)
- Feilong Wei
- Department of Orthopedics, Tangdu Hospital, Fourth Military Medical University, Xi’an 710038, China
| | - Haoren Jing
- Department of Anorectal Surgery, Tianjin Union Medical Center, Nankai University Affiliated Hospital, Tianjin 300013, China
| | - Ming Wei
- Urology Department of No. 989 Hospital, Joint Logistics Support Force of PLA, Luoyang 471000, China
| | - Lei Liu
- Department of Gastroenterology, Tangdu Hospital, Fourth Military Medical University, Xi’an 710038, China
| | - Jieheng Wu
- State Key Laboratory of Cancer Biology, Department of Immunology, Fourth Military Medical University, Xi’an 710032, China
| | - Meng Wang
- State Key Laboratory of Cancer Biology, Department of Immunology, Fourth Military Medical University, Xi’an 710032, China
| | - Donghui Han
- Department of Urology, Xijing Hospital, Fourth Military Medical University, Xi’an 710032, China
| | - Fa Yang
- Department of Urology, Xijing Hospital, Fourth Military Medical University, Xi’an 710032, China
| | - Bo Yang
- Department of Urology, Xijing Hospital, Fourth Military Medical University, Xi’an 710032, China
| | - Dian Jiao
- Department of Urology, Tangdu Hospital, Fourth Military Medical University, Xi’an 710038, China
| | - Guoxu Zheng
- State Key Laboratory of Cancer Biology, Department of Immunology, Fourth Military Medical University, Xi’an 710032, China
| | - Lingling Zhang
- State Key Laboratory of Cancer Biology, Department of Immunology, Fourth Military Medical University, Xi’an 710032, China
| | - Wenjin Xi
- State Key Laboratory of Cancer Biology, Department of Immunology, Fourth Military Medical University, Xi’an 710032, China
| | - Zhangyan Guo
- State Key Laboratory of Cancer Biology, Department of Immunology, Fourth Military Medical University, Xi’an 710032, China
| | - An-Gang Yang
- State Key Laboratory of Cancer Biology, Department of Immunology, Fourth Military Medical University, Xi’an 710032, China
| | - Weijun Qin
- Department of Urology, Xijing Hospital, Fourth Military Medical University, Xi’an 710032, China
| | - Yi Zhou
- Department of Anorectal Surgery, Tianjin Union Medical Center, Nankai University Affiliated Hospital, Tianjin 300013, China
| | - Weihong Wen
- Institute of Medical Research, Northwestern Polytechnical University, Xi'an 710072, China
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Lin Z, Ling LQR, Ng M, Matlub L, Mehta K, Linus RA, Looker MJ, Melia Y, Loong J, Paolini R, Farah CS, Celentano A. The effect of anticoagulants on oral squamous cell carcinoma: A systematic review. J Oral Pathol Med 2020; 50:118-121. [PMID: 33184943 DOI: 10.1111/jop.13125] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2020] [Accepted: 10/18/2020] [Indexed: 01/06/2023]
Abstract
Tumour progression allows for aberrant angiogenesis. Consequently, cancer-associated thrombosis is a prevalent complication that is coupled with poor prognosis. Anticoagulants have therefore been prescribed with chemotherapeutic agents to target potential thrombo-embolic risk. A systematic review was carried out to summarise existing evidence on the interactions between anticoagulants and oral cancer. This treatment paradigm has demonstrated beneficial results in some oncology patients, thus associating anticoagulants with anticancer effects. Increasing prevalence of oral cancer presents a need to source alternative therapeutic means to prevent disease progression, and thus the use of anticoagulants in these patients may provide an avenue for this to occur. The paucity of evidence regarding the interactions between oral squamous cell carcinoma and anticoagulants emphasises the urgency with which further research should be conducted.
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Affiliation(s)
- Zichen Lin
- Melbourne Dental School, The University of Melbourne, Carlton, Vic, Australia
| | - Li-Qiao R Ling
- Melbourne Dental School, The University of Melbourne, Carlton, Vic, Australia
| | - Mabel Ng
- Melbourne Dental School, The University of Melbourne, Carlton, Vic, Australia
| | - Laith Matlub
- Melbourne Dental School, The University of Melbourne, Carlton, Vic, Australia
| | - Kunal Mehta
- Melbourne Dental School, The University of Melbourne, Carlton, Vic, Australia
| | - Roshine A Linus
- Melbourne Dental School, The University of Melbourne, Carlton, Vic, Australia
| | - Mitchell J Looker
- Melbourne Dental School, The University of Melbourne, Carlton, Vic, Australia
| | - Yovita Melia
- Melbourne Dental School, The University of Melbourne, Carlton, Vic, Australia
| | - Junhan Loong
- Melbourne Dental School, The University of Melbourne, Carlton, Vic, Australia
| | - Rita Paolini
- Melbourne Dental School, The University of Melbourne, Carlton, Vic, Australia
| | - Camile S Farah
- Australian Centre for Oral Oncology Research & Education, Nedlands, WA, Australia.,Oral, Maxillofacial and Dental Surgery, Fiona Stanley Hospital, Murdoch, WA, Australia.,Head and Neck Pathology, Australian Clinical Labs, Subiaco, WA, Australia
| | - Antonio Celentano
- Melbourne Dental School, The University of Melbourne, Carlton, Vic, Australia
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Yuan S, Gong Y, Chen R, Du J, Zhang H, Chen T. Chinese herbal formula QHF inhibits hepatocellular carcinoma metastasis via HGF/c-Met signaling pathway. Biomed Pharmacother 2020; 132:110867. [PMID: 33075668 DOI: 10.1016/j.biopha.2020.110867] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2020] [Revised: 10/06/2020] [Accepted: 10/07/2020] [Indexed: 12/29/2022] Open
Abstract
Hepatocellular Carcinoma (HCC) is one of the most common malignant tumors, and high recurrence and metastasis are the major obstacles to successful treatment of HCC. Traditional Chinese medicine has little known and unique advantages in the treatment of HCC. Previous studies have confirmed that Chinese herbal formula Qingrejiedu (clears away heat and toxins), Huoxuehuayu (promotes blood flow to remove stasis) and Fuzhengguben (strengthens healthy qi and root) (QHF) has a significant effect on patients with advanced HCC, improves the quality of life and prolongs the survival time of patients significantly. In this study, we investigated the effect of QHF on proliferation, migration and invasion of human high metastatic hepatocellular carcinoma cell line HCCLM3 and its underlying mechanism. The results from our in vitro experiments showed that QHF has the ability to inhibit the proliferation by inducing G2/M phase cell cycle arrest and induce apoptosis. Moreover, QHF can also inhibit migration and invasion of HCCLM3 cells and the expression of the p-c-Met protein in HCCLM3 cells was down-regulated. c-Met is closely related to the metastasis of HCC, then we constructed a stable transfected cell line HepG2-met with high expression of c-Met by transfection. Further study in vivo revealed that c-Met gene will promote the growth of tumors and lung metastases in nude mice, and QHF intervention can reduce tumor lung metastases by inhibiting the HGF/c-Met signaling pathway. In conclusion, our study reveals that QHF can inhibit the proliferation, migration and invasion of HCCLM3, and this effect may be related to inhibiting HGF/c-Met signaling pathway.
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Affiliation(s)
- Shenjun Yuan
- College of Medical Science, China Three Gorges University, Yichang, 443002, China; Department of Pathology, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430014, China
| | - Yuyuan Gong
- College of Medical Science, China Three Gorges University, Yichang, 443002, China; Third-Grade Pharmacological Laboratory on Chinese Medicine Approved by State Administration of Traditional Chinese Medicine, China Three Gorges University, Yichang, 443002, China
| | - Ruobing Chen
- College of Medical Science, China Three Gorges University, Yichang, 443002, China; Third-Grade Pharmacological Laboratory on Chinese Medicine Approved by State Administration of Traditional Chinese Medicine, China Three Gorges University, Yichang, 443002, China
| | - Juan Du
- College of Medical Science, China Three Gorges University, Yichang, 443002, China; Third-Grade Pharmacological Laboratory on Chinese Medicine Approved by State Administration of Traditional Chinese Medicine, China Three Gorges University, Yichang, 443002, China
| | - Hongfeng Zhang
- Department of Pathology, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430014, China
| | - Tao Chen
- College of Medical Science, China Three Gorges University, Yichang, 443002, China; Third-Grade Pharmacological Laboratory on Chinese Medicine Approved by State Administration of Traditional Chinese Medicine, China Three Gorges University, Yichang, 443002, China.
