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Sharafutdinov I, Friedrich B, Rottner K, Backert S, Tegtmeyer N. Cortactin: A major cellular target of viral, protozoal, and fungal pathogens. Mol Microbiol 2024; 122:165-183. [PMID: 38868928 DOI: 10.1111/mmi.15284] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2023] [Revised: 05/22/2024] [Accepted: 05/27/2024] [Indexed: 06/14/2024]
Abstract
Many viral, protozoal, and fungal pathogens represent major human and animal health problems due to their great potential of causing infectious diseases. Research on these pathogens has contributed substantially to our current understanding of both microbial virulence determinants and host key factors during infection. Countless studies have also shed light on the molecular mechanisms of host-pathogen interactions that are employed by these microbes. For example, actin cytoskeletal dynamics play critical roles in effective adhesion, host cell entry, and intracellular movements of intruding pathogens. Cortactin is an eminent host cell protein that stimulates actin polymerization and signal transduction, and recently emerged as fundamental player during host-pathogen crosstalk. Here we review the important role of cortactin as major target for various prominent viral, protozoal and fungal pathogens in humans, and its role in human disease development and cancer progression. Most if not all of these important classes of pathogens have been reported to hijack cortactin during infection through mediating up- or downregulation of cortactin mRNA and protein expression as well as signaling. In particular, pathogen-induced changes in tyrosine and serine phosphorylation status of cortactin at its major phospho-sites (Y-421, Y-470, Y-486, S-113, S-298, S-405, and S-418) are addressed. As has been reported for various Gram-negative and Gram-positive bacteria, many pathogenic viruses, protozoa, and fungi also control these regulatory phospho-sites, for example, by activating kinases such as Src, PAK, ERK1/2, and PKD, which are known to phosphorylate cortactin. In addition, the recruitment of cortactin and its interaction partners, like the Arp2/3 complex and F-actin, to the contact sites between pathogens and host cells is highlighted, as this plays an important role in the infection process and internalization of several pathogens. However, there are also other ways in which the pathogens can exploit the function of cortactin for their needs, as the cortactin-mediated regulation of cellular processes is complex and involves numerous different interaction partners. Here, the current state of knowledge is summarized.
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Affiliation(s)
- Irshad Sharafutdinov
- Department of Biology, Division of Microbiology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Barbara Friedrich
- Department of Biology, Division of Microbiology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Klemens Rottner
- Department of Cell Biology, Helmholtz Centre for Infection Research, Braunschweig, Germany
- Division of Molecular Cell Biology, Zoological Institute, Technische Universität Braunschweig, Braunschweig, Germany
| | - Steffen Backert
- Department of Biology, Division of Microbiology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Nicole Tegtmeyer
- Department of Biology, Division of Microbiology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
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Vuletić A, Mirjačić Martinović K, Spasić J. Role of Histone Deacetylase 6 and Histone Deacetylase 6 Inhibition in Colorectal Cancer. Pharmaceutics 2023; 16:54. [PMID: 38258065 PMCID: PMC10818982 DOI: 10.3390/pharmaceutics16010054] [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: 11/28/2023] [Revised: 12/22/2023] [Accepted: 12/27/2023] [Indexed: 01/24/2024] Open
Abstract
Histone deacetylase 6 (HDAC6), by deacetylation of multiple substrates and association with interacting proteins, regulates many physiological processes that are involved in cancer development and invasiveness such as cell proliferation, apoptosis, motility, epithelial to mesenchymal transition, and angiogenesis. Due to its ability to remove misfolded proteins, induce autophagy, and regulate unfolded protein response, HDAC6 plays a protective role in responses to stress and enables tumor cell survival. The scope of this review is to discuss the roles of HDCA6 and its implications for the therapy of colorectal cancer (CRC). As HDAC6 is overexpressed in CRC, correlates with poor disease prognosis, and is not essential for normal mammalian development, it represents a good therapeutic target. Selective inhibition of HDAC6 impairs growth and progression without inducing major adverse events in experimental animals. In CRC, HDAC6 inhibitors have shown the potential to reduce tumor progression and enhance the therapeutic effect of other drugs. As HDAC6 is involved in the regulation of immune responses, HDAC6 inhibitors have shown the potential to improve antitumor immunity by increasing the immunogenicity of tumor cells, augmenting immune cell activity, and alleviating immunosuppression in the tumor microenvironment. Therefore, HDAC6 inhibitors may represent promising candidates to improve the effect of and overcome resistance to immunotherapy.
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Affiliation(s)
- Ana Vuletić
- Department of Experimental Oncology, Institute of Oncology and Radiology of Serbia, Pasterova 14, 11000 Belgrade, Serbia;
| | - Katarina Mirjačić Martinović
- Department of Experimental Oncology, Institute of Oncology and Radiology of Serbia, Pasterova 14, 11000 Belgrade, Serbia;
| | - Jelena Spasić
- Clinic for Medical Oncology, Institute of Oncology and Radiology of Serbia, Pasterova 14, 11000 Belgrade, Serbia;
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Son H, Jee S, Cha H, Song K, Bang S, Kim H, Paik S, Park H, Myung J. Effects of Cortactin Expression on Prognosis in Patients with Breast Cancer. Diagnostics (Basel) 2023; 13:2876. [PMID: 37761244 PMCID: PMC10530131 DOI: 10.3390/diagnostics13182876] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2023] [Revised: 09/05/2023] [Accepted: 09/06/2023] [Indexed: 09/29/2023] Open
Abstract
BACKGROUND Cortactin is overexpressed in several types of invasive cancers. However, the role of cortactin expression in breast cancer prognosis has not been sufficiently elucidated. Therefore, we investigated the clinicopathological significance of cortactin in breast cancer. METHODS Tissue microarrays were prepared from a cohort of 506 patients with breast cancer, and cortactin expression was evaluated using immunohistochemistry. The cortactin immunoreactivity score (IRS) was quantified as the product of the intensity score and the percentage of immunoreactive cells. Cortactin expression was classified as low or high using the IRS (IRS ≤ 4 as a cortactin-low value and IRS > 4 as a cortactin-high value). We compared cortactin expression and clinicopathological factors according to the molecular subtypes of breast cancer. RESULTS Of 506 breast cancer cases, 333 and 173 showed high and low cortactin expression, respectively. Of the 333 patients with high cortactin expression, 204, 58, and 71 had luminal, HER2, and triple-negative breast cancer (TNBC), respectively. In the univariate and multivariate analyses of patients with TNBC, cortactin expression was found to be a significant prognostic factor for overall survival (OS). However, in all patients with non-TNBC, cortactin expression had no significant association with prognosis or overall survival. Survival curves revealed that among patients with TNBC, the high-cortactin group had a better prognosis in disease-free survival and OS. CONCLUSIONS Cortactin expression may be a good biomarker for predicting the prognosis of patients with TNBC.
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Affiliation(s)
| | | | | | | | | | | | | | - Hosub Park
- Department of Pathology, Hanyang University College of Medicine, Seoul 04763, Republic of Korea
| | - Jaekyung Myung
- Department of Pathology, Hanyang University College of Medicine, Seoul 04763, Republic of Korea
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Zhao Y, Hu F, Wang Q. Cortactin contributes to the tumorigenesis of gastric cancer by activating ERK/MMP pathway. Heliyon 2023; 9:e18289. [PMID: 37539204 PMCID: PMC10395536 DOI: 10.1016/j.heliyon.2023.e18289] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2022] [Revised: 07/10/2023] [Accepted: 07/13/2023] [Indexed: 08/05/2023] Open
Abstract
Gastric cancer is a malignant tumor with high mortality and high incidence. This study aims to explore the function and molecular mechanism of Cortactin on gastric cancer progression in vitro and in vivo. A bioinformatics analysis from TCGA displayed that Cortactin was highly expressed in gastric cancer samples, and patients with a high Cortactin level had a worse survival rate. Subsequently, we investigated the specific mechanism of action of A in gastric cancer by collecting patient samples for immunohistochemistry, WB, qRT-PCR, cell transfection, cell invasion and metastasis, and constructing tumor xenografts in nude mice. Overexpression of Cortactin inhibited apoptosis and enhanced cellular proliferation and mobility in AGS cells, while those activities were reversed by the knockdown of MMP2 or MMP9. Conversely, the deletion of Cortactin induced apoptosis and suppressed cell growth and metastasis in SGC7901 cells, whereas those behaviors were inhibited by overexpression of MMP2 or MMP9. Additionally, the ERK pathway was activated by Cortactin upregulation. In vivo studies presented that overexpression of Cortactin promoted tumor growth, increased Ki67 expression, and reduced caspase 3 expression, which was reversed by ERK inhibitor treatment. In conclusion, Cortactin acted as an oncogene in gastric cancer and exerted its function by ERK/MMP2/MMP9 signaling pathway.
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Affiliation(s)
- Yi Zhao
- Department of Gastroenterology, The First Affiliated Hospital of Bengbu Medical College, Bengbu Anhui 233004, China
| | - Fang Hu
- Department of Hematology, The First Affiliated Hospital of Bengbu Medical College, Bengbu Anhui 233004, China
| | - Qizhi Wang
- Department of Gastroenterology, The First Affiliated Hospital of Bengbu Medical College, Bengbu Anhui 233004, China
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Bumrungthai S, Ekalaksananan T, Kleebkaow P, Pongsawatkul K, Phatnithikul P, Jaikan J, Raumsuk P, Duangjit S, Chuenchai D, Pientong C. Mathematical Modelling of Cervical Precancerous Lesion Grade Risk Scores: Linear Regression Analysis of Cellular Protein Biomarkers and Human Papillomavirus E6/ E7 RNA Staining Patterns. Diagnostics (Basel) 2023; 13:1084. [PMID: 36980391 PMCID: PMC10047622 DOI: 10.3390/diagnostics13061084] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2022] [Revised: 03/01/2023] [Accepted: 03/09/2023] [Indexed: 03/15/2023] Open
Abstract
The current practice of determining histologic grade with a single molecular biomarker can facilitate differential diagnosis but cannot predict the risk of lesion progression. Cancer is caused by complex mechanisms, and no single biomarker can both make accurate diagnoses and predict progression risk. Modelling using multiple biomarkers can be used to derive scores for risk prediction. Mathematical models (MMs) may be capable of making predictions from biomarker data. Therefore, this study aimed to develop MM-based scores for predicting the risk of precancerous cervical lesion progression and identifying precancerous lesions in patients in northern Thailand by evaluating the expression of multiple biomarkers. The MMs (Models 1-5) were developed in the test sample set based on patient age range (five categories) and biomarker levels (cortactin, p16INK4A, and Ki-67 by immunohistochemistry [IHC], and HPV E6/E7 ribonucleic acid (RNA) by in situ hybridization [ISH]). The risk scores for the prediction of cervical lesion progression ("risk biomolecules") ranged from 2.56-2.60 in the normal and low-grade squamous intraepithelial lesion (LSIL) cases and from 3.54-3.62 in cases where precancerous lesions were predicted to progress. In Model 4, 23/86 (26.7%) normal and LSIL cases had biomolecule levels that suggested a risk of progression, while 5/86 (5.8%) cases were identified as precancerous lesions. Additionally, histologic grading with a single molecular biomarker did not identify 23 cases with risk, preventing close patient monitoring. These results suggest that biomarker level-based risk scores are useful for predicting the risk of cervical lesion progression and identifying precancerous lesion development. This multiple biomarker-based strategy may ultimately have utility for predicting cancer progression in other contexts.
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Affiliation(s)
- Sureewan Bumrungthai
- Division of Biopharmacy, Faculty of Pharmaceutical Sciences, Ubon Ratchathani University, Ubon Ratchathani 34190, Thailand;
- Division of Microbiology and Parasitology, School of Medical Sciences, University of Phayao, Phayao 56000, Thailand
- HPV & EBV and Carcinogenesis Research Group, Khon Kaen University, Khon Kaen 40002, Thailand
| | - Tipaya Ekalaksananan
- HPV & EBV and Carcinogenesis Research Group, Khon Kaen University, Khon Kaen 40002, Thailand
- Department of Microbiology, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand
| | - Pilaiwan Kleebkaow
- Department of Obstetrics and Gynecology, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand
| | | | | | - Jirad Jaikan
- Department of Cytopathology, Phayao Hospital, Phayao 56000, Thailand
| | - Puntanee Raumsuk
- Department of Cytopathology, Phayao Hospital, Phayao 56000, Thailand
| | - Sureewan Duangjit
- Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmaceutical Sciences, Ubon Ratchathani University, Ubon Ratchathani 34190, Thailand
| | - Datchani Chuenchai
- Division of Microbiology and Parasitology, School of Medical Sciences, University of Phayao, Phayao 56000, Thailand
| | - Chamsai Pientong
- HPV & EBV and Carcinogenesis Research Group, Khon Kaen University, Khon Kaen 40002, Thailand
- Department of Microbiology, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand
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Wang X, Zhang N, Li M, Hong T, Meng W, Ouyang T. Ubiquitin C‑terminal hydrolase‑L1: A new cancer marker and therapeutic target with dual effects (Review). Oncol Lett 2023; 25:123. [PMID: 36844618 PMCID: PMC9950345 DOI: 10.3892/ol.2023.13709] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2022] [Accepted: 12/08/2022] [Indexed: 02/11/2023] Open
Abstract
Ubiquitin C-terminal hydrolase-L1 (UCH-L1), a member of the lesser-known deubiquitinating enzyme family, has deubiquitinase and ubiquitin (Ub) ligase activity and the role of stabilizing Ub. UCH-L1 was first discovered in the brain and is associated with regulating cell differentiation, proliferation, transcriptional regulation and numerous other biological processes. UCH-L1 is predominantly expressed in the brain and serves a role in tumor promotion or inhibition. There is still controversy about the effect of UCH-L1 dysregulation in cancer and its mechanisms are unknown. Extensive research to investigate the mechanism of UCH-L1 in different types of cancer is key for the future treatment of UCH-L1-associated cancer. The present review details the molecular structure and function of UCH-L1. The role of UCH-L1 in different types of cancer is also summarized and how novel treatment targets provide a theoretical foundation in cancer research is discussed.
