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1
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Wang Y, Lu Y, Xu C. Tensin 4 facilitates aerobic glycolysis, migration and invasion of colorectal cancer cells through the β‑catenin/c‑Myc signaling pathway. Oncol Lett 2024; 28:356. [PMID: 38881712 PMCID: PMC11176887 DOI: 10.3892/ol.2024.14489] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2023] [Accepted: 05/08/2024] [Indexed: 06/18/2024] Open
Abstract
Tensin 4 (TNS4) is overexpressed in multiple cancers, including colorectal cancer (CRC), and is associated with a poor prognosis of patients with CRC. However, the role and underlying mechanisms of TNS4 in CRC have yet to be elucidated. The expression of TNS4 in CRC tissues were analyzed by immunohistochemistry. Cell migration and invasion were assessed in vitro using Transwell assay. Western blot and reverse transcription (RT)-quantitative (q)PCR were used to investigate the molecular mechanisms by which TNS4 regulates aerobic glycolysis, migration and invasion of CRC cells. The present study demonstrated that TNS4 was highly expressed in the cancer tissues of patients with CRC and significantly associated with the tumor-node-metastasis stages. TNS4 silencing led to a significant decrease in glucose consumption and lactate production in CRC cells, and knockdown of TNS4 suppressed the migration and invasion of CRC cells via aerobic glycolysis through the β-catenin/c-Myc pathway. Notably, treatment with DASA-58, an activator of glycolysis, or SKL2001, an activator of β-catenin/c-Myc signaling, significantly reversed the effect of TNS4 knockdown on aerobic glycolysis, migration and invasion of CRC cells. Collectively, these results suggest that TNS4 may act as a novel regulator of aerobic glycolysis, migration and invasion of CRC cells by modulating β-catenin/c-Myc signaling, providing a new potential biomarker and therapeutic target in CRC.
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Affiliation(s)
- Yan Wang
- Department of Gastroenterology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215000, P.R. China
| | - Yongda Lu
- Department of Gastroenterology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215000, P.R. China
| | - Chunfang Xu
- Department of Gastroenterology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215000, P.R. China
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2
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Monteiro A, Delgado L, Monteiro L, Pires I, Prada J, Raposo T. Immunohistochemical Expression of Tensin-4/CTEN in Squamous Cell Carcinoma in Dogs. Vet Sci 2023; 10:86. [PMID: 36851390 PMCID: PMC9960384 DOI: 10.3390/vetsci10020086] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2022] [Revised: 01/21/2023] [Accepted: 01/22/2023] [Indexed: 01/26/2023] Open
Abstract
C-terminal tensin-like (tensin-4/TNS4/CTEN) is the fourth member of the tensin family, frequently described as displaying oncological functions, including cellular migration, invasion, adhesion, growth, metastasis, epithelial to mesenchymal transition, and apoptosis, in several different types of cancer. To investigate, for the first time, the clinical significance of CTEN in squamous cell carcinoma (SCC) of dogs, we studied a total of 45 SCC sections from various dog breeds. The mean age of the affected dogs was 8.9 ± 3.6 years. Immunohistochemistry confirmed strong cytoplasmatic CTEN expression in the basal layer of the epidermis next to the tumor. We detected high CTEN expression associated with the highest grade of the tumor (grade III) and observed 100% of immunopositivity for this tumor grading (p < 0.0001). These data suggest that CTEN is an oncogene in SCC of dogs and a promising biomarker and a therapeutic target for dogs affected by SCC.