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12
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Receptor tyrosine kinases and heparan sulfate proteoglycans: Interplay providing anticancer targeting strategies and new therapeutic opportunities. Biochem Pharmacol 2020; 178:114084. [DOI: 10.1016/j.bcp.2020.114084] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2020] [Revised: 06/04/2020] [Accepted: 06/04/2020] [Indexed: 12/13/2022]
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13
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Comparison of the Interactions of Different Growth Factors and Glycosaminoglycans. Molecules 2019; 24:molecules24183360. [PMID: 31527407 PMCID: PMC6767211 DOI: 10.3390/molecules24183360] [Citation(s) in RCA: 51] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2019] [Revised: 09/10/2019] [Accepted: 09/11/2019] [Indexed: 01/24/2023] Open
Abstract
Most growth factors are naturally occurring proteins, which are signaling molecules implicated in cellular multiple functions such as proliferation, migration and differentiation under patho/physiological conditions by interacting with cell surface receptors and other ligands in the extracellular microenvironment. Many of the growth factors are heparin-binding proteins (HBPs) that have a high affinity for cell surface heparan sulfate proteoglycans (HSPG). In the present study, we report the binding kinetics and affinity of heparin interacting with different growth factors, including fibroblast growth factor (FGF) 2,7,10, hepatocyte growth factor (HGF) and transforming growth factor (TGF β-1), using a heparin chip. Surface plasmon resonance studies revealed that all the tested growth factors bind to heparin with high affinity (with KD ranging from ~0.1 to 59 nM) and all the interactions are oligosaccharide size dependent except those involving TGF β-1. These heparin-binding growth factors also interact with other glycosaminoglycans (GAGs), as well as various chemically modified heparins. Other GAGs, including heparan sulfate, chondroitin sulfates A, B, C, D, E and keratan sulfate, showed different inhibition activities for the growth factor-heparin interactions. FGF2, FGF7, FGF10 and HGF bind heparin but the 2-O-sulfo and 6-O-sulfo groups on heparin have less impact on these interactions than do the N-sulfo groups. All the three sulfo groups (N-, 2-O and 6-O) on heparin are important for TGFβ-1-heparin interaction.
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Protease Nexin I is a feedback regulator of EGF/PKC/MAPK/EGR1 signaling in breast cancer cells metastasis and stemness. Cell Death Dis 2019; 10:649. [PMID: 31501409 PMCID: PMC6733841 DOI: 10.1038/s41419-019-1882-9] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2019] [Revised: 08/07/2019] [Accepted: 08/26/2019] [Indexed: 01/18/2023]
Abstract
Breast cancer is the most prevalent cancer in women worldwide, which remains incurable once metastatic. Breast cancer stem cells (BCSCs) are a small subset of breast cancer cells, which are the radical cause of drug resistance, tumor relapse, and metastasis in breast cancer. The extracellular serine protease inhibitor serpinE2, also named protease nexin-1 (PN-1), contributes to enhanced metastasis of cancer cells mainly by remodeling the tumor matrix. In this study, we found that PN-1 was up-regulated in breast cancer, which promoted cell invasion, migration and stemness. Furthermore, by using specific inhibitors, we discovered that epidermal growth factor (EGF) up-regulated PN-1 in breast cancer cells through cascade activation of epidermal growth factor receptor (EGFR) to the activation of protein kinase Cδ (PKCδ), mitogen-activated protein kinase (MEK) and extracellular signal-related kinase (ERK), which finally led to the up-regulation of early growth response protein 1 (EGR1). Moreover, EGF signaling was further activated as a feedback of PN-1 up-regulation through PN-1 blocking HtrA1. Taken together, our findings revealed a novel signaling axis that up-regulated PN-1 expression in breast cancer cells, and the new mechanism of PN-1-promoted breast cancer metastasis, which may provide new insights into identifying novel therapeutic targets for breast cancer.
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Xiang QF, Zhan MX, Li Y, Liang H, Hu C, Huang YM, Xiao J, He X, Xin YJ, Chen MS, Lu LG. Activation of MET promotes resistance to sorafenib in hepatocellular carcinoma cells via the AKT/ERK1/2-EGR1 pathway. ARTIFICIAL CELLS NANOMEDICINE AND BIOTECHNOLOGY 2019; 47:83-89. [PMID: 30663411 DOI: 10.1080/21691401.2018.1543195] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Sorafenib is an oral multikinase inhibitor that has become an established therapeutic approach in advanced hepatocellular carcinoma (HCC). However, the benefit of sorafenib in clinical therapy is often affected by drug resistance. Therefore, it is important to explore the mechanisms underlying sorafenib resistance and to develop individualized therapeutic strategies for coping with this problem. In this study, we found that addition of HGF to sorafenib-treated HCC cells activated MET and re-stimulated the downstream AKT and ERK1/2 pathways. Thereby, restored sorafenib-treated HCC cells proliferation, migration and invasion ability, and rescued cells from apoptosis. In addition, we found that HGF treatment of HCC cells induced early growth response protein (EGR1) expression, which is involved in sorafenib resistance. Importantly, the HGF rescued effect in sorafenib-treated HCC cells could be abrogated by inhibiting MET activation with PHA-665752 or by downregulating EGR1 expression with small interfering RNA (siRNA). Therefore, inhibition of the HGF/MET pathway may improve response to sorafenib in HCC, and combination therapy should be further investigated.
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Affiliation(s)
- Qing-Feng Xiang
- a Department of Hepatobiliary Surgery , Sun Yat-Sen University Cancer Center , Guangzhou , China.,b Department of General Surgery , Zhuhai People's Hospital, Zhuhai Hospital of Jinan University , Zhuhai , China
| | - Mei-Xiao Zhan
- c Zhuhai Interventional Medical Center, Zhuhai Precision Medicine Center , Zhuhai People's Hospital , Zhuhai Hospital of Jinan University , Zhuhai , China
| | - Yong Li
- c Zhuhai Interventional Medical Center, Zhuhai Precision Medicine Center , Zhuhai People's Hospital , Zhuhai Hospital of Jinan University , Zhuhai , China
| | - Hui Liang
- b Department of General Surgery , Zhuhai People's Hospital, Zhuhai Hospital of Jinan University , Zhuhai , China
| | - Cong Hu
- b Department of General Surgery , Zhuhai People's Hospital, Zhuhai Hospital of Jinan University , Zhuhai , China
| | - Yao-Ming Huang
- b Department of General Surgery , Zhuhai People's Hospital, Zhuhai Hospital of Jinan University , Zhuhai , China
| | - Jing Xiao
- c Zhuhai Interventional Medical Center, Zhuhai Precision Medicine Center , Zhuhai People's Hospital , Zhuhai Hospital of Jinan University , Zhuhai , China
| | - Xu He
- c Zhuhai Interventional Medical Center, Zhuhai Precision Medicine Center , Zhuhai People's Hospital , Zhuhai Hospital of Jinan University , Zhuhai , China
| | - Yong-Jie Xin
- c Zhuhai Interventional Medical Center, Zhuhai Precision Medicine Center , Zhuhai People's Hospital , Zhuhai Hospital of Jinan University , Zhuhai , China
| | - Min-Shan Chen
- a Department of Hepatobiliary Surgery , Sun Yat-Sen University Cancer Center , Guangzhou , China
| | - Li-Gong Lu
- c Zhuhai Interventional Medical Center, Zhuhai Precision Medicine Center , Zhuhai People's Hospital , Zhuhai Hospital of Jinan University , Zhuhai , China
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Li L, Chen J, Ge C, Zhao F, Chen T, Tian H, Li J, Li H. CD24 isoform a promotes cell proliferation, migration and invasion and is downregulated by EGR1 in hepatocellular carcinoma. Onco Targets Ther 2019; 12:1705-1716. [PMID: 30881025 PMCID: PMC6400134 DOI: 10.2147/ott.s196506] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
INTRODUCTION CD24 is known as a heavily glycosylated cell surface molecule that is highly expressed in a wide variety of human malignancies. Previous studies have shown that CD24 plays an important role in self-renewal, proliferation, migration, invasion and drug resistance of hepatocellular carcinoma (HCC). However, little is known about the expression and function of CD24 isoform a (CD24A) and CD24 isoform b (CD24B) in HCC. MATERIALS AND METHODS Quantitative real-time polymerase chain reaction (qPCR) and Western blotting were performed to detect CD24 and EGR1 expression in HCC cells and tissue. The function of CD24 in cell proliferation was verified with MTT assays, colony formation assays and tumor xenograft models. Wound healing assays and invasion assays were performed to clarify the function of CD24 in the regulation of cell migration and invasion in HCC. A dual luciferase reporter assay and chromatin immunoprecipitation assay were used to analyze the regulation mechanism of CD24A. RESULTS CD24A but not CD24B, which was barely detected by qPCR and Western blotting, is significantly upregulated in HCC tissue. Both CD24A and CD24B contribute to HCC cell proliferation, migration and invasion, but CD24A is more effective than CD24B. EGR1 downregulates CD24A and exerts transcription-promoting activity on the CD24A promoter. Furthermore, EGR1 represses HCC cell proliferation via downregulation of CD24A. CONCLUSION CD24A is the predominant CD24 isoform in HCC and plays a major role in cell proliferation, migration, and invasion. EGR1 can exert its antitumor effect through transcriptional downregulation of CD24A in HCC.