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Affiliation(s)
- Xiaowei Wang
- Department of Neurosurgery, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China,Department of The Second Clinical Medical College of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Na Zhang
- Department of Neurology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Meihua Li
- Department of Neurosurgery, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Tao Hong
- Department of Neurosurgery, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Wei Meng
- Department of Neurosurgery, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China,Correspondence to: Dr Wei Meng or Dr Taohui Ouyang, Department of Neurosurgery, The First Affiliated Hospital of Nanchang University, 17 Yongwai Street, Nanchang, Jiangxi 330006, P.R. China, E-mail:
| | - Taohui Ouyang
- Department of Neurosurgery, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China,Correspondence to: Dr Wei Meng or Dr Taohui Ouyang, Department of Neurosurgery, The First Affiliated Hospital of Nanchang University, 17 Yongwai Street, Nanchang, Jiangxi 330006, P.R. China, E-mail:
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Tang WC, Tsao SW, Jones GE, Liu X, Tsai MH, Delecluse HJ, Dai W, You C, Zhang J, Huang SCM, Leung MMH, Liu T, Ching YP, Chen H, Lo KW, Li X, Tsang CM. Latent membrane protein 1 and macrophage-derived TNFα synergistically activate and mobilize invadopodia to drive invasion of nasopharyngeal carcinoma. J Pathol 2023; 259:163-179. [PMID: 36420735 PMCID: PMC10108171 DOI: 10.1002/path.6036] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2022] [Revised: 11/07/2022] [Accepted: 11/21/2022] [Indexed: 11/25/2022]
Abstract
Invadopodia are actin-rich membrane protrusions that digest the matrix barrier during cancer metastasis. Since the discovery of invadopodia, they have been visualized as localized and dot-like structures in different types of cancer cells on top of a 2D matrix. In this investigation of Epstein-Barr virus (EBV)-associated nasopharyngeal carcinoma (NPC), a highly invasive cancer frequently accompanied by neck lymph node and distal organ metastases, we revealed a new form of invadopodium with mobilizing features. Integration of live-cell imaging and molecular assays revealed the interaction of macrophage-released TNFα and EBV-encoded latent membrane protein 1 (LMP1) in co-activating the EGFR/Src/ERK/cortactin and Cdc42/N-WASP signaling axes for mobilizing the invadopodia with lateral movements. This phenomenon endows the invadopodia with massive degradative power, visualized as a shift of focal dot-like digestion patterns on a 2D gelatin to a dendrite-like digestion pattern. Notably, single stimulation of either LMP1 or TNFα could only enhance the number of ordinary dot-like invadopodia, suggesting that the EBV infection sensitizes the NPC cells to form mobilizing invadopodia when encountering a TNFα-rich tumor microenvironment. This study unveils the interplay of EBV and stromal components in driving the invasive potential of NPC via unleashing the propulsion of invadopodia in overcoming matrix hurdles. © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
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Affiliation(s)
- Wing Chung Tang
- Department of Anatomical and Cellular Pathology and State Key Laboratory of Translational Oncology, The Chinese University of Hong Kong, Hong Kong SAR, PR China.,School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, PR China
| | - Sai Wah Tsao
- School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, PR China
| | - Gareth E Jones
- Randall Centre for Cell and Molecular Biophysics, King's College London, London, UK
| | - Xiong Liu
- Department of Otolaryngology - Head and Neck Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, PR China
| | - Ming Han Tsai
- Institute of Microbiology and Immunology, National Yang-Ming University, Taipei, Taiwan
| | | | - Wei Dai
- Department of Clinical Oncology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, PR China
| | - Chanping You
- School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, PR China
| | - Jun Zhang
- School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, PR China.,Guangdong Key Laboratory of Genome Instability and Human Disease Prevention, Department of Biochemistry and Molecular Biology, Shenzhen University, School of Medicine, Shenzhen, PR China
| | - Shaina Chor Mei Huang
- School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, PR China
| | - Manton Man-Hon Leung
- School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, PR China
| | - Tengfei Liu
- School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, PR China
| | - Yick Pang Ching
- School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, PR China
| | - Honglin Chen
- Department of Microbiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, PR China
| | - Kwok Wai Lo
- Department of Anatomical and Cellular Pathology and State Key Laboratory of Translational Oncology, The Chinese University of Hong Kong, Hong Kong SAR, PR China
| | - Xin Li
- Shenzhen Key Laboratory of Viral Oncology, The Clinical Innovation & Research Center (CIRC), Shenzhen Hospital, Southern Medical University, Shenzhen, PR China
| | - Chi Man Tsang
- Department of Anatomical and Cellular Pathology and State Key Laboratory of Translational Oncology, The Chinese University of Hong Kong, Hong Kong SAR, PR China.,School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, PR China
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Comparative RNA-Sequencing Analysis Reveals High Complexity and Heterogeneity of Transcriptomic and Immune Profiles in Hepatocellular Carcinoma Tumors of Viral (HBV, HCV) and Non-Viral Etiology. MEDICINA (KAUNAS, LITHUANIA) 2022; 58:medicina58121803. [PMID: 36557005 PMCID: PMC9785216 DOI: 10.3390/medicina58121803] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 10/31/2022] [Revised: 12/01/2022] [Accepted: 12/02/2022] [Indexed: 12/12/2022]
Abstract
Background and Objectives: Hepatocellular carcinoma (HCC), the most common type of primary liver cancer, is the leading cause of cancer-related mortality. It arises and progresses against fibrotic or cirrhotic backgrounds mainly due to infection with hepatitis viruses B (HBV) or C (HCV) or non-viral causes that lead to chronic inflammation and genomic changes. A better understanding of molecular and immune mechanisms in HCC subtypes is needed. Materials and Methods: To identify transcriptional changes in primary HCC tumors with or without hepatitis viral etiology, we analyzed the transcriptomes of 24 patients by next-generation sequencing. Results: We identified common and unique differentially expressed genes for each etiological tumor group and analyzed the expression of SLC, ATP binding cassette, cytochrome 450, cancer testis, and heat shock protein genes. Metascape functional enrichment analysis showed mainly upregulated cell-cycle pathways in HBV and HCV and upregulated cell response to stress in non-viral infection. GeneWalk analysis identified regulator, hub, and moonlighting genes and highlighted CCNB1, ACTN2, BRCA1, IGF1, CDK1, AURKA, AURKB, and TOP2A in the HCV group and HSF1, HSPA1A, HSP90AA1, HSPB1, HSPA5, PTK2, and AURKB in the group without viral infection as hub genes. Immune infiltrate analysis showed that T cell, cytotoxic, and natural killer cell markers were significantly more highly expressed in HCV than in non-viral tumors. Genes associated with monocyte activation had the highest expression levels in HBV, while high expression of genes involved in primary adaptive immune response and complement receptor activity characterized tumors without viral infection. Conclusions: Our comprehensive study underlines the high degree of complexity of immune profiles in the analyzed groups, which adds to the heterogeneous HCC genomic landscape. The biomarkers identified in each HCC group might serve as therapeutic targets.
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Hui TX, Sutikno T, Kasim S, Md Fudzee MF, Halim SA, Hassan R, Sen SC. An Entropy-based Directed Random Walk for Pathway Activity Inference Using Topological Importance and Gene Interactions.. [DOI: 10.1101/2021.11.05.467449] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/02/2023]
Abstract
AbstractThe integration of microarray technologies and machine learning methods has become popular in predicting pathological condition of diseases and discovering risk genes. The traditional microarray analysis considers pathways as simple gene sets, treating all genes in the pathway identically while ignoring the pathway network’s structure information. This study, however, proposed an entropy-based directed random walk (e-DRW) method to infer pathway activity. This study aims (1) To enhance the gene-weighting method in Directed Random Walk (DRW) by incorporating t-test statistic scores and correlation coefficient values, (2) To implement entropy as a parameter variable for random walking in a biological network, and (3) To apply Entropy Weight Method (EWM) in DRW pathway activity inference. To test the objectives, the gene expression dataset was used as input datasets while the pathway dataset was used as reference datasets to build a directed graph. An equation was proposed to assess the connectivity of nodes in the directed graph via probability values calculated from the Shannon entropy formula. A direct proof of calculation based on the proposed mathematical formula was presented using e-DRW with gene expression data. Based on the results, there was an improvement in terms of sensitivity of prediction and accuracy of cancer classification between e-DRW and conventional DRW. The within-dataset experiments indicated that our novel method demonstrated robust and superior performance in terms of accuracy and number of predicted risk-active pathways compared to the other DRW methods. In conclusion, the results revealed that e-DRW not only improved prediction performance, but also effectively extracted topologically important pathways and genes that are specifically related to the corresponding cancer types.
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10
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Sharafutdinov I, Backert S, Tegtmeyer N. The Helicobacter pylori type IV secretion system upregulates epithelial cortactin expression by a CagA- and JNK-dependent pathway. Cell Microbiol 2021; 23:e13376. [PMID: 34197673 DOI: 10.1111/cmi.13376] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2021] [Revised: 06/18/2021] [Accepted: 06/28/2021] [Indexed: 12/11/2022]
Abstract
Cortactin represents an important actin-binding factor, which controls actin-cytoskeletal remodelling in host cells. In this way, cortactin has been shown to exhibit crucial functions both for cell movement and tumour cell invasion. In addition, the cortactin gene cttn is amplified in various cancer types of humans. Helicobacter pylori is the causative agent of multiple gastric diseases and represents a significant risk factor for the development of gastric adenocarcinoma. It has been repeatedly shown that H. pylori manipulates cancer-related signal transduction events in infected gastric epithelial cells such as the phosphorylation status of cortactin. In fact, H. pylori modifies the activity of cortactin's binding partners to stimulate changes in the actin-cytoskeleton, cell adhesion and motility. Here we show that H. pylori infection of cultured AGS and Caco-2 cells for 24-48 hr leads to the overexpression of cortactin by 2-3 fold at the protein level. We demonstrate that this activity requires the integrity of the type IV secretion system (T4SS) encoded by the cag pathogenicity island (cagPAI) as well as the translocated effector protein CagA. We further show that ectopic expression of CagA is sufficient to stimulate cortactin overexpression. Furthermore, phosphorylation of CagA at the EPIYA-repeat region is not required, suggesting that this CagA activity proceeds in a phosphorylation-independent fashion. Inhibitor studies further demonstrate that the involved signalling pathway comprises the mitogen-activated protein kinase JNK (c-Jun N-terminal kinase), but not ERK1/2 or p38. Taken together, using H. pylori as a model system, this study discovered a previously unrecognised cortactin activation cascade by a microbial pathogen. We suggest that H. pylori targets cortactin to manipulate the cellular architecture and epithelial barrier functions that can impact gastric cancer development. TAKE AWAYS: Helicobacter pylori infection induces overexpression of cortactin at the protein level Cortactin upregulation requires the T4SS and effector protein CagA Ectopic expression of CagA is sufficient to stimulate cortactin overexpression Overexpression of cortactin proceeds CagA phosphorylation-independent The involved host cell signalling pathway comprises the MAP kinase JNK.
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Affiliation(s)
- Irshad Sharafutdinov
- Department of Biology, Division of Microbiology, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, 91058, Germany
| | - Steffen Backert
- Department of Biology, Division of Microbiology, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, 91058, Germany
| | - Nicole Tegtmeyer
- Department of Biology, Division of Microbiology, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, 91058, Germany
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Peng JL, Wu JZ, Li GJ, Wu JL, Xi YM, Li XQ, Wang L. Identification of potential biomarkers of peripheral blood mononuclear cell in hepatocellular carcinoma using bioinformatic analysis: A protocol for systematic review and meta-analysis. Medicine (Baltimore) 2021; 100:e24172. [PMID: 33466191 PMCID: PMC7808450 DOI: 10.1097/md.0000000000024172] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/02/2020] [Accepted: 12/11/2020] [Indexed: 12/29/2022] Open
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is the cause of an overwhelming number of cancer-related deaths across the world. Developing precise and noninvasive biomarkers is critical for diagnosing HCC. Our research was designed to explore potentially useful biomarkers of host peripheral blood mononuclear cell (PBMC) in HCC by integrating comprehensive bioinformatic analysis. METHODS Gene expression data of PBMC in both healthy individuals and patients with HCC were extracted from the Gene Expression Omnibus (GEO) to identify differentially expressed genes (DEGs). The gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis were applied to annotate the function of DEGs. Protein-protein interaction analysis was performed to screen the hub genes from DEGs. cBioportal database analysis was performed to assess the prognostic significance of hub genes. The Cancer Cell Line Encyclopedia (CCLE) and The Human Protein Atlas (HPA) database analyses were performed to confirm the expression levels of the hub genes in HCC cells and tissue. RESULTS A total of 95 DEGs were screened. Results of the GO analysis revealed that DEGs were primarily involved in platelet degranulation, cytoplasm, and protein binding. Results of the KEGG analysis indicated that DEGs were primarily enriched in focal adhesion. Five genes, namely, myosin light chain kinase (MYLK), interleukin 1 beta (IL1B), phospholipase D1 (PLD1), cortactin (CTTN), and moesin (MSN), were identified as hub genes. A search in the CCLE and HPA database showed that the expression levels of these hub genes were remarkably increased in the HCC samples. Survival analysis revealed that the overexpression of MYLK, IL1B, and PLD1 may have a significant effect on HCC survival. The aberrant high expression levels of MYLK, IL1B, and PLD1 strongly indicated worse prognosis in patients with HCC. CONCLUSIONS The identified hub genes may be closely linked with HCC tumorigenicity and may act as potentially useful biomarkers for the prognostic prediction of HCC in PBMC samples.