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Affiliation(s)
- Alexandra Monteiro
- Department of Biology and Environment, University of Trás-os-Montes and Alto Douro, 5000-801 Vila Real, Portugal
- Instituto de Investigação e Inovação em Saúde, Universidade do Porto (i3S), 4200-135 Porto, Portugal
| | - Leonor Delgado
- UNIPRO-Oral Pathology and Rehabilitation Research Unit, University Institute of Health Sciences-CESPU (IUCS-CESPU), 4585-116 Gandra, Portugal
- Pathology Department, INNO Serviços Especializados em Veterinária, 4710-503 Braga, Portugal
| | - Luís Monteiro
- UNIPRO-Oral Pathology and Rehabilitation Research Unit, University Institute of Health Sciences-CESPU (IUCS-CESPU), 4585-116 Gandra, Portugal
- Pathology Department, INNO Serviços Especializados em Veterinária, 4710-503 Braga, Portugal
| | - Isabel Pires
- Department of Veterinary Science, University of Trás-os-Montes and Alto Douro, 5000-801 Vila Real, Portugal
- CECAV-Veterinary and Animal Research Center, University of Trás-os-Montes and Alto Douro, 5001-801 Vila Real, Portugal
| | - Justina Prada
- Department of Veterinary Science, University of Trás-os-Montes and Alto Douro, 5000-801 Vila Real, Portugal
- CECAV-Veterinary and Animal Research Center, University of Trás-os-Montes and Alto Douro, 5001-801 Vila Real, Portugal
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3
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Liu F, Gao X, Liu W, Xue W. Mining TCGA and GEO databases for the prediction of poor prognosis in lung adenocarcinoma based on up-regulated expression of TNS4. Medicine (Baltimore) 2022; 101:e31120. [PMID: 36281194 PMCID: PMC9592303 DOI: 10.1097/md.0000000000031120] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
Abstract
To investigate the clinical significance of Tensin4 (TNS4) in human cancers, particularly lung cancer, we mined the Cancer Genome Atlas database for lung adenocarcinoma (TCGA-LUAD) and the Gene Expression Omnibus database to predict poor prognosis based on the up-regulated expression of TNS4 in LUAD. The correlation between the clinical pathologic features of patients and TNS4 gene expression was analyzed using the Wilcoxon signed-rank test. Cox regression analysis was used to evaluate the association of clinicopathologic characteristics with the overall survival (OS) of cancer patients using TCGA data. The relationship between TNS4 expression and cancer patient survival was evaluated with Kaplan-Meier survival curves and meta-analyses. GO and KEGG were also included in the data mining methods. The expression level of TNS4 in LUAD tissue was higher than that in adjacent normal tissue (P < .001). According to the Kaplan-Meier survival curve, LUAD patients with high TNS4 expression had worse prognosis than those with low TNS4 expression (P < .001 for OS; P = .028 for progression-free survival). A positive correlation between TNS4 expression and poor OS was found with both univariate and multivariate analyses. Increased TNS4 expression in LUAD was closely correlated with a higher disease stage (P = .007), positive lymph nodes (P = .005), and larger tumor size (P = .002). Moreover, meta-analysis including seven independent datasets showed LUAD patients with higher TNS4 had poorer OS (combined hazard ratio = 1.27, 95% confidence interval 1.16-1.39). In the high-TNS4 population, regulation of the actin cytoskeleton, extracellular matrix receptor interactions, and focal adhesion were differentially enriched. Integrin α6β4 and laminin-5 genes were also associated with TNS4. TNS4 expression may be a potential biomarker for predicting poor survival in LUAD. Moreover, the correlation between TNS4 and integrin α6β4 may be attributed to the role of TNS4 in LUAD.
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Affiliation(s)
- Feng Liu
- Department of Kidney Transplantation, Nephropathy Hospital, the First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, PR China
- Department of Thoracic Surgery, Wuxi People’s Hospital Affiliated to Nanjing Medical University, Wuxi, PR China
| | - Xinliang Gao
- Department of Thoracic Surgery, The First Hospital of Jilin University, Changchun, PR China
| | - Wei Liu
- Department of Thoracic Surgery, The First Hospital of Jilin University, Changchun, PR China
| | - Wujun Xue
- Department of Kidney Transplantation, Nephropathy Hospital, the First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, PR China
- * Correspondence: Wujun Xue, Department of Kidney Transplantation, Nephropathy Hospital, the First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, PR China (e-mail: )
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4
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Nizioł M, Zińczuk J, Zaręba K, Guzińska-Ustymowicz K, Pryczynicz A. Increased tensin 4 expression is related to the histological type of gastric cancer. World J Clin Oncol 2021; 12:1202-1214. [PMID: 35070739 PMCID: PMC8716987 DOI: 10.5306/wjco.v12.i12.1202] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/15/2021] [Revised: 06/29/2021] [Accepted: 11/18/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Gastric cancer (GC) is one of the most common malignant tumors worldwide. Tensin 4 (TNS4) is an adhesive protein belonging to the tensin family. This protein is located in focal adhesion sites. The TNS4 gene is considered an oncogene in numerous cancers. This protein plays an important role in adhesion, migration and proliferation of cells.
AIM To evaluate expression of TNS4 protein in GC tissues and analysis of the clinical and histopathological parameters as well as the overall survival rate of patients.
METHODS The expression of TNS4 was assessed in 89 patients using immunohistochemistry.