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Affiliation(s)
- Liangyu Li
- Key Laboratory of Medical Molecular Virology, Shanghai Medical College, Fudan University, Shanghai, People's Republic of China
| | - Jing Chen
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, People's Republic of China,
| | - Chao Ge
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, People's Republic of China,
| | - Fangyu Zhao
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, People's Republic of China,
| | - Taoyang Chen
- Qi Dong Liver Cancer Institute, Qi Dong, Jiangsu Province, People's Republic of China
| | - Hua Tian
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, People's Republic of China,
| | - Jinjun Li
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, People's Republic of China,
| | - Hong Li
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, People's Republic of China,
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17
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He C, Ji H, Qian Y, Wang Q, Liu X, Zhao W, Zhao C. Heparin-based and heparin-inspired hydrogels: size-effect, gelation and biomedical applications. J Mater Chem B 2019; 7:1186-1208. [PMID: 32255159 DOI: 10.1039/c8tb02671h] [Citation(s) in RCA: 78] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
Abstract
Heparin is the highest negatively charged biomolecule, which is a polysaccharide belonging to the glycosaminoglycan family, and its role as a regulator of various proteins, cells and tissues in the human body makes it an indispensable macromolecule. Heparin-based hydrogels are widely investigated in various applications including implantation, tissue engineering, biosensors, and drug-controlled release due to the 3D-constructs of hydrogels. However, heparin has supply and safety problems because it is usually derived from animal sources, and has the clinical limitations of bleeding and thrombocytopenia. Therefore, analogous heparin-mimicking polymers and hydrogels derived from non-animal and/or totally synthetic sources have been widely studied in recent years. In this review, the progress and potential biomedical applications of heparin-based and heparin-inspired hydrogels are highlighted. We classify the forms of these hydrogels by their size including macro-hydrogels, injectable hydrogels, and nano-hydrogels. Then, we summarize the various fabrication strategies for these hydrogels including chemical covalent bonding, physical conjugation, and the combination of chemical and physical interactions. Covalent bonding includes free radical polymerization of vinyl-containing components, amide bond formation reaction, Michael-type addition reaction, click-chemistry, divinyl sulfone crosslinking, and mussel-inspired coating. Hydrogels physically conjugated via host-guest interaction, electrostatic interaction, hydrogen bonding, and hydrophobic interaction are also discussed. Finally, we conclude with the challenges and future directions for the fabrication and the industrialization of heparin-based and heparin-inspired hydrogels. We believe that this review will attract more attention toward the design of heparin-based and heparin-inspired hydrogels, leading to future advancements in this emerging research field.
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Affiliation(s)
- Chao He
- College of Polymer Science and Engineering, State Key Laboratory of Polymer Materials Engineering, Sichuan University, Chengdu 610065, China.
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18
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Prostate cancer promotes a vicious cycle of bone metastasis progression through inducing osteocytes to secrete GDF15 that stimulates prostate cancer growth and invasion. Oncogene 2019; 38:4540-4559. [PMID: 30755731 DOI: 10.1038/s41388-019-0736-3] [Citation(s) in RCA: 65] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2018] [Revised: 01/15/2019] [Accepted: 01/27/2019] [Indexed: 12/11/2022]
Abstract
Bone is the most frequent site of prostate cancer (PCa) metastasis; however, little is known about the role of the most common cell in bone, the osteocyte (OCy), in cancer biology. In this study we explored the crosstalk between PCa cells and OCys to determine if it contributes to PCa progression. PCa cells induced OCys to promote PCa proliferation, migration and invasion. A chemokine screen revealed that PCa cell induced OCys to produce growth-derived factor 15 (GDF15). Knockdown of GDF15 in OCys demonstrated that PCa cells conferred the ability on OCys to promote PCa proliferation, migration and invasion through GDF15. Consistent with this finding was the observation that the GDF15 receptor, GFRAL, was expressed on multiple PCa cell lines. Transcription factor array screening of PCa cells exposed to OCys with or without knockdown of GDF15 revealed that GDF15 in OCys promoted early growth response 1 (EGR1) expression in the PCa cells. Knockdown of EGR1 expression in PCa cells revealed it was required for the OCy-derived GDF15-mediated induction of in vitro PCa cell proliferation, migration and invasion. Subcutaneous co-injection of PCa cells and OCys into mice revealed that OCys promoted tumor growth in vivo, which was diminished by knockdown of GDF15 in the OCys. Knockdown of GDF15 in the tibiae diminished growth of PCa cancer cells injected into the tibiae, which was accompanied by decreased tumor cell proliferation and EGR1 expression. These results shed light on a novel mechanism through which PCa cells educate OCys to promote progression of PCa bone metastasis. They also suggest that targeting of GDF15-based and EGR1-based signaling pathways should be further explored for their potential to diminish progression of PCa bone metastasis.
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Tan YF, Tang L, OuYang WX, Jiang T, Zhang H, Li SJ. β-catenin-coordinated lncRNA MALAT1 up-regulation of ZEB-1 could enhance the telomerase activity in HGF-mediated differentiation of bone marrow mesenchymal stem cells into hepatocytes. Pathol Res Pract 2019; 215:546-554. [PMID: 30658864 DOI: 10.1016/j.prp.2019.01.002] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/25/2018] [Revised: 12/18/2018] [Accepted: 01/05/2019] [Indexed: 12/16/2022]
Abstract
OBJECTIVE To investigate role of β-catenin and lncRNA MALAT1/miR-217 axis to converge into the regulation of ZEB-1 in hepatocyte growth factor (HGF)-induced hepatocytes differentiated from bone marrow mesenchymal stem cells (BM-MSCs). METHODS BM-MSCs were isolated and HGF was used to induce the differentiation of BM-MSCs into hepatocytes. HSC-T6 cells, BRL-3 A cells and differentiated BM-MSCs were treated by lipopolysaccharide(LPS). shRNAs were used to silence β-catenin and recombinant plasmids were used to over-express ZEB1. Measurement of cell viability was conducted using MTT assay and Hoechst 33342 staining. RNA immunoprecipitation (RIP) assay was used to determine binding of miR-217-3p and MALAT1. RESULTS BM-MSCs successfully differentiated into hepatocytes by HGF treatment. Expression of β-catenin, ZEB-1 and TERT was up-regulated to a higher level in hepatocytes differentiated from BM-MSCs than HSC-T6 cells and BRL-3 A cells after LPS stimulation. When β-catenin was knocked down in all cell lines, expression of β-catenin, ZEB-1 and TERT was significantly decreased as well as telomerase activity. While when ZEB1 was over-expressed, expression of TERT and telomerase activity was all significantly up-regulated. In hepatocytes differentiated from BM-MSCs, miR-217 was down-regulated and lncRNA MALAT1 was up-regulated. RIP analysis showed MALAT1 was physically associated with miR-217 and might function in the regulation of ZEB-1, further enhancing the expression of TERT so as to augment telomerase activity. CONCLUSION We successfully used HGF to mediate differentiation of BM-MSCs into hepatocytes, and found that β-catenin-coordinated MALAT1/miR-217 axis could up-regulate expression of ZEB-1 and further enhanced the telomerase activity through regulation of TERT in BM-MSCs differentiating into hepatocytes.
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Affiliation(s)
- Yan-Fang Tan
- Department of Hepatopathy Center, Hunan Children's Hospital, Changsha 410007, PR China
| | - Lian Tang
- Department of Hepatopathy Center, Hunan Children's Hospital, Changsha 410007, PR China
| | - Wen-Xian OuYang
- Department of Hepatopathy Center, Hunan Children's Hospital, Changsha 410007, PR China
| | - Tao Jiang
- Department of Hepatopathy Center, Hunan Children's Hospital, Changsha 410007, PR China
| | - Hui Zhang
- Department of Hepatopathy Center, Hunan Children's Hospital, Changsha 410007, PR China
| | - Shuang-Jie Li
- Department of Hepatopathy Center, Hunan Children's Hospital, Changsha 410007, PR China.
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Korhan P, Yılmaz Y, Bağırsakçı E, Güneş A, Topel H, Carr BI, Atabey N. Pleiotropic Effects of Heparins: From Clinical Applications to Molecular Mechanisms in Hepatocellular Carcinoma. Can J Gastroenterol Hepatol 2018; 2018:7568742. [PMID: 30425976 PMCID: PMC6217885 DOI: 10.1155/2018/7568742] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2018] [Revised: 10/04/2018] [Accepted: 10/09/2018] [Indexed: 12/27/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is a major health problem worldwide and most cases are incurable because of late presentation. It is the most common primary neoplasm of the liver and often arises in the context of a chronic liver disease that impairs coagulation. Portal vein thrombosis (PVT) is a common complication of HCC that is associated with a poor prognosis. Heparin derivatives are widely used in the management of venous thromboembolism (VTE). Among them low molecular weight heparin (LMWH) favorably influences the survival in patients with advanced cancer, including HCC. Due to their pleiotropic function, heparins affect tumorigenesis in many ways and may promote or hamper tumorigenic transformation depending on the cancer type and cancer stage along with their structural properties and concentration. Thus, their application as an antithrombotic along with the conventional therapy regime should be carefully planned to develop the best management strategies. In this review, we first will briefly review clinical applications of heparin derivatives in the management of cancer with a particular focus on HCC. We then summarize the state of knowledge whereby heparin can crosstalk with molecules playing a role in hepatocarcinogenesis. Lastly, we highlight new experimental and clinical research conducted with the aim of moving towards personalized therapy in cancer patients at risk of thromboembolism.