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Affiliation(s)
- Jin-lin Peng
- Department of Infectious Disease, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, Nanning, Guangxi
| | - Ji-zhou Wu
- Department of Infectious Disease, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, Nanning, Guangxi
| | - Guo-jian Li
- Department of Infectious Disease, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, Nanning, Guangxi
| | - Jian-lin Wu
- Department of Infectious Disease, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, Nanning, Guangxi
| | - Yu-mei Xi
- Department of Infectious Disease, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, Nanning, Guangxi
| | - Xiao-qing Li
- Department of Infectious Disease, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, Nanning, Guangxi
| | - Lei Wang
- College of Health and Rehabilitation, Chengdu University of Chinese Medicine, Chengdu, Sichuan, PR China
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12
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Cortactin Interacts with Hepatitis C Virus Core and NS5A Proteins: Implications for Virion Assembly. J Virol 2020; 94:JVI.01306-20. [PMID: 32727880 DOI: 10.1128/jvi.01306-20] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2020] [Accepted: 07/17/2020] [Indexed: 12/11/2022] Open
Abstract
Hepatitis C virus (HCV) exploits cellular proteins to facilitate viral propagation. To identify the cellular factors involved in the HCV life cycle, we previously performed protein microarray assays using either HCV nonstructural 5A (NS5A) protein or core protein as a probe. Interestingly, cellular cortactin strongly interacted with both NS5A and core. Cortactin is an actin-binding protein critically involved in tumor progression by regulating the migration and invasion of cancerous cells. Protein interaction between cortactin and NS5A or core was confirmed by coimmunoprecipitation and immunofluorescence assays. We showed that cortactin interacted with NS5A and core via the N-terminal acidic domain of cortactin. Cortactin expression levels were not altered by HCV infection. Small interfering RNA (siRNA)-mediated knockdown of cortactin dramatically decreased HCV protein expression and infectivity levels, whereas overexpression of cortactin increased viral propagation. Ectopic expression of the siRNA-resistant cortactin recovered the viral infectivity, suggesting that cortactin was specifically required for HCV propagation. We further showed that cortactin was involved in the assembly step without affecting viral entry, HCV internal ribosome entry site (IRES)-mediated translation, and the replication steps of the HCV life cycle. Of note, silencing of cortactin markedly reduced both NS5A and core protein levels on the lipid droplets (LDs), and this effect was reversed by the overexpression of cortactin. Importantly, NS5A and core promoted cell migration by activating the phosphorylation of cortactin at tyrosine residues 421 and 466. Taken together, these data suggest that cortactin is not only involved in HCV assembly but also plays an important role in the cell migration.IMPORTANCE Cortactin is a cytoskeletal protein that regulates cell migration in response to a number of extracellular stimuli. The functional involvement of cortactin in the virus life cycle is not yet fully understood. The most significant finding is that cortactin strongly interacted with both hepatitis C virus (HCV) core and NS5A. Cortactin is involved in HCV assembly by tethering core and NS5A on the lipid droplets (LDs) with no effect on LD biogenesis. It was noteworthy that HCV NS5A and core activated cortactin by phosphorylation at tyrosines 421 and 466 to regulate cell migration. Collectively, our study shows that cortactin is a novel host factor involved in viral production and HCV-associated pathogenesis.
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13
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Barczak W, Jin L, Carr SM, Munro S, Ward S, Kanapin A, Samsonova A, La Thangue NB. PRMT5 promotes cancer cell migration and invasion through the E2F pathway. Cell Death Dis 2020; 11:572. [PMID: 32709847 PMCID: PMC7382496 DOI: 10.1038/s41419-020-02771-9] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2020] [Revised: 07/04/2020] [Accepted: 07/09/2020] [Indexed: 12/31/2022]
Abstract
The pRb-E2F pathway is a critical point of regulation in the cell cycle and loss of control of the pathway is a hallmark of cancer. E2F1 is the major target through which pRb exerts its effects and arginine methylation by PRMT5 plays a key role in dictating E2F1 activity. Here we have explored the functional role of the PRMT5-E2F1 axis and highlight its influence on different aspects of cancer cell biology including viability, migration, invasion and adherence. Through a genome-wide expression analysis, we identified a distinct set of genes under the control of PRMT5 and E2F1, including some highly regulated genes, which influence cell migration, invasio and adherence through a PRMT5-dependent mechanism. Most significantly, a coincidence was apparent between the expression of PRMT5 and E2F1 in human tumours, and elevated levels of PRMT5 and E2F1 correlated with poor prognosis disease. Our results suggest a causal relationship between PRMT5 and E2F1 in driving the malignant phenotype and thereby highlight an important pathway for therapeutic intervention.
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Affiliation(s)
- Wojciech Barczak
- Laboratory of Cancer Biology Department of Oncology, University of Oxford, Old Road Campus Research Building, Oxford, OX3 7DQ, UK
| | - Li Jin
- Laboratory of Cancer Biology Department of Oncology, University of Oxford, Old Road Campus Research Building, Oxford, OX3 7DQ, UK
| | - Simon Mark Carr
- Laboratory of Cancer Biology Department of Oncology, University of Oxford, Old Road Campus Research Building, Oxford, OX3 7DQ, UK
| | - Shonagh Munro
- Argonaut Therapeutics Ltd Magdalen Centre, Oxford Science Park, Oxford, OX4 4GA, UK
| | - Samuel Ward
- Argonaut Therapeutics Ltd Magdalen Centre, Oxford Science Park, Oxford, OX4 4GA, UK
| | - Alexander Kanapin
- Centre for Genome Bioinformatics, St. Petersburg State University, St. Petersburg, 199034, Russia
| | - Anastasia Samsonova
- Centre for Genome Bioinformatics, St. Petersburg State University, St. Petersburg, 199034, Russia
| | - Nicholas B La Thangue
- Laboratory of Cancer Biology Department of Oncology, University of Oxford, Old Road Campus Research Building, Oxford, OX3 7DQ, UK.
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14
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Zhao Y, Lei Y, He SW, Li YQ, Wang YQ, Hong XH, Liang YL, Li JY, Chen Y, Luo WJ, Zhang PP, Yang XJ, He QM, Ma J, Liu N, Tang LL. Hypermethylation of UCHL1 Promotes Metastasis of Nasopharyngeal Carcinoma by Suppressing Degradation of Cortactin (CTTN). Cells 2020; 9:E559. [PMID: 32120844 PMCID: PMC7140450 DOI: 10.3390/cells9030559] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2020] [Revised: 02/15/2020] [Accepted: 02/26/2020] [Indexed: 12/25/2022] Open
Abstract
Epigenetic regulation plays an important role in the development and progression of nasopharyngeal carcinoma (NPC), but the epigenetic mechanisms underlying NPC metastasis remain poorly understood. Here, we demonstrate that hypermethylation of the UCHL1 promoter leads to its downregulation in NPC. Restoration of UCHL1 inhibited the migration and invasion of NPC cells in vitro and in vivo, and knockdown of UCHL1 promoted NPC cell migration and invasion in vitro and in vivo. Importantly, we found that UCHL1 interacts with CTTN, and may function as a ligase promoting CTTN degradation by increasing K48-linked ubiquitination of CTTN. Additionally, restoration of CTTN in NPC cells that overexpressed UCHL1 rescued UCHL1 suppressive effects on NPC cell migration and invasion, which indicated that CTTN is a functional target of UCHL1 in NPC. Our findings revealed that UCHL1 acts as a tumor suppressor gene in NPC and thus provided a novel therapeutic target for NPC treatment.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | - Ling-Long Tang
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangzhou 510060, China; (Y.Z.); (Y.L.); (S.-W.H.); (Y.-Q.L.); (Y.-Q.W.); (X.-H.H.); (Y.-L.L.); (J.-Y.L.); (Y.C.); (W.-J.L.); (P.-P.Z.); (X.-J.Y.); (Q.-M.H.); (J.M.); (N.L.)
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15
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Sharafutdinov I, Backert S, Tegtmeyer N. Cortactin: A Major Cellular Target of the Gastric Carcinogen Helicobacter pylori. Cancers (Basel) 2020; 12:E159. [PMID: 31936446 PMCID: PMC7017262 DOI: 10.3390/cancers12010159] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2019] [Revised: 01/04/2020] [Accepted: 01/06/2020] [Indexed: 12/19/2022] Open
Abstract
Cortactin is an actin binding protein and actin nucleation promoting factor regulating cytoskeletal rearrangements in nearly all eukaryotic cell types. From this perspective, cortactin poses an attractive target for pathogens to manipulate a given host cell to their own benefit. One of the pathogens following this strategy is Helicobacter pylori, which can cause a variety of gastric diseases and has been shown to be the major risk factor for the onset of gastric cancer. During infection of gastric epithelial cells, H. pylori hijacks the cellular kinase signaling pathways, leading to the disruption of key cell functions. Specifically, by overruling the phosphorylation status of cortactin, H. pylori alternates the activity of molecular interaction partners of this important protein, thereby manipulating the performance of actin-cytoskeletal rearrangements and cell movement. In addition, H. pylori utilizes a unique mechanism to activate focal adhesion kinase, which subsequently prevents host epithelial cells from extensive lifting from the extracellular matrix in order to achieve chronic infection in the human stomach.
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Affiliation(s)
| | | | - Nicole Tegtmeyer
- Division of Microbiology, Department of Biology, Friedrich Alexander University Erlangen-Nuremberg, Staudtstr. 5, D-91058 Erlangen, Germany; (I.S.); (S.B.)
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16
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Multiple novel hepatocellular carcinoma signature genes are commonly controlled by the master pluripotency factor OCT4. Cell Oncol (Dordr) 2019; 43:279-295. [PMID: 31848930 DOI: 10.1007/s13402-019-00487-3] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/22/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Worldwide, hepatocellular carcinoma (HCC) is a common solid tumor with a poor prognosis. HCC is often due to hepatitis B virus (HBV) infection. As yet, efficacious HCC treatment regimens for late-stage HCC patients are lacking. Therefore, the identification of more specific and sensitive biomarkers for its early diagnosis and treatment remains an urgent need. METHODS Total RNAs from paired HBV-derived HCC tumors and adjacent peritumor tissues (APTs) were subjected to RNA sequencing (RNA-seq), and differentially expressed genes (DEGs) between HCC tumors and APTs were selected and verified. RESULTS We identified 166 DEGs and found that eight top-ranked and verified DEGs (TK1, CTTN, CEP72, TRIP13, FTH1, FLAD1, CHRM2, AMBP) all contained putative OCT4 binding motifs in their promoter regions. TK1, TRIP13 and OCT4 were found to exhibit concurrent higher expression levels in HCC tumors than in APTs. The mRNA levels of TK1, TRIP13 and OCT4 in a cohort of 384 HCC samples from the TCGA database were all found to be negatively correlated with patient overall survival, relapse-free survival and progression-free survival, underscoring the HCC biomarker status of TK1 and TRIP13 on one hand, and implicating their association with OCT4 on the other hand. Furthermore, OCT4 proteins were found to bind to the promoters of both genes in vitro and in vivo. Knocking out OCT4 in HCC-derived cell lines reduced the expression of TK1 and TRIP13 and significantly decreased their tumorigenicity. CONCLUSIONS Using RNA-seq, we identified several novel HCC signature genes that may serve as biomarkers for its diagnosis and prognosis. Their common transcriptional regulation by OCT4 suggests key roles in the development of HCC, and indicates that OCT4 may serve as a potential therapeutic target.
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17
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Li Y, Fu Y, Hu X, Sun L, Tang D, Li N, Peng F, Fan XG. The HBx-CTTN interaction promotes cell proliferation and migration of hepatocellular carcinoma via CREB1. Cell Death Dis 2019; 10:405. [PMID: 31138777 PMCID: PMC6538608 DOI: 10.1038/s41419-019-1650-x] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2018] [Revised: 04/30/2019] [Accepted: 05/03/2019] [Indexed: 02/06/2023]
Abstract
Hepatitis B virus-encoded X protein (HBx) acts as a tumor promoter during hepatocellular carcinoma (HCC) development, probably by regulating the expression of host proteins through protein–protein interaction. A proteomics approach was used to identify HBx-interacting proteins involved in HBx-induced hepatocarcinogenesis. We validated the proteomics findings by co-immunoprecipitation and confocal microscopy. We performed cell proliferation, migration assays and cell cycle analyses in HCC cells. Finally, we confirmed the clinical significance of our findings in samples from patients. We found that cortactin (CTTN) is a novel HBx-interacting protein, and HBx regulates the expression of CTTN in the HCC cell lines MHCC-LM3 and HepG2. Mechanistically, by upregulating the expression of cAMP response element-binding protein (CREB1) and its downstream targets, such as cyclin D1 and MMP-9, the effects of the HBx-CTTN interaction on the enhancement of cellular proliferation and migration were maintained by inhibiting cell cycle arrest. In addition, we demonstrated that the levels of CTTN and CREB1 were closely correlated in clinical samples from HBV-infected patients with HCC. Overall, our data suggests that HBx contributes to cell migration and proliferation of HCC cells by interacting with CTTN and regulating the expression of CTTN and CREB1. Therefore, the HBx/CTTN/CREB1 axis is a potential novel therapeutic target in HCC.
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Affiliation(s)
- Yajun Li
- Department of Infectious Diseases and Hunan Key Laboratory of Viral Hepatitis, Xiangya Hospital, Central South University, Changsha, China
| | - Yongming Fu
- Department of Infectious Diseases and Hunan Key Laboratory of Viral Hepatitis, Xiangya Hospital, Central South University, Changsha, China
| | - Xingwang Hu
- Department of Infectious Diseases and Hunan Key Laboratory of Viral Hepatitis, Xiangya Hospital, Central South University, Changsha, China
| | - Lunquan Sun
- Center for Molecular Medicine, Xiangya Hospital, Central South University, Changsha, China
| | - Daolin Tang
- Department of Surgery, UT Southwestern Medical Center, Dallas, Texas, USA
| | - Ning Li
- Department of Blood Transfusion, Xiangya Hospital, Central South University, Changsha, China
| | - Fang Peng
- NHC Key Laboratory of Cancer Proteomics, XiangYa Hospital, Central South University, Changsha, China.
| | - Xue-Gong Fan
- Department of Infectious Diseases and Hunan Key Laboratory of Viral Hepatitis, Xiangya Hospital, Central South University, Changsha, China.