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Affiliation(s)
- Peyda Korhan
- Izmir Biomedicine and Genome Center, 35340, Turkey
| | - Yeliz Yılmaz
- Izmir Biomedicine and Genome Center, 35340, Turkey
- Medical Biology and Genetics, Heath Sciences Institute, Dokuz Eylul University, 35340, Turkey
| | - Ezgi Bağırsakçı
- Izmir Biomedicine and Genome Center, 35340, Turkey
- Izmir International Biomedicine and Genome Institute, Dokuz Eylul University, 35340, Turkey
| | - Ayşim Güneş
- Izmir Biomedicine and Genome Center, 35340, Turkey
| | - Hande Topel
- Izmir Biomedicine and Genome Center, 35340, Turkey
- Medical Biology and Genetics, Heath Sciences Institute, Dokuz Eylul University, 35340, Turkey
| | | | - Neşe Atabey
- Izmir Biomedicine and Genome Center, 35340, Turkey
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Shan J, Dudenhausen E, Kilberg MS. Induction of early growth response gene 1 (EGR1) by endoplasmic reticulum stress is mediated by the extracellular regulated kinase (ERK) arm of the MAPK pathways. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH 2018; 1866:371-381. [PMID: 30290239 DOI: 10.1016/j.bbamcr.2018.09.009] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/07/2018] [Revised: 09/13/2018] [Accepted: 09/23/2018] [Indexed: 12/11/2022]
Abstract
Endoplasmic reticulum (ER) stress activates three principal signaling pathways, collectively known as the unfolded protein response, leading to translational and transcriptional control mechanisms that dictate the cell's response as adaptive or apoptotic. The present study illustrates that for HepG2 human hepatocellular carcinoma cells the signaling pathways triggered by ER stress extend beyond the three principal pathways to include mitogen-activated protein kinase (MAPK) signaling, leading to activation of transcription from the early growth response 1 (EGR1) gene. Analysis provided evidence for a SRC-RAS-RAF-MEK-ERK cascade mechanism that leads to enhanced phosphorylation of the transcription factor ELK1. ELK1 and serum response factor (SRF) are constitutively bound to the EGR1 promoter and are phosphorylated by nuclear localized ERK. The promoter abundance of both phospho-SRF and phopsho-ELK1 was increased by ER stress, but the SRF phosphorylation was transient. Knockdown of ELK1 had little effect on the basal EGR1 mRNA content, but completely blocked the increase in response to ER stress. Conversely, knockdown of SRF suppressed basal EGR1 mRNA content, but had only a small effect on the induction by ER stress. This research highlights the importance of MAPK signaling in response to ER stress and identifies ELK1 as a transcriptional mediator and the EGR1 gene as a target.
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Affiliation(s)
- Jixiu Shan
- Department of Biochemistry and Molecular Biology, Genetics Institute, Shands Cancer Center and Center for Nutritional Sciences, University of Florida College of Medicine, Gainesville 32610, FL, United States of America
| | - Elizabeth Dudenhausen
- Department of Biochemistry and Molecular Biology, Genetics Institute, Shands Cancer Center and Center for Nutritional Sciences, University of Florida College of Medicine, Gainesville 32610, FL, United States of America
| | - Michael S Kilberg
- Department of Biochemistry and Molecular Biology, Genetics Institute, Shands Cancer Center and Center for Nutritional Sciences, University of Florida College of Medicine, Gainesville 32610, FL, United States of America.
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22
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Zhao J, Geng L, Duan G, Xu W, Cheng Y, Huang Z, Zhou Z, Gong S. REC8 inhibits EMT by downregulating EGR1 in gastric cancer cells. Oncol Rep 2018; 39:1583-1590. [PMID: 29393474 PMCID: PMC5868373 DOI: 10.3892/or.2018.6244] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2017] [Accepted: 12/07/2017] [Indexed: 12/11/2022] Open
Abstract
REC8 is a component of the meiotic cohesion complex that plays a critical role in chromosome dynamics during meiosis. However, the functional role of REC8 in gastric cancer has not been elucidated. In the present study, REC8 suppressed the growth and metastasis of gastric cancer cells in vitro. Whole Human Genome Oligo Microarray results revealed that a wide range of genes with broad function were targeted by REC8. Among them early growth response-1 (EGR1), a transcription factor and an epithelial-mesenchymal transition (EMT)-associated protein in the AGR-RAGE pathway was significantly downregulated when REC8 was overexpressed in gastric cancer cells. We hypothesized that REC8 inhibits EMT by downregulating EGR1 in gastric cancer cells. Consistent with our prediction, REC8 overexpression decreased EMT in gastric cancer cells, whereas the REC8 ablation reversed these effects. In addition, the phenotypes of EGR1 overexpressed cells were similar to the phenotypes of REC8 ablated cells. Furthermore, we determined that REC8 interacted with EGR1, and inhibited EMT in gastric cancer cells. We thus propose further studies of the pathways associated with REC8 and EGR1 to potentially find novel targets in the treatment for gastric cancer.
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Affiliation(s)
- Junhong Zhao
- Department of Gastroenterology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, Guangdong 510120, P.R. China
| | - Lanlan Geng
- Department of Gastroenterology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, Guangdong 510120, P.R. China
| | - Gaoyang Duan
- Department of Gastroenterology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, Guangdong 510120, P.R. China
| | - Wanfu Xu
- Department of Gastroenterology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, Guangdong 510120, P.R. China
| | - Yang Cheng
- Department of Gastroenterology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, Guangdong 510120, P.R. China
| | - Zhiliang Huang
- Cancer Center of Guangzhou Medical University, Guangzhou, Guangdong 510089, P.R. China
| | - Zhenwen Zhou
- Department of Gastroenterology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, Guangdong 510120, P.R. China
| | - Sitang Gong
- Department of Gastroenterology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, Guangdong 510120, P.R. China
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Sahin A, Arici MA, Yilmaz Y, Kalkan S, Durmus N, Ergur BU, Yakut Aksu I, Atabey N, Tuncok Y. A Comparison of the Effectiveness of Silibinin and Resveratrol in Preventing Alpha-Amanitin-Induced Hepatotoxicity. Basic Clin Pharmacol Toxicol 2018; 122:633-642. [PMID: 29285878 DOI: 10.1111/bcpt.12954] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2017] [Accepted: 12/18/2017] [Indexed: 01/17/2023]
Abstract
Amanita phalloides species mushrooms containing alpha-amanitin (α-AMA) are responsible for the majority of fatal mushroom intoxications and can lead to severe poisonings resulting in hepatotoxicity and acute hepatic failure. Existing antidotes, such as silibinin, are not sufficiently effective in the prevention and/or resolution of α-AMA-induced hepatotoxicity. We investigated the effects of resveratrol on α-AMA-induced hepatotoxicity and compared with silibinin, a known antidote using in vivo and in vitro toxicity models. In the in vivo protocol, resveratrol (30 mg/kg) was given simultaneously with α-AMA (α-AMA + SR) or 12 (α-AMA + 12R) or 24 (α-AMA + 24R) hr after α-AMA administration. Silibinin (5 mg/kg) (α-AMA + Sil) and normal saline (α-AMA + NS) were given simultaneously with α-AMA. We found that liver transaminase levels in α-AMA + SR and α-AMA + 12R groups and histomorphologic injury score in the α-AMA + SR, α-AMA + 12R, α-AMA + 24R and α-AMA + Sil groups were significantly lower than that of the α-AMA + NS group. Resveratrol decreased mononuclear cell infiltration, necrosis and active caspase-3 immunopositivity in the liver. In the in vitro protocol, the effects of resveratrol and silibinin were evaluated in a reduction in cell viability induced by α-AMA in THLE-2 and THLE-3 hepatocytes. Neither resveratrol nor silibinin was found to be effective in increasing cell viability decreased by α-AMA + NS. As a conclusion, resveratrol was found to be effective in α-AMA-induced hepatotoxicity with its anti-inflammatory properties in in vivo conditions. It is a promising compound with the potential for use in the treatment of hepatotoxicity associated with Amanita phalloides type mushroom poisonings.