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18
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Stock K, Borrink R, Mikesch JH, Hansmeier A, Rehkämper J, Trautmann M, Wardelmann E, Hartmann W, Sperveslage J, Steinestel K. Overexpression and Tyr421-phosphorylation of cortactin is induced by three-dimensional spheroid culturing and contributes to migration and invasion of pancreatic ductal adenocarcinoma (PDAC) cells. Cancer Cell Int 2019; 19:77. [PMID: 30976201 PMCID: PMC6441202 DOI: 10.1186/s12935-019-0798-x] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2018] [Accepted: 03/23/2019] [Indexed: 01/06/2023] Open
Abstract
BACKGROUND The nucleation-promoting factor cortactin is expressed and promotes tumor progression and metastasis in various cancers. However, little is known about the biological role of cortactin in the progression of pancreatic ductal adenocarcinoma (PDAC). METHODS Cortactin and phosphorylated cortactin (Y421) were investigated immunohistochemically in 66 PDAC tumor specimens. To examine the functional role of cortactin in PDAC, we modulated cortactin expression by establishing two cortactin knockout cell lines (Panc-1 and BxPC-3) with CRISPR/Cas9 technique. Cortactin knockout was verified by immunoblotting and immunofluorescence microscopy and functional effects were determined by cell migration and invasion assays. A proteomic screening approach was performed to elucidate potential binding partners of cortactin. RESULTS Immunohistochemically, we observed higher cortactin expression and Tyr421-phosphorylation in PDAC metastases compared to primary tumor tissues. In PDAC cell lines Panc-1 and BxPC-3, knockdown of cortactin impaired migration and invasion, while cell proliferation was not affected. Three-dimensional spheroid culturing as a model for collective cell migration enhanced cortactin expression and Tyr421-phosphorylation. The activation of cortactin as well as the migratory capacity of PDAC cells could significantly be reduced by dasatinib, a Src family kinase inhibitor. Finally, we identified gelsolin as a novel protein interaction partner of cortactin in PDAC. CONCLUSION Our data provides evidence that cohesive cell migration induces cortactin expression and phosphorylation as a prerequisite for the gain of an invasive, pro-migratory phenotype in PDAC that can effectively be targeted with dasatinib.
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Affiliation(s)
- Katharina Stock
- Gerhard-Domagk-Institute of Pathology, University Hospital Münster, Münster, Germany
| | - Rebekka Borrink
- Gerhard-Domagk-Institute of Pathology, University Hospital Münster, Münster, Germany
| | | | - Anna Hansmeier
- Department of Medicine A, University Hospital Münster, Münster, Germany
| | - Jan Rehkämper
- Gerhard-Domagk-Institute of Pathology, University Hospital Münster, Münster, Germany
| | - Marcel Trautmann
- Gerhard-Domagk-Institute of Pathology, University Hospital Münster, Münster, Germany
- Division of Translational Pathology, Gerhard-Domagk-Institute of Pathology, University Hospital Münster, Münster, Germany
| | - Eva Wardelmann
- Gerhard-Domagk-Institute of Pathology, University Hospital Münster, Münster, Germany
| | - Wolfgang Hartmann
- Gerhard-Domagk-Institute of Pathology, University Hospital Münster, Münster, Germany
- Division of Translational Pathology, Gerhard-Domagk-Institute of Pathology, University Hospital Münster, Münster, Germany
| | - Jan Sperveslage
- Gerhard-Domagk-Institute of Pathology, University Hospital Münster, Münster, Germany
| | - Konrad Steinestel
- Gerhard-Domagk-Institute of Pathology, University Hospital Münster, Münster, Germany
- Institute of Pathology and Molecular Pathology, Bundeswehrkrankenhaus Ulm, Ulm, Germany
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19
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Cortactin as a potential predictor of second esophageal neoplasia in hypopharyngeal carcinoma. Auris Nasus Larynx 2018; 46:260-266. [PMID: 30107961 DOI: 10.1016/j.anl.2018.08.002] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2018] [Revised: 06/22/2018] [Accepted: 08/01/2018] [Indexed: 12/20/2022]
Abstract
OBJECTIVE Hypopharyngeal carcinoma has a very poor prognosis. The high incidence of second esophageal neoplasia is one of the major causes. To establish an efficient follow-up scheme for increasing the diagnostic yield and reducing the adverse impact of second esophageal neoplasia on survival, the purpose of this study was to explore a biomarker to predict second esophageal neoplasia. METHODS In this retrospective cohort study, consecutive tissue specimens from those patients who underwent tumor resection between September 2007 and October 2015 were collected. Gene amplification was performed by real-time PCR. The expression of cortactin was evaluated by immunohistochemistry. The predictive risk factors of developing second esophageal neoplasia and prognostic factors related to survival were analyzed. RESULTS A total of 187 patients were included with a mean follow-up of 48months (12-118months). Second esophageal tumors were found in 53 (28.3%), including 41 (21.9%) esophageal squamous cell carcinoma and 12 severe dysplasia. The results of multivariate analyses revealed that age (OR 2.81, 95% CI 1.16-6.78), cortactin overexpression (OR 2.49, 95% CI 1.17-5.33), and stage IV versus I (OR 6.49, 95% CI 1.68-25.18) were independent predictors of second esophageal neoplasia, and second esophageal neoplasia (HR 1.78, 95% CI 1.05-3.01) was an independent predictor of overall survival. CONCLUSION This is the first report to identify a potential biomarker for predicting second esophageal neoplasia in patients with hypopharyngeal carcinoma. In those patients with cortactin overexpression and younger age (≤60years old), close surveillance for second esophageal neoplasia is required. In addition, the real effect of cortactin overexpression on development of primary esophageal carcinoma is required to be validated in a large cohort study.
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20
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Ramos-García P, González-Moles MÁ, González-Ruiz L, Ayén Á, Ruiz-Ávila I, Navarro-Triviño FJ, Gil-Montoya JA. An update of knowledge on cortactin as a metastatic driver and potential therapeutic target in oral squamous cell carcinoma. Oral Dis 2018; 25:949-971. [PMID: 29878474 DOI: 10.1111/odi.12913] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2018] [Revised: 05/15/2018] [Accepted: 06/05/2018] [Indexed: 12/12/2022]
Abstract
Cortactin is a protein encoded by the CTTN gene, localized on chromosome band 11q13. As a result of the amplification of this band, an important event in oral carcinogenesis, CTTN is also usually amplified, promoting the frequent overexpression of cortactin. Cortactin enhances cell migration in oral cancer, playing a key role in the regulation of filamentous actin and of protrusive structures (invadopodia and lamellipodia) on the cell membrane that are necessary for the acquisition of a migratory phenotype. We also analyze a series of emerging functions that cortactin may exert in oral cancer (cell proliferation, angiogenesis, regulation of exosomes, and interactions with the tumor microenvironment). We review its molecular structure, its most important interactions (with Src, Arp2/3 complex, and SH3-binding partners), the regulation of its functions, and its specific oncogenic role in oral cancer. We explore the mechanisms of its overexpression in cancer, mainly related to genetic amplification. We analyze the prognostic implications of the oncogenic activation of cortactin in potentially malignant disorders and in head and neck cancer, where it appears to be relevant in the development of lymph node metastasis. Finally, we discuss its usefulness as a therapeutic target and suggest future research lines.
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Affiliation(s)
| | - Miguel Ángel González-Moles
- School of Dentistry, University of Granada, Granada, Spain.,Instituto de Investigación Biosanitaria, Granada, Spain
| | - Lucía González-Ruiz
- Servicio de Dermatología, Hospital General Universitario de Ciudad Real, Ciudad Real, Spain
| | - Ángela Ayén
- School of Medicine, University of Granada, Granada, Spain
| | - Isabel Ruiz-Ávila
- Instituto de Investigación Biosanitaria, Granada, Spain.,Servicio de Anatomía Patológica, Complejo Hospitalario Universitario de Granada, Granada, Spain
| | | | - José Antonio Gil-Montoya
- School of Dentistry, University of Granada, Granada, Spain.,Instituto de Investigación Biosanitaria, Granada, Spain
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21
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Bertier L, Hebbrecht T, Mettepenningen E, De Wit N, Zwaenepoel O, Verhelle A, Gettemans J. Nanobodies targeting cortactin proline rich, helical and actin binding regions downregulate invadopodium formation and matrix degradation in SCC-61 cancer cells. Biomed Pharmacother 2018; 102:230-241. [DOI: 10.1016/j.biopha.2018.03.064] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2017] [Revised: 03/10/2018] [Accepted: 03/12/2018] [Indexed: 01/19/2023] Open
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22
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Cortactin recruits FMNL2 to promote actin polymerization and endosome motility in invadopodia formation. Cancer Lett 2018; 419:245-256. [DOI: 10.1016/j.canlet.2018.01.023] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2017] [Revised: 12/23/2017] [Accepted: 01/08/2018] [Indexed: 01/28/2023]
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23
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Zhang X, Liu K, Zhang T, Wang Z, Qin X, Jing X, Wu H, Ji X, He Y, Zhao R. Cortactin promotes colorectal cancer cell proliferation by activating the EGFR-MAPK pathway. Oncotarget 2018; 8:1541-1554. [PMID: 27903975 PMCID: PMC5352075 DOI: 10.18632/oncotarget.13652] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2016] [Accepted: 11/15/2016] [Indexed: 02/07/2023] Open
Abstract
Cortactin (CTTN) is overexpressed in various tumors, including head and neck squamous cell carcinoma and colorectal cancer (CRC), and can serve as a biomarker of cancer metastasis. We observed that CTTN promotes cancer cell proliferation in vitro and increases CRC tumor xenograft growth in vivo. CTTN expression increases EGFR protein levels and enhances the activation of the MAPK signaling pathway. CTTN expression also inhibits the ubiquitin-mediated degradation of EGFR by suppressing the coupling of c-Cbl with EGFR. CoIP experiments indicate CTTN can interact with c-Cbl in CRC cells. These results demonstrate that CTTN promotes the proliferation of CRC cells and suppresses the degradation of EGFR.
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Affiliation(s)
- Xiaojian Zhang
- Department of Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China.,Shanghai Institute of Digestive Surgery, Shanghai, People's Republic of China
| | - Kun Liu
- Department of Surgery, Ruijin Hospital North, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China
| | - Tao Zhang
- Department of Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China
| | - Zhenlei Wang
- Department of Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China.,Department of Surgery, Henan Cancer Hospital, The Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, Henan Province, People's Republic of China
| | - Xuan Qin
- Department of Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China.,Shanghai Institute of Digestive Surgery, Shanghai, People's Republic of China
| | - Xiaoqian Jing
- Department of Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China.,Shanghai Institute of Digestive Surgery, Shanghai, People's Republic of China
| | - Haoxuan Wu
- Department of Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China.,Shanghai Institute of Digestive Surgery, Shanghai, People's Republic of China
| | - Xiaopin Ji
- Department of Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China
| | - Yonggang He
- Department of Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China
| | - Ren Zhao
- Department of Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China
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Abstract
Actin remodeling plays an essential role in diverse cellular processes such as cell motility, vesicle trafficking or cytokinesis. The scaffold protein and actin nucleation promoting factor Cortactin is present in virtually all actin-based structures, participating in the formation of branched actin networks. It has been involved in the control of endocytosis, and vesicle trafficking, axon guidance and organization, as well as adhesion, migration and invasion. To migrate and invade through three-dimensional environments, cells have developed specialized actin-based structures called invadosomes, a generic term to designate invadopodia and podosomes. Cortactin has emerged as a critical regulator of invadosome formation, function and disassembly. Underscoring this role, Cortactin is frequently overexpressed in several types of invasive cancers. Herein we will review the roles played by Cortactin in these specific invasive structures.
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Affiliation(s)
- Pauline Jeannot
- CRCT INSERM UMR1037, Université Toulouse III Paul Sabatier , CNRS ERL5294, Toulouse, France.,Cell Signalling Group, Cancer Research UK Manchester Institute, The University of Manchester , Manchester M20 4BX, UK
| | - Arnaud Besson
- CRCT INSERM UMR1037, Université Toulouse III Paul Sabatier , CNRS ERL5294, Toulouse, France.,LBCMCP , Centre de Biologie Intégrative, Université de Toulouse , CNRS, UPS, Toulouse Cedex, France
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25
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Yin M, Ma W, An L. Cortactin in cancer cell migration and invasion. Oncotarget 2017; 8:88232-88243. [PMID: 29152154 PMCID: PMC5675706 DOI: 10.18632/oncotarget.21088] [Citation(s) in RCA: 54] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2016] [Accepted: 08/29/2017] [Indexed: 12/20/2022] Open
Abstract
Cortactin, a substrate of sarcoma (Src) kinases, is an actin-binding protein that is involved in cytoskeletal regulation, and is frequently overexpressed in cancer cells. Binding to the actin related protein 2/3 (Arp2/3) complex stimulates cortactin activity, which promotes F-actin nucleation and assembly. Cortactin promotes cancer cell migration and invasion, and plays a pivotal role in invadopodia formation and extra cellular matrix degradation. Overexpression of cortactin, by amplification of the chromosomal band 11q13, increases tumor aggressiveness. In this review, we report on the current knowledge and potential mechanisms of action of cortactin as a critical mediator of cancer cell migration and invasion.
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Affiliation(s)
- Miao Yin
- Shandong Provincial Key Laboratory of Animal Resistance Biology, College of Life Sciences, Shandong Normal University, Jinan 250014, China
| | - Wenqing Ma
- Shandong Provincial Key Laboratory of Animal Resistance Biology, College of Life Sciences, Shandong Normal University, Jinan 250014, China
| | - Liguo An
- Shandong Provincial Key Laboratory of Animal Resistance Biology, College of Life Sciences, Shandong Normal University, Jinan 250014, China
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26
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Liu YC, Ho HC, Lee MR, Yeh CM, Tseng HC, Lin YC, Chung JG. Cortactin is a prognostic marker for oral squamous cell carcinoma and its overexpression is involved in oral carcinogenesis. ENVIRONMENTAL TOXICOLOGY 2017; 32:799-812. [PMID: 27148699 DOI: 10.1002/tox.22280] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/03/2016] [Revised: 04/13/2016] [Accepted: 04/17/2016] [Indexed: 06/05/2023]
Abstract
EMS1 (chromosome eleven, band q13, mammary tumor and squamous cell carcinoma-associated gene 1) gene amplification and the concomitant cortactin overexpression have been reported to associate with poor prognosis and tumor metastasis. In this study, we examined cortactin expression by immunohistochemistry in human oral tumors and murine tongue tumors which were induced by the carcinogen 4-nitroquinoline 1-oxide (4-NQO). The immunostaining results show over- to moderate expression of cortactin in 85% (104/122) of oral squamous cell carcinoma (OSCC) tissues and in all 15 leukoplakia tissues examined. Further, statistical analysis indicates that cortactin overexpression appears to be a predictor for shorter survival and poorer prognosis in OSCC patients. In an animal model, cortactin is shown to upregulate in infiltrating squamous cell carcinoma, papilloma, and epithelia with squamous hyperplasia, indicating that cortactin induction is an early event during oral carcinogenesis. It is suggested that cortactin expression is mediated in the progression of pre-malignancy to papilloma, based on earlier cortactin induction in pre-malignancy preceding cyclin D1 in papilloma. In conclusion, cortactin overexpression is frequently observed in human OSCC and mouse tongue tumors. Thus, cortactin may have an important role in the development of oral tumors in human and mice. © 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 799-812, 2017.
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Affiliation(s)
- Yu-Ching Liu
- Department of Medical Research, China Medical University Hospital, Taichung, Taiwan
- Department of Veterinary Medicine, National Chung Hsing University, Taichung, Taiwan
| | - Heng-Chien Ho
- Departments of Biochemistry, China Medical University, Taichung, Taiwan
| | - Miau-Rong Lee
- Departments of Biochemistry, China Medical University, Taichung, Taiwan
| | - Chung-Min Yeh
- Department of Pathology, Changhua Christian Hospital, Changhua, Taiwan
| | - Hsien-Chang Tseng
- Department of Otolaryngology, China Medical University Hospital, Taichung, Taiwan
| | - Yung-Chang Lin
- Department of Veterinary Medicine, National Chung Hsing University, Taichung, Taiwan
| | - Jing-Gung Chung
- Departments of Biological Science and Technology, China Medical University, Taichung, 404, Taiwan
- Department of Biotechnology, Asia University, Taichung, 413, Taiwan
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27
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Lu Z, Dong TH, Si PR, Shen W, Bi YL, Min M, Chen X, Liu Y. Continuous Low-dose-rate Irradiation of Iodine-125 Seeds Inhibiting Perineural Invasion in Pancreatic Cancer. Chin Med J (Engl) 2017; 129:2460-2468. [PMID: 27748339 PMCID: PMC5072259 DOI: 10.4103/0366-6999.191777] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
Background: Perineural invasion (PNI) is a histopathological characteristic of pancreatic cancer (PanCa). The aim of this study was to observe the treatment effect of continuous low-dose-rate (CLDR) irradiation to PNI and assess the PNI-related pain relief caused by iodine-125 (125I) seed implantation. Methods: The in vitro PNI model established by co-culture with dorsal root ganglion (DRG) and cancer cells was interfered under 2 and 4 Gy of 125I seeds CLDR irradiation. The orthotopic models of PNI were established, and 125I seeds were implanted in tumor. The PNI-related molecules were analyzed. In 30 patients with panCa, the pain relief was assessed using a visual analog scale (VAS). Pain intensity was measured before and 1 week, 2 weeks, and 1, 3, and 6 months after 125I seed implantation. Results: The co-culture of DRG and PanCa cells could promote the growth of PanCa cells and DRG neurites. In co-culture groups, the increased number of DRG neurites and pancreatic cells in radiation group was significantly less. In orthotopic models, the PNI-positive rate in radiation and control group was 3/11 and 7/11; meanwhile, the degrees of PNI between radiation and control groups was significant difference (P < 0.05). At week 2, the mean VAS pain score in patients decreased by 50% and significantly improved than the score at baseline (P < 0.05). The pain scores were lower in all patients, and the pain-relieving effect was retained about 3 months. Conclusions: The CLDR irradiation could inhibit PNI of PanCa with the value of further study. The CLDR irradiation could do great favor in preventing local recurrence and alleviating pain.
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Affiliation(s)
- Zheng Lu
- Liver Cirrhosis Diagnosis and Therapy Center, 302 Hospital of People's Liberation Army, Beijing 100039, China
| | - Teng-Hui Dong
- Department of Gastroenterology and Hepatology, 307 Hospital of People's Liberation Army, Academy of Military Medical Sciences, Beijing 100071, China
| | - Pei-Ren Si
- Department of Gastroenterology and Hepatology, 107 Hospital of People's Liberation Army, Yantai, Shandong 264002, China
| | - Wei Shen
- Department of Gastroenterology and Hepatology, 307 Hospital of People's Liberation Army, Academy of Military Medical Sciences, Beijing 100071, China
| | - Yi-Liang Bi
- Department of Gastroenterology and Hepatology, 307 Hospital of People's Liberation Army, Academy of Military Medical Sciences, Beijing 100071, China
| | - Min Min
- Department of Gastroenterology and Hepatology, 307 Hospital of People's Liberation Army, Academy of Military Medical Sciences, Beijing 100071, China
| | - Xin Chen
- Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, CA 94143-0912, USA
| | - Yan Liu
- Department of Gastroenterology and Hepatology, 307 Hospital of People's Liberation Army, Academy of Military Medical Sciences, Beijing 100071, China
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Wang H, Liu X, Long M, Huang Y, Zhang L, Zhang R, Zheng Y, Liao X, Wang Y, Liao Q, Li W, Tang Z, Tong Q, Wang X, Fang F, Rojo de la Vega M, Ouyang Q, Zhang DD, Yu S, Zheng H. NRF2 activation by antioxidant antidiabetic agents accelerates tumor metastasis. Sci Transl Med 2016; 8:334ra51. [PMID: 27075625 DOI: 10.1126/scitranslmed.aad6095] [Citation(s) in RCA: 156] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2015] [Accepted: 02/18/2016] [Indexed: 12/18/2022]
Abstract
Cancer is a common comorbidity of diabetic patients; however, little is known about the effects that antidiabetic drugs have on tumors. We discovered that common classes of drugs used in type 2 diabetes mellitus, the hypoglycemic dipeptidyl peptidase-4 inhibitors (DPP-4i) saxagliptin and sitagliptin, as well as the antineuropathic α-lipoic acid (ALA), do not increase tumor incidence but increase the risk of metastasis of existing tumors. Specifically, these drugs induce prolonged activation of the nuclear factor E2-related factor 2 (NRF2)-mediated antioxidant response through inhibition of KEAP1-C151-dependent ubiquitination and subsequent degradation of NRF2, resulting in up-regulated expression of metastasis-associated proteins, increased cancer cell migration, and promotion of metastasis in xenograft mouse models. Accordingly, knockdown of NRF2 attenuated naturally occurring and DPP-4i-induced tumor metastasis, whereas NRF2 activation accelerated metastasis. Furthermore, in human liver cancer tissue samples, increased NRF2 expression correlated with metastasis. Our findings suggest that antioxidants that activate NRF2 signaling may need to be administered with caution in cancer patients, such as diabetic patients with cancer. Moreover, NRF2 may be a potential biomarker and therapeutic target for tumor metastasis.
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Affiliation(s)
- Hui Wang
- Department of Endocrinology, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, China
| | - Xiufei Liu
- Department of Endocrinology, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, China
| | - Min Long
- Department of Endocrinology, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, China
| | - Yi Huang
- Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Pediatrics, Chongqing Key Laboratory of Immunity and Infectious Diseases, Children's Hospital of Chongqing Medical University, Chongqing 400014, China
| | - Linlin Zhang
- Department of Endocrinology, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, China
| | - Rui Zhang
- Department of Endocrinology, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, China
| | - Yi Zheng
- Department of Endocrinology, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, China
| | - Xiaoyu Liao
- Department of Endocrinology, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, China
| | - Yuren Wang
- Department of Endocrinology, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, China
| | - Qian Liao
- Department of Endocrinology, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, China
| | - Wenjie Li
- Department of Endocrinology, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, China
| | - Zili Tang
- Molecular and Translational Radiation Oncology, Heidelberg Ion Therapy Center, Heidelberg Institute of Radiation Oncology, University of Heidelberg Medical School, National Center for Cancer Diseases, German Cancer Research Center, Heidelberg 69120, Germany
| | - Qiang Tong
- Department of Endocrinology, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, China
| | - Xiaocui Wang
- Department of Endocrinology, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, China
| | - Fang Fang
- Department of Endocrinology, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, China
| | - Montserrat Rojo de la Vega
- Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, Tucson, AZ 85721, USA
| | - Qin Ouyang
- College of Pharmacy, Third Military Medical University, Chongqing 400038, China
| | - Donna D Zhang
- Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, Tucson, AZ 85721, USA.
| | - Shicang Yu
- Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing 400038, China.
| | - Hongting Zheng
- Department of Endocrinology, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, China.
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Menyhárt O, Harami-Papp H, Sukumar S, Schäfer R, Magnani L, de Barrios O, Győrffy B. Guidelines for the selection of functional assays to evaluate the hallmarks of cancer. Biochim Biophys Acta Rev Cancer 2016; 1866:300-319. [PMID: 27742530 DOI: 10.1016/j.bbcan.2016.10.002] [Citation(s) in RCA: 77] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2016] [Revised: 10/06/2016] [Accepted: 10/08/2016] [Indexed: 01/05/2023]
Abstract
The hallmarks of cancer capture the most essential phenotypic characteristics of malignant transformation and progression. Although numerous factors involved in this multi-step process are still unknown to date, an ever-increasing number of mutated/altered candidate genes are being identified within large-scale cancer genomic projects. Therefore, investigators need to be aware of available and appropriate techniques capable of determining characteristic features of each hallmark. We review the methods tailored to experimental cancer researchers to evaluate cell proliferation, programmed cell death, replicative immortality, induction of angiogenesis, invasion and metastasis, genome instability, and reprogramming of energy metabolism. Selecting the ideal method is based on the investigator's goals, available equipment and also on financial constraints. Multiplexing strategies enable a more in-depth data collection from a single experiment - obtaining several results from a single procedure reduces variability and saves time and relative cost, leading to more robust conclusions compared to a single end point measurement. Each hallmark possesses characteristics that can be analyzed by immunoblot, RT-PCR, immunocytochemistry, immunoprecipitation, RNA microarray or RNA-seq. In general, flow cytometry, fluorescence microscopy, and multiwell readers are extremely versatile tools and, with proper sample preparation, allow the detection of a vast number of hallmark features. Finally, we also provide a list of hallmark-specific genes to be measured in transcriptome-level studies. Although our list is not exhaustive, we provide a snapshot of the most widely used methods, with an emphasis on methods enabling the simultaneous evaluation of multiple hallmark features.
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Affiliation(s)
- Otília Menyhárt
- MTA TTK Lendület Cancer Biomarker Research Group, Magyar tudósok körútja 2, H-1117 Budapest, Hungary
| | | | - Saraswati Sukumar
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Reinhold Schäfer
- German Cancer Consortium (DKTK), DKFZ, Im Neuenheimer Feld 280, D-69120 Heidelberg and Charité Comprehensive Cancer Center, Invalidenstr. 80, D-10115 Berlin, Germany
| | - Luca Magnani
- Department of Surgery and Cancer, Imperial College London, London W12 0NN, UK
| | - Oriol de Barrios
- Group of Transcriptional Regulation of Gene Expression, Department of Oncology and Hematology, IDIBAPS, Barcelona, Spain
| | - Balázs Győrffy
- MTA TTK Lendület Cancer Biomarker Research Group, Magyar tudósok körútja 2, H-1117 Budapest, Hungary; 2nd Department of Pediatrics, Semmelweis University, H-1094 Budapest, Hungary.
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Li T, Xue Y, Wang G, Gu T, Li Y, Zhu YY, Chen L. Multi-target siRNA: Therapeutic Strategy for Hepatocellular Carcinoma. J Cancer 2016; 7:1317-27. [PMID: 27390607 PMCID: PMC4934040 DOI: 10.7150/jca.15157] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2016] [Accepted: 05/18/2016] [Indexed: 12/23/2022] Open
Abstract
Multiple targets RNAi strategy is a preferred way to treat multigenic diseases, especially cancers. In the study, multi-target siRNAs were designed to inhibit NET-1, EMS1 and VEGF genes in hepatocellular carcinoma (HCC) cells. And multi-target siRNAs showed better silencing effects on NET-1, EMS1 and VEGF, compared with single target siRNA. Moreover, multi-target siRNA showed greater suppression effects on proliferation, migration, invasion, angiogenesis and induced apoptosis in HCC cells. The results suggested that multi-target siRNA might be a preferred strategy for cancer therapy and NET-1, EMS1 and VEGF could be effective targets for HCC treatments.
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Affiliation(s)
- Tiejun Li
- 1. Department of Pathological Anatomy, Nantong University, Nantong, China;; 2. Small RNA Technology and Application Institute, Nantong University, Nantong, China;; 3. Biomics Biotechnologies Co., Ltd., Nantong, China
| | - Yuwen Xue
- 1. Department of Pathological Anatomy, Nantong University, Nantong, China
| | - Guilan Wang
- 1. Department of Pathological Anatomy, Nantong University, Nantong, China
| | - Tingting Gu
- 1. Department of Pathological Anatomy, Nantong University, Nantong, China
| | - Yunlong Li
- 1. Department of Pathological Anatomy, Nantong University, Nantong, China
| | - York Yuanyuan Zhu
- 2. Small RNA Technology and Application Institute, Nantong University, Nantong, China;; 3. Biomics Biotechnologies Co., Ltd., Nantong, China
| | - Li Chen
- 1. Department of Pathological Anatomy, Nantong University, Nantong, China
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Wang Y, Qin J, Liu Q, Hong X, Li T, Zhu Y, He L, Zheng B, Li M. SNF2H promotes hepatocellular carcinoma proliferation by activating the Wnt/β-catenin signaling pathway. Oncol Lett 2016; 12:1329-1336. [PMID: 27446433 PMCID: PMC4950594 DOI: 10.3892/ol.2016.4681] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2014] [Accepted: 05/10/2016] [Indexed: 01/30/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide and has an extremely poor prognosis. Surgical resection is always inapplicable to HCC patients diagnosed at an advanced tumor stage. The mechanisms underlying HCC cell proliferation remain obscure. In the present study, SWItch/sucrose nonfermentable catalytic subunit SNF2 (SNF2H) expression was tested in HCC tissues and Wnt/β-catenin pathway activation upon overexpression of SNF2H or knockdown of SNF2H expression was investigated in cultured HCC cells. It was demonstrated that SNF2H is a vital factor for HCC growth. The SNF2H expression level is increased in HCC tissues compared with paratumoral liver tissues. SNF2H promotes HCC cell proliferation and colony formation ability in vitro. SNF2H may increase the protein level of β-catenin and enhance its nuclear accumulation in HCC cells, thereby leading to the activation of the Wnt/β-catenin signaling pathway. In conclusion, the present results indicate that SNF2H plays a vital role in HCC cell growth, suggesting that SNF2H may be a promising therapeutic target for HCC treatment.