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Affiliation(s)
- Aynur Sahin
- Department of Emergency Medicine, Karadeniz Technical University School of Medicine, Trabzon, Turkey
| | - Mualla Aylin Arici
- Department of Medical Pharmacology, Dokuz Eylul University School of Medicine, Izmir, Turkey
| | - Yeliz Yilmaz
- Department of Medical Biology and Genetics, Dokuz Eylul University Institute of Health Sciences, Izmir, Turkey.,Dokuz Eylul University Izmir Biomedicine and Genome Institute (iBG-izmir), Izmir, Turkey
| | - Sule Kalkan
- Division of Clinical Toxicology, Department of Medical Pharmacology, Dokuz Eylul University School of Medicine, Izmir, Turkey
| | - Nergiz Durmus
- Department of Medical Pharmacology, Dokuz Eylul University School of Medicine, Izmir, Turkey
| | - Bekir Ugur Ergur
- Department of Histology and Embriology, Dokuz Eylul University School of Medicine, Izmir, Turkey
| | - Ilkay Yakut Aksu
- Department of Physiology, Dokuz Eylul University School of Medicine, Izmir, Turkey
| | - Neşe Atabey
- Dokuz Eylul University Izmir Biomedicine and Genome Institute (iBG-izmir), Izmir, Turkey.,Department of Medical Biology and Genetics, Dokuz Eylul University School of Medicine, Izmir, Turkey
| | - Yesim Tuncok
- Division of Clinical Toxicology, Department of Medical Pharmacology, Dokuz Eylul University School of Medicine, Izmir, Turkey
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24
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Gui Y, Khan MGM, Bobbala D, Dubois C, Ramanathan S, Saucier C, Ilangumaran S. Attenuation of MET-mediated migration and invasion in hepatocellular carcinoma cells by SOCS1. World J Gastroenterol 2017; 23:6639-6649. [PMID: 29085209 PMCID: PMC5643285 DOI: 10.3748/wjg.v23.i36.6639] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2017] [Revised: 05/07/2017] [Accepted: 07/04/2017] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate the role of suppressor of cytokine signaling 1 (SOCS1) in regulating MET-mediated invasive potential of hepatocellular carcinoma (HCC) cells.
METHODS Stable derivatives of mouse (Hepa1-6) and human (hep3B, HepG2) HCC cell lines expressing SOCS1 or control vector were evaluated for their ability to migrate towards hepatocyte growth factor (HGF) in the transwell migration assay, invade extracellular matrix in response to HGF stimulation in a 3-D invasion assay by confocal microscopy, and to undergo anchorage-independent proliferation in semisolid agar. Following intravenous and intrasplenic inoculation into NOD.scid.gamma mice, the ability of Hepa cells to form othotopic tumors was evaluated. Following HGF stimulation of Hepa and Hep3B cells, expression of proteins implicated in epithelial-to-mesenchymal transition was evaluated by western blot and qRT-PCR.
RESULTS SOCS1 expression in mouse and human HCC cells inhibited HGF-induced migration through matrigel. In the 3-D invasion assay, HGF stimulation induced invasion of HCC cells across type-I collagen matrix, and SOCS1 expression significantly reduced the depth of invasion. SOCS1 expression also reduced the number and size of colonies formed by anchorage-independent growth in semisolid agar. Following intravenous inoculation, control Hepa cell formed large tumor nodules that obliterated the liver whereas the SOCS1-expressing Hepa cells formed significantly smaller nodules. Tumors formed by SOCS1-expressing cells showed reduced phosphorylation of STAT3 and ERK that was accompanied by reduced levels of MET protein expression. HGF stimulated Hepa cells expressing SOCS1 showed increased expression of E-cadherin and decreased expression of EGR1, SNAI1 and ZEB1. Comparable results were obtained with Hep3B cells. SOCS1 expressing HCC cells also showed reduced levels of EGR1 and SNAI1 transcripts.
CONCLUSION Our findings indicate that loss of SOCS1-dependent control over epithelial-to-mesenchymal transition may contribute to MET-mediated migration, invasion and metastatic growth of HCC.
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Affiliation(s)
- Yirui Gui
- Department of Pediatrics, Immunology Division, Faculty of Medicine and Health Sciences, University of Sherbrooke, Sherbrooke, Québec J1H 5N4, Canada
| | - Md Gulam Musawwir Khan
- Department of Pediatrics, Immunology Division, Faculty of Medicine and Health Sciences, University of Sherbrooke, Sherbrooke, Québec J1H 5N4, Canada
| | - Diwakar Bobbala
- Department of Pediatrics, Immunology Division, Faculty of Medicine and Health Sciences, University of Sherbrooke, Sherbrooke, Québec J1H 5N4, Canada
| | - Claire Dubois
- Department of Pediatrics, Immunology Division, Faculty of Medicine and Health Sciences, University of Sherbrooke, Sherbrooke, Québec J1H 5N4, Canada
| | - Sheela Ramanathan
- Department of Pediatrics, Immunology Division, Faculty of Medicine and Health Sciences, University of Sherbrooke, Sherbrooke, Québec J1H 5N4, Canada
| | - Caroline Saucier
- Department of Anatomy and Cell Biology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, Québec J1H 5N4, Canada
| | - Subburaj Ilangumaran
- Department of Pediatrics, Immunology Division, Faculty of Medicine and Health Sciences, University of Sherbrooke, Sherbrooke, Québec J1H 5N4, Canada
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25
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Yılmaz Y, Güneş A, Topel H, Atabey N. Signaling Pathways as Potential Therapeutic Targets in Hepatocarcinogenesis. J Gastrointest Cancer 2017; 48:225-237. [PMID: 28819741 DOI: 10.1007/s12029-017-9958-1] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Affiliation(s)
- Yeliz Yılmaz
- Izmir International Biomedicine & Genome Institute (iBG-izmir), Dokuz Eylul University, Balcova, 35340, Izmir, Turkey
- Department of Medical Biology and Genetics, Institute of Health Sciences, Dokuz Eylul University, 35340, Izmir, Turkey
| | - Ayşim Güneş
- Izmir International Biomedicine & Genome Institute (iBG-izmir), Dokuz Eylul University, Balcova, 35340, Izmir, Turkey
| | - Hande Topel
- Izmir International Biomedicine & Genome Institute (iBG-izmir), Dokuz Eylul University, Balcova, 35340, Izmir, Turkey
- Department of Medical Biology and Genetics, Institute of Health Sciences, Dokuz Eylul University, 35340, Izmir, Turkey
| | - Neşe Atabey
- Izmir International Biomedicine & Genome Institute (iBG-izmir), Dokuz Eylul University, Balcova, 35340, Izmir, Turkey.
- Department of Medical Biology, Faculty of Medicine, Dokuz Eylul University, 35340, Izmir, Turkey.
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26
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Sun SW, Fang XM, Li YF, Wang QB, Li YX. Expression and clinical significance of EGR-1 and PTEN in the pituitary tumors of elderly patients. Oncol Lett 2017; 14:2165-2169. [PMID: 28789441 PMCID: PMC5530027 DOI: 10.3892/ol.2017.6375] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2016] [Accepted: 12/12/2017] [Indexed: 12/27/2022] Open
Abstract
The aim of the study was to investigate the expression and clinical significance of early growth response protein 1 (EGR-1) and phosphatase and tensin homolog (PTEN) in the pituitary tumors of elderly patients. From January 2014 to December 2015, we collected 25 patient cases with non-invasive pituitary tumors, 10 cases with invasive pituitary tumors and 35 cases with healthy pituitary tissues (the healthy control group). Immunohistochemical staining was used to detect the expression of EGR-1 and PTEN, and analyze specific differences. The expression of EGR-1 and PTEN in patients with invasive and non-invasive pituitary tumors increased significantly, when compared with the healthy control group, and the difference was statistically significant (p<0.05). In patients with invasive tumors, EGR-1 levels were higher than levels in patients with non-invasive tumors. The difference was statistically significant (p<0.05). PTEN levels in patients with invasive tumors were significantly lower than levels in patients with non-invasive tumors. The difference was statistically significant (p<0.05). In conclusion, EGR-1 and PTEN levels in patients with pituitary tumors were significantly higher. In addition, EGR-1 levels were higher in patients with invasive pituitary tumors, while PTEN levels were lower. The combination of increases in both levels highlights an important role in the evaluation and prognosis of elderly patients with pituitary tumors.