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Affiliation(s)
- Yanan Wang
- Department of Laboratory Medicine, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200240, P.R. China
| | - Juanxiu Qin
- Department of Laboratory Medicine, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200240, P.R. China
| | - Qian Liu
- Department of Laboratory Medicine, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200240, P.R. China
| | - Xufen Hong
- Department of Laboratory Medicine, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai 200032, P.R. China
| | - Tianming Li
- Department of Laboratory Medicine, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200240, P.R. China
| | - Yuanjun Zhu
- Department of Laboratory Medicine, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai 200032, P.R. China
| | - Lei He
- Department of Laboratory Medicine, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200240, P.R. China
| | - Bing Zheng
- Department of Laboratory Medicine, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200240, P.R. China
| | - Min Li
- Department of Laboratory Medicine, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200240, P.R. China
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LONG HAOCHENG, GAO XIA, LEI CHANGJIANG, ZHU BIN, LI LEI, ZENG CHENG, HUANG JIANBIN, FENG JIARUI. miR-542-3p inhibits the growth and invasion of colorectal cancer cells through targeted regulation of cortactin. Int J Mol Med 2016; 37:1112-8. [DOI: 10.3892/ijmm.2016.2505] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2015] [Accepted: 02/08/2016] [Indexed: 11/05/2022] Open
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Expression and clinical significance of cortactin protein in ovarian neoplasms. Clin Transl Oncol 2015; 18:220-7. [DOI: 10.1007/s12094-015-1360-5] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2015] [Accepted: 07/13/2015] [Indexed: 12/30/2022]
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Regulators of Actin Dynamics in Gastrointestinal Tract Tumors. Gastroenterol Res Pract 2015; 2015:930157. [PMID: 26345720 PMCID: PMC4539459 DOI: 10.1155/2015/930157] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/15/2015] [Revised: 07/09/2015] [Accepted: 07/21/2015] [Indexed: 02/07/2023] Open
Abstract
Reorganization of the actin cytoskeleton underlies cell migration in a wide variety of physiological and pathological processes, such as embryonic development, wound healing, and tumor cell invasion. It has been shown that actin assembly and disassembly are precisely regulated by intracellular signaling cascades that respond to changes in the cell microenvironment, ligand binding to surface receptors, or oncogenic transformation of the cell. Actin-nucleating and actin-depolymerizing (ANFs/ADFs) and nucleation-promoting factors (NPFs) regulate cytoskeletal dynamics at the leading edge of migrating cells, thereby modulating cell shape; these proteins facilitate cellular movement and mediate degradation of the surrounding extracellular matrix by secretion of lytic proteases, thus eliminating barriers for tumor cell invasion. Accordingly, expression and activity of these actin-binding proteins have been linked to enhanced metastasis and poor prognosis in a variety of malignancies. In this review, we will summarize what is known about expression patterns and the functional role of actin regulators in gastrointestinal tumors and evaluate first pharmacological approaches to prevent invasion and metastatic dissemination of malignant cells.
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Kim DY, Lee JH, Kim KY, Kang DB, Park WC, Chae SC, Lee JK. Association between genetic polymorphisms in cortactin and susceptibility to gastric cancer. Ann Surg Treat Res 2015; 89:74-80. [PMID: 26236696 PMCID: PMC4518033 DOI: 10.4174/astr.2015.89.2.74] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2014] [Revised: 03/12/2015] [Accepted: 03/19/2015] [Indexed: 01/14/2023] Open
Abstract
PURPOSE Overexpression of cortactin (CTTN) in human tumors has been proposed to result in increased cell migration and metastatic potential. Here, we determined the frequencies of CTTN g.-9101C>T, g.-8748C>T, and g.72C>T polymorphisms in apparently healthy subjects and gastric cancer patients, respectively, and the influence of the CTTN polymorphisms on gastric cancer susceptibility. METHODS Blood samples were collected from 267 patients and 533 controls. CTTN g.-8748C>T and g.-9101C>T polymorphisms were determined using polymerase chain reaction-restriction fragment length polymorphism; the g.72C>T polymorphism was determined using the TaqMan method. RESULTS Genotype frequencies of the CTTN g.-9101C>T polymorphism were 97.5% (TT), 2.5% (TC), and 0% (CC) in the patient group, and 98.6% (TT), 1.4% (TC), and 0% (CC) in the control group. Genotype frequencies of the CTTN g.-8748C>T polymorphism were 93.3% (TT), 6.8% (TC), and 0% (CC) in the patient group, and 94.2% (TT), 5.8% (TC), and 0% (CC) in the control group. Genotype frequencies of the CTTN g.72C>T polymorphism were 82.4% (CC), 17.2% (CT), and 0.4% (TT) in the patient group, and 78.0% (CC), 20.1% (CT), and 1.9% (TT) in the control group. Genotype and allele frequencies of the CTTN g.-9101C>T polymorphism differed significantly between the advanced gastric cancer and control groups. Patients with advanced gastric cancer, possessing the TC genotype, had a significantly poorer prognosis than the group with the TT genotype. CONCLUSION The CTTN g.-9101C>T polymorphism might influence advanced gastric cancer susceptibility. However, the role of the CTTN g.-9101C>T, g.-8748C>T, and g.72C>T polymorphisms requires careful interpretation and confirmation through larger studies.
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Affiliation(s)
- Dae Yong Kim
- Department of Surgery, Institute of Medical Science, Wonkwang University School of Medicine, Iksan, Korea
| | - Joo Hyun Lee
- Department of Surgery, Institute of Medical Science, Wonkwang University School of Medicine, Iksan, Korea
| | - Keun Young Kim
- Department of Surgery, Institute of Medical Science, Wonkwang University School of Medicine, Iksan, Korea
| | - Dong Baek Kang
- Department of Surgery, Institute of Medical Science, Wonkwang University School of Medicine, Iksan, Korea
| | - Won Cheol Park
- Department of Surgery, Institute of Medical Science, Wonkwang University School of Medicine, Iksan, Korea
| | - Soo Cheon Chae
- Department of Pathology, Institute of Medical Science, Wonkwang University School of Medicine, Iksan, Korea
| | - Jeong Kyun Lee
- Department of Surgery, Institute of Medical Science, Wonkwang University School of Medicine, Iksan, Korea
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36
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FUSE Binding Protein 1 Facilitates Persistent Hepatitis C Virus Replication in Hepatoma Cells by Regulating Tumor Suppressor p53. J Virol 2015; 89:7905-21. [PMID: 25995247 DOI: 10.1128/jvi.00729-15] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2015] [Accepted: 05/14/2015] [Indexed: 12/12/2022] Open
Abstract
UNLABELLED Hepatitis C virus (HCV) is a leading cause of chronic hepatitis C (CHC), liver cirrhosis, and hepatocellular carcinoma (HCC). Immunohistochemistry of archived HCC tumors showed abundant FBP1 expression in HCC tumors with the CHC background. Oncomine data analysis of normal versus HCC tumors with the CHC background indicated a 4-fold increase in FBP1 expression with a concomitant 2.5-fold decrease in the expression of p53. We found that FBP1 promotes HCV replication by inhibiting p53 and regulating BCCIP and TCTP, which are positive and negative regulators of p53, respectively. The severe inhibition of HCV replication in FBP1-knockdown Huh7.5 cells was restored to a normal level by downregulation of either p53 or BCCIP. Although p53 in Huh7.5 cells is transcriptionally inactive as a result of Y220C mutation, we found that the activation and DNA binding ability of Y220C p53 were strongly suppressed by FBP1 but significantly activated upon knockdown of FBP1. Transient expression of FBP1 in FBP1 knockdown cells fully restored the control phenotype in which the DNA binding ability of p53 was strongly suppressed. Using electrophoretic mobility shift assay (EMSA) and isothermal titration calorimetry (ITC), we found no significant difference in in vitro target DNA binding affinity of recombinant wild-type p53 and its Y220C mutant p53. However, in the presence of recombinant FBP1, the DNA binding ability of p53 is strongly inhibited. We confirmed that FBP1 downregulates BCCIP, p21, and p53 and upregulates TCTP under radiation-induced stress. Since FBP1 is overexpressed in most HCC tumors with an HCV background, it may have a role in promoting persistent virus infection and tumorigenesis. IMPORTANCE It is our novel finding that FUSE binding protein 1 (FBP1) strongly inhibits the function of tumor suppressor p53 and is an essential host cell factor required for HCV replication. Oncomine data analysis of a large number of samples has revealed that overexpression of FBP1 in most HCC tumors with chronic hepatitis C is significantly linked with the decreased expression level of p53. The most significant finding is that FBP1 not only physically interacts with p53 and interferes with its binding to the target DNA but also functions as a negative regulator of p53 under cellular stress. FBP1 is barely detectable in normal differentiated cells; its overexpression in HCC tumors with the CHC background suggests that FBP1 has an important role in promoting HCV infection and HCC tumors by suppressing p53.
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Markwell SM, Weed SA. Tumor and stromal-based contributions to head and neck squamous cell carcinoma invasion. Cancers (Basel) 2015; 7:382-406. [PMID: 25734659 PMCID: PMC4381264 DOI: 10.3390/cancers7010382] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2015] [Revised: 02/10/2015] [Accepted: 02/15/2015] [Indexed: 12/11/2022] Open
Abstract
Head and neck squamous cell carcinoma (HNSCC) is typically diagnosed at advanced stages with evident loco-regional and/or distal metastases. The prevalence of metastatic lesions directly correlates with poor patient outcome, resulting in high patient mortality rates following metastatic development. The progression to metastatic disease requires changes not only in the carcinoma cells, but also in the surrounding stromal cells and tumor microenvironment. Within the microenvironment, acellular contributions from the surrounding extracellular matrix, along with contributions from various infiltrating immune cells, tumor associated fibroblasts, and endothelial cells facilitate the spread of tumor cells from the primary site to the rest of the body. Thus far, most attempts to limit metastatic spread through therapeutic intervention have failed to show patient benefit in clinic trails. The goal of this review is highlight the complexity of invasion-promoting interactions in the HNSCC tumor microenvironment, focusing on contributions from tumor and stromal cells in order to assist future therapeutic development and patient treatment.
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Affiliation(s)
- Steven M Markwell
- Department of Neurobiology and Anatomy, Program in Cancer Cell Biology, Mary Babb Randolph Cancer Center, West Virginia University, Morgantown, WV 26506, USA.
| | - Scott A Weed
- Department of Neurobiology and Anatomy, Program in Cancer Cell Biology, Mary Babb Randolph Cancer Center, West Virginia University, Morgantown, WV 26506, USA.
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Paz H, Pathak N, Yang J. Invading one step at a time: the role of invadopodia in tumor metastasis. Oncogene 2014; 33:4193-202. [PMID: 24077283 PMCID: PMC3969876 DOI: 10.1038/onc.2013.393] [Citation(s) in RCA: 157] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2013] [Revised: 08/07/2013] [Accepted: 08/08/2013] [Indexed: 12/14/2022]
Abstract
The ability to degrade extracellular matrix is critical for tumor cells to invade and metastasize. Recent studies show that tumor cells use specialized actin-based membrane protrusions termed invadopodia to perform matrix degradation. Invadopodia provide an elegant way for tumor cells to precisely couple focal matrix degradation with directional movement. Here we discuss several key components and regulators of invadopodia that have been uniquely implicated in tumor invasion and metastasis. Furthermore, we discuss existing and new therapeutic opportunities to target invadopodia for anti-metastasis treatment.
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Affiliation(s)
- Helicia Paz
- Department of Pharmacology, University of California, San Diego, La Jolla, CA, USA
| | - Navneeta Pathak
- Department of Pharmacology, University of California, San Diego, La Jolla, CA, USA
- Biomedical Sciences Program, University of California, San Diego, La Jolla, CA, USA
| | - Jing Yang
- Department of Pharmacology, University of California, San Diego, La Jolla, CA, USA
- Biomedical Sciences Program, University of California, San Diego, La Jolla, CA, USA
- Department of Pediatrics, University of California, San Diego, La Jolla, CA, USA
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Fife CM, McCarroll JA, Kavallaris M. Movers and shakers: cell cytoskeleton in cancer metastasis. Br J Pharmacol 2014; 171:5507-23. [PMID: 24665826 DOI: 10.1111/bph.12704] [Citation(s) in RCA: 385] [Impact Index Per Article: 35.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2013] [Revised: 03/14/2014] [Accepted: 03/18/2014] [Indexed: 12/11/2022] Open
Abstract
UNLABELLED Metastasis is responsible for the greatest number of cancer deaths. Metastatic disease, or the movement of cancer cells from one site to another, is a complex process requiring dramatic remodelling of the cell cytoskeleton. The various components of the cytoskeleton, actin (microfilaments), microtubules (MTs) and intermediate filaments, are highly integrated and their functions are well orchestrated in normal cells. In contrast, mutations and abnormal expression of cytoskeletal and cytoskeletal-associated proteins play an important role in the ability of cancer cells to resist chemotherapy and metastasize. Studies on the role of actin and its interacting partners have highlighted key signalling pathways, such as the Rho GTPases, and downstream effector proteins that, through the cytoskeleton, mediate tumour cell migration, invasion and metastasis. An emerging role for MTs in tumour cell metastasis is being unravelled and there is increasing interest in the crosstalk between key MT interacting proteins and the actin cytoskeleton, which may provide novel treatment avenues for metastatic disease. Improved understanding of how the cytoskeleton and its interacting partners influence tumour cell migration and metastasis has led to the development of novel therapeutics against aggressive and metastatic disease. LINKED ARTICLES This article is part of a themed section on Cytoskeleton, Extracellular Matrix, Cell Migration, Wound Healing and Related Topics. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2014.171.issue-24.
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Affiliation(s)
- C M Fife
- Tumour Biology and Targeting Program, Children's Cancer Institute Australia Lowy Cancer Research Centre, UNSW Australia, Randwick, NSW, Australia; Australian Centre for NanoMedicine, UNSW Australia, Sydney, NSW, Australia
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Radhakrishnan VM, Kojs P, Young G, Ramalingam R, Jagadish B, Mash EA, Martinez JD, Ghishan FK, Kiela PR. pTyr421 cortactin is overexpressed in colon cancer and is dephosphorylated by curcumin: involvement of non-receptor type 1 protein tyrosine phosphatase (PTPN1). PLoS One 2014; 9:e85796. [PMID: 24465712 PMCID: PMC3899080 DOI: 10.1371/journal.pone.0085796] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2013] [Accepted: 12/02/2013] [Indexed: 02/06/2023] Open
Abstract
Cortactin (CTTN), first identified as a major substrate of the Src tyrosine kinase, actively participates in branching F-actin assembly and in cell motility and invasion. CTTN gene is amplified and its protein is overexpressed in several types of cancer. The phosphorylated form of cortactin (pTyr421) is required for cancer cell motility and invasion. In this study, we demonstrate that a majority of the tested primary colorectal tumor specimens show greatly enhanced expression of pTyr421-CTTN, but no change at the mRNA level as compared to healthy subjects, thus suggesting post-translational activation rather than gene amplification in these tumors. Curcumin (diferulolylmethane), a natural compound with promising chemopreventive and chemosensitizing effects, reduced the indirect association of cortactin with the plasma membrane protein fraction in colon adenocarcinoma cells as measured by surface biotinylation, mass spectrometry, and Western blotting. Curcumin significantly decreased the pTyr421-CTTN in HCT116 cells and SW480 cells, but was ineffective in HT-29 cells. Curcumin physically interacted with PTPN1 tyrosine phosphatases to increase its activity and lead to dephosphorylation of pTyr421-CTTN. PTPN1 inhibition eliminated the effects of curcumin on pTyr421-CTTN. Transduction with adenovirally-encoded CTTN increased migration of HCT116, SW480, and HT-29. Curcumin decreased migration of HCT116 and SW480 cells which highly express PTPN1, but not of HT-29 cells with significantly reduced endogenous expression of PTPN1. Curcumin significantly reduced the physical interaction of CTTN and pTyr421-CTTN with p120 catenin (CTNND1). Collectively, these data suggest that curcumin is an activator of PTPN1 and can reduce cell motility in colon cancer via dephosphorylation of pTyr421-CTTN which could be exploited for novel therapeutic approaches in colon cancer therapy based on tumor pTyr421-CTTN expression.
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Affiliation(s)
- Vijayababu M. Radhakrishnan
- Department of Pediatrics, Steele Children's Research Center, University of Arizona Health Sciences Center, Tucson, Arizona, United States of America
| | - Pawel Kojs
- Department of Nutritional Sciences, Tucson, Arizona, United States of America
| | - Gavin Young
- Arizona Cancer Center, Tucson, Arizona, United States of America
| | - Rajalakshmy Ramalingam
- Department of Pediatrics, Steele Children's Research Center, University of Arizona Health Sciences Center, Tucson, Arizona, United States of America
| | - Bhumasamudram Jagadish
- Arizona Cancer Center, Tucson, Arizona, United States of America
- Department of Chemistry and Biochemistry, The University of Arizona, Tucson, Arizona, United States of America
| | - Eugene A. Mash
- Arizona Cancer Center, Tucson, Arizona, United States of America
- Department of Chemistry and Biochemistry, The University of Arizona, Tucson, Arizona, United States of America
| | | | - Fayez K. Ghishan
- Department of Pediatrics, Steele Children's Research Center, University of Arizona Health Sciences Center, Tucson, Arizona, United States of America
| | - Pawel R. Kiela
- Department of Pediatrics, Steele Children's Research Center, University of Arizona Health Sciences Center, Tucson, Arizona, United States of America
- Department of Immunobiology, University of Arizona Health Sciences Center, Tucson, Arizona, United States of America
- * E-mail:
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Ghasemi R, Ghaffari SH, Momeny M, Pirouzpanah S, Yousefi M, Malehmir M, Alimoghaddam K, Ghavamzadeh A. Multitargeting and antimetastatic potentials of silibinin in human HepG-2 and PLC/PRF/5 hepatoma cells. Nutr Cancer 2013; 65:590-9. [PMID: 23659451 DOI: 10.1080/01635581.2013.770043] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Hepatocellular carcinoma (HCC) is the most common sort of primary liver malignancy with poor prognosis. This study aimed at examining the effects of silibinin (a putative antimetastatic agent) on some transcriptional markers mechanistically related to HCC recurrence and metastasis in HepG-2 [hepatitis B virus (HBV)-negative and P53 intact) and PLC/PRF/5 (HBV-positive and P53 mutated) cells. The expression of 27 genes in response to silibinin was evaluated by real-time RT-PCR. The MMP gelatinolytic assay and microculture tetrazolium test (MTT) were tested. Silibinin was capable of suppressing the transcriptional levels of ANGPT2, ATP6L, CAP2, CCR6, CCR7, CLDN-10, cortactin, CXCR4, GLI2, HK2, ID1, KIAA0101, mortalin, PAK1, RHOA, SPINK1, and STMN1 as well as the enzymatic activity of MMP-2 but promoted the transcripts of CREB3L3, DDX3X, and PROX1 in both cells. Some significant differences between the cells in response to silibinin were detected that might be related to the differences of the cells in terms of HBV infection and/or P53 mutation, suggesting the possible influence of silibinin on HCC through biological functions of these 2 prognostic factors. In conclusion, our findings suggest that silibinin could potentially function as a multitargeting antimetastatic agent and might provide new insights for HCC therapy particularly for HBV-related and/or P53-mutated HCCs.
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Affiliation(s)
- Reza Ghasemi
- Hematology, Oncology and Stem Cell Transplantation Research Center, Tehran University of Medical Sciences, Tehran, Iran
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Jia D, Jing Y, Zhang Z, Liu L, Ding J, Zhao F, Ge C, Wang Q, Chen T, Yao M, Li J, Gu J, He X. Amplification of MPZL1/PZR promotes tumor cell migration through Src-mediated phosphorylation of cortactin in hepatocellular carcinoma. Cell Res 2013; 24:204-17. [PMID: 24296779 DOI: 10.1038/cr.2013.158] [Citation(s) in RCA: 59] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2013] [Revised: 09/10/2013] [Accepted: 09/25/2013] [Indexed: 12/15/2022] Open
Abstract
We have previously identified 1 241 regions of somatic copy number alterations (CNAs) in hepatocellular carcinoma (HCC). In the present study, we found that a novel recurrent focal amplicon, 1q24.1-24.2, targets the MPZL1 gene in HCC. Notably, there is a positive correlation between the expression levels of MPZL1 and intrahepatic metastasis of the HCC specimens. MPZL1 can significantly enhance the migratory and metastatic potential of the HCC cells. Moreover, we found that one of the mechanisms by which MPZL1 promotes HCC cell migration is by inducing the phosphorylation and activation of the pro-metastatic protein, cortactin. Additionally, we found that Src kinase mediates the phosphorylation and activation of cortactin induced by MPZL1 overexpression. Taken together, these findings suggest that MPZL1 is a novel pro-metastatic gene targeted by a recurrent region of copy number amplification at 1q24.1-24.2 in HCC.
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Affiliation(s)
- Deshui Jia
- 1] State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200032, China [2] Shanghai Medical College, Fudan University, Shanghai 200032, China
| | - Ying Jing
- 1] State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200032, China [2] Shanghai Medical College, Fudan University, Shanghai 200032, China
| | - Zhenfeng Zhang
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200032, China
| | - Li Liu
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200032, China
| | - Jie Ding
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200032, China
| | - Fangyu Zhao
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200032, China
| | - Chao Ge
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200032, China
| | - Qifeng Wang
- Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai Medical College, Fudan University, Shanghai 200032, China
| | - Taoyang Chen
- Qidong Liver Cancer Institute, Qidong, Jiangsu 226200, China
| | - Ming Yao
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200032, China
| | - Jinjun Li
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200032, China
| | - Jianren Gu
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200032, China
| | - Xianghuo He
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200032, China
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Chuma M, Sakamoto N, Nakai A, Hige S, Nakanishi M, Natsuizaka M, Suda G, Sho T, Hatanaka K, Matsuno Y, Yokoo H, Kamiyama T, Taketomi A, Fujii G, Tashiro K, Hikiba Y, Fujimoto M, Asaka M, Maeda S. Heat shock factor 1 accelerates hepatocellular carcinoma development by activating nuclear factor-κB/mitogen-activated protein kinase. Carcinogenesis 2013; 35:272-81. [PMID: 24130164 DOI: 10.1093/carcin/bgt343] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Heat shock factor 1 (HSF1), a major transactivator of stress responses, has been implicated in carcinogenesis in various organs. However, little is known about the biological functions of HSF1 in the development of hepatocellular carcinoma (HCC). To clarify the functional role of HSF1 in HCC, we established HSF1-knockdown (HSF1 KD) KYN2 HCC cells by stably expressing either small hairpin RNA (shRNA) against HSF1 (i.e. HSF1 KD) or control shRNA (HSF1 control). Tumorigenicity was significantly reduced in orthotopic mice with HSF1 KD cells compared with those with HSF1 control cells. Reduced tumorigenesis in HSF1 KD cells appeared attributable to increased apoptosis and decreased proliferation. Tumor necrosis factor-α-induced apoptosis was increased in HSF1 KD cells and HSF1(-/-) mouse hepatocytes compared with controls. Decreased expression of IκB kinase γ, a positive regulator of nuclear factor-κB, was also observed in HSF1 KD cells and HSF1(-/-) mouse hepatocytes. Furthermore, expression of bcl-2-associated athanogene domain 3 (BAG3) was dramatically reduced in HSF1 KD cells and HSF1(-/-) mouse hepatocytes. We also found that epidermal growth factor-stimulated mitogen-activated protein kinase signaling was impaired in HSF1 KD cells. Clinicopathological analysis demonstrated frequent overexpression of HSF1 in human HCCs. Significant correlations between HSF1 and BAG3 protein levels and prognosis were also observed. In summary, these results identify a mechanistic link between HSF1 and liver tumorigenesis and may provide as a potential molecular target for the development of anti-HCC therapies.
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Affiliation(s)
- Makoto Chuma
- Department of Gastroenterology and Hepatology, Hokkaido University, Kita 15, Nishi 7, Kita-ku, Sapporo 060-8638, Japan
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Liu Y, Zhang JB, Qin Y, Wang W, Wei L, Teng Y, Guo L, Zhang B, Lin Z, Liu J, Ren ZG, Ye QH, Xie Y. PROX1 promotes hepatocellular carcinoma metastasis by way of up-regulating hypoxia-inducible factor 1α expression and protein stability. Hepatology 2013; 58:692-705. [PMID: 23505027 DOI: 10.1002/hep.26398] [Citation(s) in RCA: 76] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/18/2013] [Accepted: 03/10/2013] [Indexed: 12/12/2022]
Abstract
UNLABELLED Hepatocellular carcinoma (HCC) is one of the most common cancers and the third leading cause of death from cancer worldwide. HCC has a very poor prognosis because of tumor invasiveness, frequent intrahepatic spread, and extrahepatic metastasis. The molecular mechanism of HCC invasiveness and metastasis is poorly understood. The homeobox protein PROX1 is required for hepatocyte migration during mouse embryonic liver development. In this study, we show that high PROX1 protein expression in primary HCC tissues is associated with significantly worse survival and early tumor recurrence in postoperative HCC patients. Knockdown of PROX1 expression in HCC cells inhibited cell migration and invasiveness in vitro and HCC metastasis in nude mice while overexpression of PROX1 in HCC cells promoted these processes. PROX1's pro-metastasis activity is most likely attributed to its up-regulation of hypoxia-inducible factor 1α (HIF-1α) transcription and stabilization of HIF-1α protein by recruiting histone deacetylase 1 (HDAC1) to prevent the acetylation of HIF-1α, which subsequently induces an epithelial-mesenchymal transition response in HCC cells. We further demonstrated the prognostic value of using the combination of PROX1 and HDAC1 levels to predict postoperative survival and early recurrence of HCC. CONCLUSION PROX1 is a critical factor that promotes HCC metastasis.