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Affiliation(s)
- Shu-Wen Sun
- Department of Neurosurgery, Health Examination Center, The Binhai Development Zone People's Hospital of Weifang, Weifang, Shandong 262737, P.R. China
| | - Xiao-Mei Fang
- Department of Neurosurgery, Health Examination Center, The Binhai Development Zone People's Hospital of Weifang, Weifang, Shandong 262737, P.R. China
| | - Yi-Fei Li
- Department of Neurosurgery, Health Examination Center, The Binhai Development Zone People's Hospital of Weifang, Weifang, Shandong 262737, P.R. China
| | - Qing-Bo Wang
- Department of Neurosurgery, Health Examination Center, The Binhai Development Zone People's Hospital of Weifang, Weifang, Shandong 262737, P.R. China
| | - Yu-Xin Li
- Department of Neurosurgery, Health Examination Center, The Binhai Development Zone People's Hospital of Weifang, Weifang, Shandong 262737, P.R. China
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27
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The Inhibitory Effect of Mesenchymal Stem Cells with rAd-NK4 on Liver Cancer. Appl Biochem Biotechnol 2017; 183:444-459. [DOI: 10.1007/s12010-017-2456-x] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2017] [Accepted: 03/12/2017] [Indexed: 12/18/2022]
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28
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Yao M, Wang X, Zhao Y, Wang X, Gao F. Expression of MMPs is dependent on the activity of mitogen-activated protein kinase in chondrosarcoma. Mol Med Rep 2016; 15:915-921. [PMID: 28035378 DOI: 10.3892/mmr.2016.6077] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2015] [Accepted: 11/10/2016] [Indexed: 11/05/2022] Open
Abstract
Matrix metalloproteinases (MMPs) and tissue inhibitors of matrix metalloproteinases (TIMPs) serve an important role in chondrosarcoma. The present study investigated whether the expression of MMPs was dependent on the activity of mitogen-activated protein kinase (MAPK) in chondrosarcoma. Surgical pathological specimens were collected to detect MMP-1, MMP-13, TIMP-1, type II collagen and phosphorylated MAPK levels in normal cartilage, enchondroma and chondrosarcoma tissues. The expression of MMP‑1, MMP‑13, TIMP‑1 and type II collagen was investigated utilizing MAPK inhibitors in chondrosarcoma cells. It was noted that the expression levels of MMP‑1, MMP‑13 and TIMP‑1 were increased in chondrosarcoma with the activity of MAPK. After chondrosarcoma cells were pretreated with MAPK inhibitors, the levels of MMP‑1, MMP‑13 and TIMP‑1 were inhibited. Furthermore, MMP‑1 and MMP‑13 are essential in regulating the degradation of type II collagen and decomposing cartilage matrix major. The high expression levels of MMP‑1 and MMP‑13 in chondrosarcoma expedite the invasion by chondrosarcoma cells and their expression can be depressed by MAPK inhibitors.
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Affiliation(s)
- Min Yao
- Department of Pathology, The Third Hospital of Hebei Medical University, Shijiazhuang, Hebei 050051, P.R. China
| | - Xiaomei Wang
- Department of Pathology, The Third Hospital of Hebei Medical University, Shijiazhuang, Hebei 050051, P.R. China
| | - Yufeng Zhao
- Department of Pathology, The Third Hospital of Hebei Medical University, Shijiazhuang, Hebei 050051, P.R. China
| | - Xiaomeng Wang
- Department of Pathology, The Third Hospital of Hebei Medical University, Shijiazhuang, Hebei 050051, P.R. China
| | - Feng Gao
- Department of Pathology, The Third Hospital of Hebei Medical University, Shijiazhuang, Hebei 050051, P.R. China
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29
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İşcan E, Güneş A, Korhan P, Yılmaz Y, Erdal E, Atabey N. The regulatory role of heparin on c-Met signaling in hepatocellular carcinoma cells. J Cell Commun Signal 2016; 11:155-166. [PMID: 27975162 DOI: 10.1007/s12079-016-0368-0] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2016] [Accepted: 11/22/2016] [Indexed: 02/06/2023] Open
Abstract
The role of heparin as an anticoagulant is well defined; however, its role in tumorigenesis and tumor progression is not clear yet. Some studies have shown that anticoagulant treatment in cancer patients improve overall survival, however, recent clinical trials have not shown a survival benefit in cancer patients receiving heparin treatment. In our previous studies we have shown the inhibitory effects of heparin on Hepatocyte Growth Factor (HGF)-induced invasion and migration in hepatocellular carcinoma (HCC) cells. In this study, we showed the differential effects of heparin on the behaviors of HCC cells based on the presence or absence of HGF. In the absence of HGF, heparin activated HGF/c-Met signaling and promoted motility and invasion in HCC cells. Heparin treatment led to c-Met receptor dimerization and activated c-Met signaling in an HGF independent manner. Heparin-induced c-Met activation increased migration and invasion through ERK1/2, early growth response factor 1 (EGR1) and Matrix Metalloproteinases (MMP) axis. Interestingly, heparin modestly decreased the proliferation of HCC cells by inhibiting activatory phosphorylation of Akt. The inhibition of c-Met signaling reversed heparin-induced increase in motility and invasion and, proliferation inhibition. Our study provides a new perspective into the role of heparin on c-Met signaling in HCC.
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Affiliation(s)
- Evin İşcan
- Izmir International Biomedicine and Genome Institute, Dokuz Eylul University, 35340 Balçova, Izmir, Turkey
| | - Aysim Güneş
- Izmir International Biomedicine and Genome Institute, Dokuz Eylul University, 35340 Balçova, Izmir, Turkey.,Department of Medical Biology, Faculty of Medicine, Dokuz Eylul University, Izmir, Turkey
| | - Peyda Korhan
- Department of Medical Biology, Faculty of Medicine, Dokuz Eylul University, Izmir, Turkey
| | - Yeliz Yılmaz
- Izmir International Biomedicine and Genome Institute, Dokuz Eylul University, 35340 Balçova, Izmir, Turkey.,Department of Medical Biology, Faculty of Medicine, Dokuz Eylul University, Izmir, Turkey
| | - Esra Erdal
- Izmir International Biomedicine and Genome Institute, Dokuz Eylul University, 35340 Balçova, Izmir, Turkey.,Department of Medical Biology, Faculty of Medicine, Dokuz Eylul University, Izmir, Turkey
| | - Neşe Atabey
- Izmir International Biomedicine and Genome Institute, Dokuz Eylul University, 35340 Balçova, Izmir, Turkey. .,Department of Medical Biology, Faculty of Medicine, Dokuz Eylul University, Izmir, Turkey.
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30
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Bulla SC, Badial PR, Silva RC, Lunsford K, Bulla C. Platelets Inhibit Migration of Canine Osteosarcoma Cells. J Comp Pathol 2016; 156:3-13. [PMID: 27890405 DOI: 10.1016/j.jcpa.2016.10.001] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2016] [Revised: 09/23/2016] [Accepted: 10/05/2016] [Indexed: 10/20/2022]
Abstract
The interaction between platelets and tumour cells is important for tumour growth and metastasis. Thrombocytopenia or antiplatelet treatment negatively impact on cancer metastasis, demonstrating potentially important roles for platelets in tumour progression. To our knowledge, there is no information regarding the role of platelets in cancer progression in dogs. This study was designed to test whether canine platelets affected the migratory behaviour of three canine osteosarcoma cell lines and to give insights of molecular mechanisms. Intact platelets, platelet lysate and platelet releasate inhibited the migration of canine osteosarcoma cell lines. Addition of blood leucocytes to the platelet samples did not alter the inhibitory effect on migration. Platelet treatment also significantly downregulated the transcriptional levels of SNAI2 and TWIST1 genes. The interaction between canine platelets or molecules released during platelet activation and these tumour cell lines inhibits their migration, which suggests that canine platelets might antagonize metastasis of canine osteosarcoma. This effect is probably due to, at least in part, downregulation of genes related to epithelial-mesenchymal transition.
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Affiliation(s)
- S C Bulla
- Department of Pathobiology and Population Medicine, College of Veterinary Medicine, Mississippi State University, USA.
| | - P R Badial
- Department of Pathobiology and Population Medicine, College of Veterinary Medicine, Mississippi State University, USA
| | - R C Silva
- Department of Pathobiology and Population Medicine, College of Veterinary Medicine, Mississippi State University, USA
| | - K Lunsford
- Department of Clinical Sciences and Animal Health Center, College of Veterinary Medicine, Mississippi State University, MS, USA
| | - C Bulla
- Department of Pathobiology and Population Medicine, College of Veterinary Medicine, Mississippi State University, USA
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31
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Oleanolic acid-loaded PLGA-TPGS nanoparticles combined with heparin sodium-loaded PLGA-TPGS nanoparticles for enhancing chemotherapy to liver cancer. Life Sci 2016; 165:63-74. [DOI: 10.1016/j.lfs.2016.09.008] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2016] [Revised: 08/07/2016] [Accepted: 09/14/2016] [Indexed: 01/26/2023]
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32
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Kim SH, Park YY, Cho SN, Margalit O, Wang D, DuBois RN. Krüppel-Like Factor 12 Promotes Colorectal Cancer Growth through Early Growth Response Protein 1. PLoS One 2016; 11:e0159899. [PMID: 27442508 PMCID: PMC4956169 DOI: 10.1371/journal.pone.0159899] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2015] [Accepted: 07/11/2016] [Indexed: 01/05/2023] Open
Abstract
Krüppel-like factor 12 (KLF12) is a transcription factor that plays a role in normal kidney development and repression of decidualization. KLF12 is frequently elevated in esophageal adenocarcinoma and has been reported to promote gastric cancer progression. Here, we examined the role of KLF12 in colorectal cancer (CRC). Indeed, KLF12 promotes tumor growth by directly activating early growth response protein 1 (EGR1). The levels of KLF12 and EGR1 correlate synergistically with a poor prognosis. These results indicate that KLF12 likely plays an important role in CRC and could serve as a potential prognostic marker and therapeutic target.
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Affiliation(s)
- Sun-Hee Kim
- Departments of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America
| | - Yun-Yong Park
- ASAN Institute for Life Sciences, ASAN Medical Center, Department of Medicine, University of Ulsan College of Medicine, Seoul 138–736, Korea
| | - Sung-Nam Cho
- Department of Thoracic Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America
| | - Ofer Margalit
- Biodesign Institute of Arizona State University, Tempe, Arizona, United States of America
| | - Dingzhi Wang
- Biodesign Institute of Arizona State University, Tempe, Arizona, United States of America
| | - Raymond N. DuBois
- Biodesign Institute of Arizona State University, Tempe, Arizona, United States of America
- Department of Chemistry and Biochemistry, Arizona State University, Tempe, Arizona, United States of America
- Department of Research and Division of Gastroenterology, Mayo Clinic, Scottsdale, Arizona, United States of America
- Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, South Carolina, United States of America
- * E-mail:
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33
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Ma Y, Han CC, Huang Q, Sun WY, Wei W. GRK2 overexpression inhibits IGF1-induced proliferation and migration of human hepatocellular carcinoma cells by downregulating EGR1. Oncol Rep 2016; 35:3068-74. [PMID: 26936374 DOI: 10.3892/or.2016.4641] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2015] [Accepted: 02/01/2016] [Indexed: 11/05/2022] Open
Abstract
G protein-coupled receptor kinase 2 (GRK2) is a serine/threonine kinase that is involved in a variety of important signaling pathways and alternation of GRK2 protein level or activity causes diseases such as heart failure, rheumatoid arthritis, and obesity. However, the role and mechanism of GRK2 in hepatocellular carcinoma (HCC) progression is not fully investigated. In this study we found that GRK2 plays an inhibitory role in IGF1-induced HCC cell proliferation and migration. Overexpression of GRK2 causes a decrease in early growth response-1 (EGR1) expression, while knockdown of GRK2 leads to marked increase in EGR1 expression in the treatment of IGF1. Through co-immunoprecipitation and western blot assay, we confirmed that GRK2 can interact with insulin-like growth factor 1 receptor (IGF-1R) and inhibits IGF1-induced activation of IGF1R signaling pathway. Silencing EGR1 attenuates GRK2 overexpression-caused inhibition of cell proliferation, tumor colony number and migration activity, while overexpressing of EGR1 restores the anti-proliferative and migratory effect by GRK2 overexpression in HCCLM3 cells. Collectively, these results suggest that GRK2 may inhibit IGF1-induced HCC cell growth and migration through downregulation of EGR1 and indicate that enforced GRK2 may offer a potential therapeutic approach against HCC.
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Affiliation(s)
- Yang Ma
- Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Hefei, Anhui 230032, P.R. China
| | - Chen-Chen Han
- Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Hefei, Anhui 230032, P.R. China
| | - Qiong Huang
- Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Hefei, Anhui 230032, P.R. China
| | - Wu-Yi Sun
- Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Hefei, Anhui 230032, P.R. China
| | - Wei Wei
- Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Hefei, Anhui 230032, P.R. China
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34
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Firtina Karagonlar Z, Koc D, Iscan E, Erdal E, Atabey N. Elevated hepatocyte growth factor expression as an autocrine c-Met activation mechanism in acquired resistance to sorafenib in hepatocellular carcinoma cells. Cancer Sci 2016; 107:407-16. [PMID: 26790028 PMCID: PMC4832867 DOI: 10.1111/cas.12891] [Citation(s) in RCA: 101] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2015] [Revised: 12/31/2015] [Accepted: 01/14/2016] [Indexed: 01/14/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer and the third leading cause of cancer‐related deaths worldwide. Limitations in HCC treatment result due to poor prognosis and resistance against traditional radiotherapy and chemotherapies. The multikinase inhibitor sorafenib is the only FDA approved drug available for advanced HCC patients, and development of second‐line treatment options for patients who cannot tolerate or develop resistance to sorafenib is an urgent medical need. In this study, we established sorafenib‐resistant cells from Huh7 and Mahlavu cell lines by long‐term sorafenib exposure. Sorafenib‐resistant HCC cells acquired spindle‐shape morphology, upregulated mesenchymal markers, and showed significant increase in both migration and invasion abilities compared to their parental counterparts. Moreover, after long‐term sorafenib treatment, HCC cells showed induction of hepatocyte growth factor (HGF) synthesis and secretion along with increased levels of c‐Met kinase and its active phosphorylated form, indicating autocrine activation of HGF/c‐Met signaling. Importantly, the combined treatment of the resistant cells with c‐Met kinase inhibitor SU11274 and HGF neutralizing antibody significantly reversed the increased invasion ability of the cells. The combined treatment also significantly augmented sorafenib‐induced apoptosis, suggesting restoration of sorafenib sensitivity. These results describe, for the first time, compensatory upregulation of HGF synthesis leading to autocrine activation of HGF/c‐Met signaling as a novel cellular strategy in the acquisition of sorafenib resistance. Therefore, we suggest that combinatorial therapeutic strategies with HGF and c‐Met inhibitors comprise promising candidates for overcoming sorafenib resistance.
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Affiliation(s)
- Zeynep Firtina Karagonlar
- Faculty of Engineering and Computer Science, Izmir University of Economics, Izmir.,Izmir International Biomedicine and Genome Institute, Dokuz Eylul University, Izmir
| | - Dogukan Koc
- Izmir International Biomedicine and Genome Institute, Dokuz Eylul University, Izmir
| | - Evin Iscan
- Izmir International Biomedicine and Genome Institute, Dokuz Eylul University, Izmir
| | - Esra Erdal
- Izmir International Biomedicine and Genome Institute, Dokuz Eylul University, Izmir.,Department of Medical Biology, Faculty of Medicine, Dokuz Eylul University, Izmir, Turkey
| | - Neşe Atabey
- Izmir International Biomedicine and Genome Institute, Dokuz Eylul University, Izmir.,Department of Medical Biology, Faculty of Medicine, Dokuz Eylul University, Izmir, Turkey
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35
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Chai X, Han Y, Yang J, Zhao X, Liu Y, Hou X, Tang Y, Zhao S, Li X. Identification of the transcriptional regulators by expression profiling infected with hepatitis B virus. Clin Res Hepatol Gastroenterol 2016; 40:57-72. [PMID: 26119596 DOI: 10.1016/j.clinre.2015.04.005] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/23/2014] [Revised: 12/18/2014] [Accepted: 04/28/2015] [Indexed: 02/07/2023]
Abstract
BACKGROUND The molecular pathogenesis of infection by hepatitis B virus with human is extremely complex and heterogeneous. To date the molecular information is not clearly defined despite intensive research efforts. Thus, studies aimed at transcription and regulation during virus infection or combined researches of those already known to be beneficial are needed. AIMS With the purpose of identifying the transcriptional regulators related to infection of hepatitis B virus in gene level, the gene expression profiles from some normal individuals and hepatitis B patients were analyzed in our study. METHODS In this work, the differential expressed genes were selected primarily. The several genes among those were validated in an independent set by qRT-PCR. Then the differentially co-expression analysis was conducted to identify differentially co-expressed links and differential co-expressed genes. Next, the analysis of the regulatory impact factors was performed through mapping the links and regulatory data. In order to give a further insight to these regulators, the co-expression gene modules were identified using a threshold-based hierarchical clustering method. Incidentally, the construction of the regulatory network was generated using the computer software. RESULTS A total of 137,284 differentially co-expressed links and 780 differential co-expressed genes were identified. These co-expressed genes were significantly enriched inflammatory response. The results of regulatory impact factors revealed several crucial regulators related to hepatocellular carcinoma and other high-rank regulators. Meanwhile, more than one hundred co-expression gene modules were identified using clustering method. CONCLUSIONS In our study, some important transcriptional regulators were identified using a computational method, which may enhance the understanding of disease mechanisms and lead to an improved treatment of hepatitis B. However, further experimental studies are required to confirm these findings.
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Affiliation(s)
- Xiaoqiang Chai
- College of Life Sciences, Sichuan University, Ministry of Education Key Laboratory for Bio-resource and Eco-environment, Sichuan Key Laboratory of Molecular Biology and Biotechnology, 610064 Chengdu, PR China
| | - Yanan Han
- College of Life Sciences, Sichuan University, Ministry of Education Key Laboratory for Bio-resource and Eco-environment, Sichuan Key Laboratory of Molecular Biology and Biotechnology, 610064 Chengdu, PR China
| | - Jian Yang
- College of Life Sciences, Sichuan University, Ministry of Education Key Laboratory for Bio-resource and Eco-environment, Sichuan Key Laboratory of Molecular Biology and Biotechnology, 610064 Chengdu, PR China
| | - Xianxian Zhao
- College of Life Sciences, Sichuan University, Ministry of Education Key Laboratory for Bio-resource and Eco-environment, Sichuan Key Laboratory of Molecular Biology and Biotechnology, 610064 Chengdu, PR China
| | - Yewang Liu
- College of Life Sciences, Sichuan University, Ministry of Education Key Laboratory for Bio-resource and Eco-environment, Sichuan Key Laboratory of Molecular Biology and Biotechnology, 610064 Chengdu, PR China
| | - Xugang Hou
- College of Life Sciences, Sichuan University, Ministry of Education Key Laboratory for Bio-resource and Eco-environment, Sichuan Key Laboratory of Molecular Biology and Biotechnology, 610064 Chengdu, PR China
| | - Yiheng Tang
- College of Life Sciences, Sichuan University, Ministry of Education Key Laboratory for Bio-resource and Eco-environment, Sichuan Key Laboratory of Molecular Biology and Biotechnology, 610064 Chengdu, PR China
| | - Shirong Zhao
- College of Life Sciences, Sichuan University, Ministry of Education Key Laboratory for Bio-resource and Eco-environment, Sichuan Key Laboratory of Molecular Biology and Biotechnology, 610064 Chengdu, PR China
| | - Xiao Li
- College of Life Sciences, Sichuan University, Ministry of Education Key Laboratory for Bio-resource and Eco-environment, Sichuan Key Laboratory of Molecular Biology and Biotechnology, 610064 Chengdu, PR China.