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Affiliation(s)
- Yanfeng Liu
- Key Laboratory of Medical Molecular Virology (MOE & MOH), Institute of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, China
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Liu W, Li C, Xu Y, Yang H, Yao Q, Han J, Shang D, Zhang C, Su F, Li X, Xiao Y, Zhang F, Dai M, Li X. Topologically inferring risk-active pathways toward precise cancer classification by directed random walk. ACTA ACUST UNITED AC 2013; 29:2169-77. [PMID: 23842813 DOI: 10.1093/bioinformatics/btt373] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
MOTIVATION The accurate prediction of disease status is a central challenge in clinical cancer research. Microarray-based gene biomarkers have been identified to predict outcome and outperform traditional clinical parameters. However, the robustness of the individual gene biomarkers is questioned because of their little reproducibility between different cohorts of patients. Substantial progress in treatment requires advances in methods to identify robust biomarkers. Several methods incorporating pathway information have been proposed to identify robust pathway markers and build classifiers at the level of functional categories rather than of individual genes. However, current methods consider the pathways as simple gene sets but ignore the pathway topological information, which is essential to infer a more robust pathway activity. RESULTS Here, we propose a directed random walk (DRW)-based method to infer the pathway activity. DRW evaluates the topological importance of each gene by capturing the structure information embedded in the directed pathway network. The strategy of weighting genes by their topological importance greatly improved the reproducibility of pathway activities. Experiments on 18 cancer datasets showed that the proposed method yielded a more accurate and robust overall performance compared with several existing gene-based and pathway-based classification methods. The resulting risk-active pathways are more reliable in guiding therapeutic selection and the development of pathway-specific therapeutic strategies. AVAILABILITY DRW is freely available at http://210.46.85.180:8080/DRWPClass/
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Affiliation(s)
- Wei Liu
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, China
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Zhao G, Huang ZM, Kong YL, Wen DQ, Li Y, Ren L, Zhang HY. Cortactin is a sensitive biomarker relative to the poor prognosis of human hepatocellular carcinoma. World J Surg Oncol 2013; 11:74. [PMID: 23518204 PMCID: PMC3620941 DOI: 10.1186/1477-7819-11-74] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2012] [Accepted: 03/10/2013] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Cortactin is an important regulator involved in invasion and migration of hepatocellular carcinoma (HCC). The aim of this study was to elucidate the forecasting role of cortactin in resectable HCCs. METHODS We compared the invasiveness and motility among liver epithelial cell line and HCC cell lines by using Transwell assay and wound healing assay. We further investigated the CTTN mRNA expression by real-time PCR. Next, 91 HCC and 20 normal liver tissue samples were detected by IHC and real-time PCR. Finally, we analyzed the clinicopathologic features and survival time of the HCC cases. RESULTS We identified that HepG2, LM3, and SK-Hep-1 had more invasiveness and motility (P <0.05). Compared with liver epithelial cell line, CTTN expression was higher in LM3, HepG2, and MHCC97-L (P <0.01) and lower in SK-Hep-1 (P <0.05). IHC examination showed cortactin expression was closely relative to TNM stage (AJCC/UICC), cancer embolus, and metastasis (P <0.01). Cortactin overexpression indicated a longer survival time of 52 ± 8.62 months and low expression of a shorter survival time of 20 ± 4.95 months (P <0.01). Cortactin examination has more predictive power in patients with Child-Pugh grade A and BCLC stage 0-B. CONCLUSIONS Overexpression of cortactin is closely associated with poor human HCCs prognosis that caused by cancer embolus and metastasis. Cortactin and CTTN should be used for differentiating varieties of survival for patients after HCC resection.
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Affiliation(s)
- Gang Zhao
- Department of Hepatobiliary Surgery, Chinese PLA Air Force General Hospital, No,30 Fucheng Road, Haidian District, Beijing 100142, China
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Xuan W, Murphy E, Beeckman T, Audenaert D, De Smet I. Synthetic molecules: helping to unravel plant signal transduction. J Chem Biol 2013; 6:43-50. [PMID: 24432124 DOI: 10.1007/s12154-013-0091-8] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2012] [Accepted: 02/05/2013] [Indexed: 11/30/2022] Open
Abstract
The application of small molecules has played a crucial role in identifying novel components involved in plant signalling. Compared to classic genetic approaches, small molecule screens offer notable advantages in dissecting plant biological processes, such as technical simplicity, low start-up costs, and most importantly, bypassing the problems of lethality and redundancy. To identify small molecules that target a biological process or protein of interest, robust and well-reasoned high-throughput screening approaches are essential. In this review, we present a series of principles and valuable approaches in small molecule screening in the plant model system Arabidopsis thaliana. We also provide an overview of small molecules that led to breakthroughs in uncovering phytohormone signalling pathways, endomembrane signalling cascades, novel growth regulators, and plant defence mechanisms. Meanwhile, the strategies to deciphering the mechanisms of these small molecules on Arabidopsis are highlighted. Moreover, the opportunities and challenges of small molecule applications in translational biology are discussed.
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Affiliation(s)
- Wei Xuan
- Department of Plant Systems Biology, VIB, Technologiepark 927, B-9052 Ghent, Belgium ; Department of Plant Biotechnology and Genetics, Ghent University, Technologiepark 927, B-9052 Ghent, Belgium
| | - Evan Murphy
- Division of Plant and Crop Sciences, School of Biosciences, University of Nottingham, Loughborough, LE12 5RD UK
| | - Tom Beeckman
- Department of Plant Systems Biology, VIB, Technologiepark 927, B-9052 Ghent, Belgium ; Department of Plant Biotechnology and Genetics, Ghent University, Technologiepark 927, B-9052 Ghent, Belgium
| | - Dominique Audenaert
- Compound Screening Facility, VIB, Technologiepark 927, B-9052 Ghent, Belgium
| | - Ive De Smet
- Division of Plant and Crop Sciences, School of Biosciences, University of Nottingham, Loughborough, LE12 5RD UK ; Centre for Plant Integrative Biology, University of Nottingham, Nottingham, LE12 5RD UK
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Fukuma M, Tanese K, Effendi K, Yamazaki K, Masugi Y, Suda M, Sakamoto M. Leucine-rich repeat-containing G protein-coupled receptor 5 regulates epithelial cell phenotype and survival of hepatocellular carcinoma cells. Exp Cell Res 2012; 319:113-21. [PMID: 23127514 DOI: 10.1016/j.yexcr.2012.10.011] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2012] [Revised: 10/11/2012] [Accepted: 10/26/2012] [Indexed: 11/19/2022]
Abstract
The leucine-rich repeat containing G protein-coupled receptor 5 (LGR5), also known as GPR49, is a seven-transmembrane receptor that is expressed in stem cells of the intestinal crypts and hair follicles of mice. LGR5 is overexpressed in some types of human cancer, and is one of the target genes of the Wnt signaling pathway. To explore the function of LGR5 in cancer cells, stable hepatocellular carcinoma (HCC) cell lines expressing FLAG-tagged LGR5 were established. Overexpression of LGR5 resulted in changes in cell shape from an extended flat (mesenchymal) phenotype to a round aggregated (stem cell-like) phenotype. Cells transfected with LGR5 showed higher colony forming activity, and were more resistant to a cytotoxic drug than cells transfected with empty vector. Overexpression of LGR5 inhibited cell motility. LGR5-transfected cells formed nodule type tumors in the livers of immunodeficient mice, whereas empty vector-transfected cells formed more invasive tumors. Down-regulation of LGR5 changed the morphology of HCC cells from the aggregated phenotype to an extended spindle phenotype, and cell motility was increased. This is the first study reporting the functional role of LGR5 in the biology of HCC cells, and the results suggest that aberrant expression of LGR5 regulates epithelial cell phenotype and survival.
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MESH Headings
- Animals
- Carcinoma, Hepatocellular/genetics
- Carcinoma, Hepatocellular/pathology
- Cell Survival/genetics
- Cells, Cultured
- Epithelial Cells/metabolism
- Epithelial Cells/physiology
- Gene Expression Regulation, Neoplastic
- Hep G2 Cells
- Humans
- Liver Neoplasms/genetics
- Liver Neoplasms/pathology
- Mice
- Mice, Inbred NOD
- Mice, SCID
- Mice, Transgenic
- Phenotype
- Receptors, G-Protein-Coupled/genetics
- Receptors, G-Protein-Coupled/metabolism
- Receptors, G-Protein-Coupled/physiology
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Affiliation(s)
- Mariko Fukuma
- Department of Pathology, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan
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49
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You TK, Kim KM, Noh SJ, Bae JS, Jang KY, Chung MJ, Moon WS, Kang MJ, Lee DG, Park HS. Expressions of E-cadherin, Cortactin and MMP-9 in Pseudoepitheliomatous Hyperplasia and Squamous Cell Carcinoma of the Head and Neck: Their Relationships with Clinicopathologic Factors and Prognostic Implication. KOREAN JOURNAL OF PATHOLOGY 2012; 46:331-40. [PMID: 23110025 PMCID: PMC3479816 DOI: 10.4132/koreanjpathol.2012.46.4.331] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/14/2012] [Revised: 07/23/2012] [Accepted: 07/24/2012] [Indexed: 01/18/2023]
Abstract
BACKGROUND E-cadherin, cortactin, and matrix metalloproteinase (MMP)-9 have roles in tumor development or progression, but their expression has not been fully investigated in pseudoepitheliomatous hyperplasia (PEH) and squamous cell carcinoma (SCC) of the head and neck. METHODS We evaluated the immunohistochemical expression of E-cadherin, cortactin, and MMP-9 in 29 cases of PEH and 97 cases of SCC. Additionally, we evaluated their relationship with clinicopathologic factors and prognostic implications in SCC. RESULTS Thirty-five cases of SCC showed reduced expression of E-cadherin, whereas none of the PEH did. A total of 20 cases and 11 cases of SCC were immunoreactive for cortactin and MMP-9, respectively, whereas none of the PEH did. In SCC, reduced expression of E-cadherin was correlated with cortactin expression and invasion depth. Cortactin expression was correlated with differentiation, T classification, and recurrence and/or metastasis. MMP-9 expression was correlated with invasion depth. Cortactin expression was correlated with poor overall survival and relapse-free survival and it was an independent prognostic factor. CONCLUSIONS The reduced expression of E-cadherin and the expression of cortactin may be helpful for the differential diagnosis of PEH and SCC. Furthermore, cortactin expression in association with reduced E-cadherin expression is correlated with poor prognosis in SCC.
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Affiliation(s)
- Tack Kune You
- Department of Pathology, Chonbuk National University Medical School, Jeonju, Korea
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50
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Ying J, Shan L, Li J, Zhong L, Xue L, Zhao H, Li L, Langford C, Guo L, Qiu T, Lu N, Tao Q. Genome-wide screening for genetic alterations in esophageal cancer by aCGH identifies 11q13 amplification oncogenes associated with nodal metastasis. PLoS One 2012; 7:e39797. [PMID: 22761904 PMCID: PMC3382571 DOI: 10.1371/journal.pone.0039797] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2011] [Accepted: 05/30/2012] [Indexed: 01/25/2023] Open
Abstract
Background Esophageal squamous cell carcinoma (ESCC) is highly prevalent in China and other Asian countries, as a major cause of cancer-related mortality. ESCC displays complex chromosomal abnormalities, including multiple structural and numerical aberrations. Chromosomal abnormalities, such as recurrent amplifications and homozygous deletions, directly contribute to tumorigenesis through altering the expression of key oncogenes and tumor suppressor genes. Methodology/Principle Findings To understand the role of genetic alterations in ESCC pathogenesis and identify critical amplification/deletion targets, we performed genome-wide 1-Mb array comparative genomic hybridization (aCGH) analysis for 10 commonly used ESCC cell lines. Recurrent chromosomal gains were frequently detected on 3q26-27, 5p15-14, 8p12, 8p22-24, 11q13, 13q21-31, 18p11 and 20q11-13, with frequent losses also found on 8p23-22, 11q22, 14q32 and 18q11-23. Gain of 11q13.3-13.4 was the most frequent alteration in ESCC. Within this region, CCND1 oncogene was identified with high level of amplification and overexpression in ESCC, while FGF19 and SHANK2 was also remarkably over-expressed. Moreover, a high concordance (91.5%) of gene amplification and protein overexpression of CCND1 was observed in primary ESCC tumors. CCND1 amplification/overexpression was also significantly correlated with the lymph node metastasis of ESCC. Conclusion These findings suggest that genomic gain of 11q13 is the major mechanism contributing to the amplification. Novel oncogenes identified within the 11q13 amplicon including FGF19 and SHANK2 may play important roles in ESCC tumorigenesis.
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Affiliation(s)
- Jianming Ying
- Department of Pathology, Cancer Hospital, Peking Union Medical College & Chinese Academy of Medical Sciences, Beijing, China
- Cancer Epigenetics Laboratory, Department of Clinical Oncology, State Key Laboratory of Oncology in South China, Sir YK Pao Center for Cancer and Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong
- * E-mail: (QT); (NL); (JY)
| | - Ling Shan
- Department of Pathology, Cancer Hospital, Peking Union Medical College & Chinese Academy of Medical Sciences, Beijing, China
| | - Jisheng Li
- Cancer Epigenetics Laboratory, Department of Clinical Oncology, State Key Laboratory of Oncology in South China, Sir YK Pao Center for Cancer and Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong
- Department of Chemotherapy, Cancer Center, Qilu Hospital, Shandong University, Jinan, China
| | - Lan Zhong
- Cancer Epigenetics Laboratory, Department of Clinical Oncology, State Key Laboratory of Oncology in South China, Sir YK Pao Center for Cancer and Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong
| | - Liyan Xue
- Department of Pathology, Cancer Hospital, Peking Union Medical College & Chinese Academy of Medical Sciences, Beijing, China
| | - Hong Zhao
- Department of Abdominal Surgical Oncology, Cancer Hospital, Peking Union Medical College & Chinese Academy of Medical Sciences, Beijing, China
| | - Lili Li
- Cancer Epigenetics Laboratory, Department of Clinical Oncology, State Key Laboratory of Oncology in South China, Sir YK Pao Center for Cancer and Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong
| | - Cordelia Langford
- Microarray Facility, Wellcome Trust Sanger Institute, Cambridge, United Kingdom
| | - Lei Guo
- Department of Pathology, Cancer Hospital, Peking Union Medical College & Chinese Academy of Medical Sciences, Beijing, China
| | - Tian Qiu
- Department of Pathology, Cancer Hospital, Peking Union Medical College & Chinese Academy of Medical Sciences, Beijing, China
| | - Ning Lu
- Department of Pathology, Cancer Hospital, Peking Union Medical College & Chinese Academy of Medical Sciences, Beijing, China
- * E-mail: (QT); (NL); (JY)
| | - Qian Tao
- Cancer Epigenetics Laboratory, Department of Clinical Oncology, State Key Laboratory of Oncology in South China, Sir YK Pao Center for Cancer and Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong
- * E-mail: (QT); (NL); (JY)
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