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Gunes A, Iscan E, Topel H, Avci ST, Gumustekin M, Erdal E, Atabey N. Heparin treatment increases thioredoxin interacting protein expression in hepatocellular carcinoma cells. Int J Biochem Cell Biol 2015; 65:169-81. [DOI: 10.1016/j.biocel.2015.05.025] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2015] [Revised: 04/30/2015] [Accepted: 05/28/2015] [Indexed: 10/23/2022]
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Xue TC, Ge NL, Zhang L, Cui JF, Chen RX, You Y, Ye SL, Ren ZG. Goosecoid promotes the metastasis of hepatocellular carcinoma by modulating the epithelial-mesenchymal transition. PLoS One 2014; 9:e109695. [PMID: 25343336 PMCID: PMC4208742 DOI: 10.1371/journal.pone.0109695] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2014] [Accepted: 09/12/2014] [Indexed: 01/30/2023] Open
Abstract
The homeobox gene, goosecoid (GSC), is a transcription factor that participates in cell migration during embryonic development. Because cell migration during development has characteristics similar to cell invasion during metastasis, we evaluated the potential role of GSC in the metastasis of hepatocellular carcinoma (HCC). GSC expression in HCC cell lines and tissues was evaluated, and its effects on the migration potential of HCC cells were determined by GSC knock-down and overexpression methods. In addition, the prognostic role of GSC expression in the metastasis of cancer cells in HCC patients was determined. Our data showed that GSC was highly expressed in several HCC cell lines, particularly in a highly metastatic HCC cell line. Overexpression of GSC promoted cell migration and invasion of HCC cells in vitro. Gain-of-function induced the epithelial-mesenchymal transition but not collective cell migration, whereas loss-of-function induced the reverse change. High-level expression of GSC correlated closely with poor survival and lung metastasis in HCC patients; lung metastases showed more upregulated GSC expression than the primary tumor. We conclude that GSC promotes metastasis of HCC potentially through initiating the epithelial-mesenchymal transition. GSC is also a prognostic factor for poor survival and metastasis of HCC, which suggests its potential as a therapeutic target for metastatic HCC.
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Affiliation(s)
- Tong-Chun Xue
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, P.R. China
- Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Shanghai, P.R. China
| | - Ning-Ling Ge
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, P.R. China
- Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Shanghai, P.R. China
| | - Lan Zhang
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, P.R. China
- Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Shanghai, P.R. China
| | - Jie-Feng Cui
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, P.R. China
- Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Shanghai, P.R. China
| | - Rong-Xin Chen
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, P.R. China
- Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Shanghai, P.R. China
| | - Yang You
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, P.R. China
- Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Shanghai, P.R. China
| | - Sheng-Long Ye
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, P.R. China
- Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Shanghai, P.R. China
| | - Zheng-Gang Ren
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, P.R. China
- Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Shanghai, P.R. China
- * E-mail:
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Shan J, Balasubramanian MN, Donelan W, Fu L, Hayner J, Lopez MC, Baker HV, Kilberg MS. A mitogen-activated protein kinase/extracellular signal-regulated kinase kinase (MEK)-dependent transcriptional program controls activation of the early growth response 1 (EGR1) gene during amino acid limitation. J Biol Chem 2014; 289:24665-79. [PMID: 25028509 DOI: 10.1074/jbc.m114.565028] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023] Open
Abstract
Amino acid (AA) limitation in mammalian cells triggers a collection of signaling cascades jointly referred to as the AA response (AAR). In human HepG2 hepatocellular carcinoma, the early growth response 1 (EGR1) gene was induced by either AA deprivation or endoplasmic reticulum stress. AAR-dependent EGR1 activation was discovered to be independent of the well characterized GCN2-ATF4 pathway and instead dependent on MEK-ERK signaling, one of the MAPK pathways. ChIP showed that constitutively bound ELK1 at the EGR1 proximal promoter region was phosphorylated after AAR activation. Increased p-ELK1 binding was associated with increased de novo recruitment of RNA polymerase II to the EGR1 promoter. EGR1 transcription was not induced in HEK293T cells lacking endogenous MEK activity, but overexpression of exogenous constitutively active MEK in HEK293T cells resulted in increased basal and AAR-induced EGR1 expression. ChIP analysis of the human vascular endothelial growth factor A (VEGF-A) gene, a known EGR1-responsive gene, revealed moderate increases in AAR-induced EGR1 binding within the proximal promoter and highly inducible binding to a site within the first intron. Collectively, these data document a novel AA-activated MEK-ERK-ELK1 signaling mechanism.
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Affiliation(s)
- Jixiu Shan
- From the Department of Biochemistry and Molecular Biology, Shands Cancer Center and Center for Nutritional Sciences and
| | - Mukundh N Balasubramanian
- From the Department of Biochemistry and Molecular Biology, Shands Cancer Center and Center for Nutritional Sciences and
| | - William Donelan
- From the Department of Biochemistry and Molecular Biology, Shands Cancer Center and Center for Nutritional Sciences and
| | - Lingchen Fu
- From the Department of Biochemistry and Molecular Biology, Shands Cancer Center and Center for Nutritional Sciences and
| | - Jaclyn Hayner
- From the Department of Biochemistry and Molecular Biology, Shands Cancer Center and Center for Nutritional Sciences and
| | - Maria-Cecilia Lopez
- the Department of Molecular Genetics and Microbiology, Genetics Institute, University of Florida College of Medicine, Gainesville, Florida 32610
| | - Henry V Baker
- the Department of Molecular Genetics and Microbiology, Genetics Institute, University of Florida College of Medicine, Gainesville, Florida 32610
| | - Michael S Kilberg
- From the Department of Biochemistry and Molecular Biology, Shands Cancer Center and Center for Nutritional Sciences and
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Hu CT, Cheng CC, Pan SM, Wu JR, Wu WS. PKC mediates fluctuant ERK-paxillin signaling for hepatocyte growth factor-induced migration of hepatoma cell HepG2. Cell Signal 2013; 25:1457-67. [PMID: 23524339 DOI: 10.1016/j.cellsig.2013.03.011] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2013] [Accepted: 03/12/2013] [Indexed: 12/23/2022]
Abstract
Hepatocyte growth factor (HGF) is critical for triggering metastasis of hepatocellular carcinoma cell (HCC). Extracellular signal-regulated kinase (ERK) mediates HGF-induced cell migration via focal adhesion signaling. Protein kinase C (PKC) is a negative regulator of ERK activation, however, both PKC and ERK were required for HGF-induced cell migration. To address this intriguing issue, the signal mechanisms for HGF-induced HepG2 cell migration were investigated in a long-term fashion. HGF-induced phosphorylations of ERK, Src (at Tyr 416) and paxillin (at Ser178 and Tyr31) were up and down for 3 times within 24h. HGF also induced fluctuant PKC activation and Rac degradation. Consistently, HGF induced intermittent actin polarization within 24h, which can be blocked by the inhibitors of PKC (Bisindolymaleimide) and ERK. Inhibitor studies revealed that ERK was required for HGF-induced paxillin phosphorylation at Ser178, whereas PKC and Rac-1 may suppress HGF-induced phosphorylation of ERK and paxillin (at Ser178) and upregulate phosphorylation of paxillin at Tyr31. Based on shRNA technique, PKCα and δ were responsible for suppressing HGF-induced phosphorylation of ERK and paxillin (at Ser178), whereas PKC ε and ζ were required for phosphorylation of paxillin at Tyr31. The HGF-induced fluctuant signaling is reminiscent of c-Met endocytosis. Using Concanavalin A, an inhibitor of endocytosis, we found that c-Met endocytosis was required for PKC to suppress ERK phosphorylation. Moreover, HGF-induced c-Met degradation was also fluctuant, which can be prevented by Bisindolymaleimide. In conclusion, PKC is critical for mediating HGF-induced fluctuant ERK-paxillin signaling during cell migration, probably via triggering endosomal degradation of c-Met.
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Affiliation(s)
- Chi-Tan Hu
- Research Centre for Hepatology, Department of Internal Medicine, Buddhist Tzu Chi General Hospital and Tzu Chi University, Hualien, Taiwan
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