RESULTS Positive expression of TNS4 was observed in 49 of 89 patients (55.06%). Higher TNS4 expression was more common in GC tumors with a diameter ≥ 5 cm (P = 0.040). We demonstrated that an increase in TNS4 expression was more frequent in tumors of the histological type without mucinous components than in tumors from mucosal cancers (P = 0.023). Furthermore, TNS4 expression was higher in moderately differentiated tumors than in poorly differentiated and non-differentiated tumors (P = 0.002). Increased TNS4 expression was also noted in the intestinal type of GC according to Lauren’s classification (P = 0.020). No statistically significant correlation was found between the expression of TNS4 and the overall survival rate of patients.
CONCLUSION TNS4 expression was significantly higher in tumors with a diameter ≥ 5 cm of the moderately differentiated intestinal type (according to Lauren’s classification) of GC without a mucinous component. Therefore, increased TNS4 expression is related to the histological type of GC with a better prognosis.
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Affiliation(s)
- Marcin Nizioł
- Department of General Pathomorphology, Medical University of Bialystok, Białystok 15-089, Poland
| | - Justyna Zińczuk
- Department of Clinical Laboratory Diagnostics, Medical University of Białystok, Bialystok 15-089, Poland
| | - Konrad Zaręba
- The Second Clinical Department of General and Gastroenterological Surgery, Medical University of Bialystok, Białystok 15-089, Poland
| | | | - Anna Pryczynicz
- Department of General Pathomorphology, Medical University of Bialystok, Białystok 15-089, Poland
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5
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Lu X, Zhou B, Cao M, Shao Q, Pan Y, Zhao T. CTEN Inhibits Tumor Angiogenesis and Growth by Targeting VEGFA Through Down-Regulation of β-Catenin in Breast Cancer. Technol Cancer Res Treat 2021; 20:15330338211045506. [PMID: 34817293 PMCID: PMC8661028 DOI: 10.1177/15330338211045506] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
C-terminal tensin-like (CTEN) belongs to the tensin gene family, which encodes
proteins that localize to focal adhesions and modulate integrin function.
Accumulating studies have reported that CTEN expression can be upregulated or
downregulated in different types of cancers, suggesting that CTEN has both
oncogenic and tumor suppressor functions. In this study, by analyzing the
expression level of CTEN in the human breast cancer (BRCA) samples from the
clinically annotated genomic database, The Cancer Genome Atlas, we found that
CTEN was downregulated in different BRCA subclasses, including luminal, human
epidermal growth factor receptor 2 positive and triple-negative BRCA.
Consistently, the protein level of CTEN was also reduced in BRCA based on the
Proteomic Tumor Analysis Consortium. In contrast, vascular endothelial growth
factor A (VEGFA), a signal protein that stimulates the formation of blood
vessels, was upregulated in BRCA. CTEN overexpression in human umbilical vein
endothelial cells and MCF7 significantly suppressed the expression of VEGFA,
inhibited cell proliferation, migration, and tube formation in vitro.
Mechanistically, CTEN bind to casitas B-lineage lymphoma (c-Cbl), an E3
ubiquitin-protein ligase, and decreased the β-catenin expression. In turn, the
downregulation of β-catenin reduced the expression of VEGFA. Rescuing β-catenin
expression effectively ameliorated the effect of CTEN overexpression in cell
proliferation, migration, and tube formation. In conclusion, CTEN inhibited
tumor angiogenesis by targeting VEGFA through c-Cbl-mediated down-regulation of
β-catenin and may serve as a tumor suppressor in BRCA.
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Affiliation(s)
- Xiangdong Lu
- Jiangyin People's Hospital, Jiangyin, Jiangsu Province, 214400, P.R. China
| | - Bin Zhou
- Jiangyin People's Hospital, Jiangyin, Jiangsu Province, 214400, P.R. China
| | - Minmin Cao
- Jiangyin People's Hospital, Jiangyin, Jiangsu Province, 214400, P.R. China
| | - Qin Shao
- Jiangyin People's Hospital, Jiangyin, Jiangsu Province, 214400, P.R. China
| | - Yukai Pan
- Jiangyin People's Hospital, Jiangyin, Jiangsu Province, 214400, P.R. China
| | - Tao Zhao
- Jiangyin People's Hospital, Jiangyin, Jiangsu Province, 214400, P.R. China
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6
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Tolomeo M, Cascio A. The Multifaced Role of STAT3 in Cancer and Its Implication for Anticancer Therapy. Int J Mol Sci 2021; 22:ijms22020603. [PMID: 33435349 PMCID: PMC7826746 DOI: 10.3390/ijms22020603] [Citation(s) in RCA: 191] [Impact Index Per Article: 47.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2020] [Revised: 12/24/2020] [Accepted: 01/05/2021] [Indexed: 12/12/2022] Open
Abstract
Signal transducer and activator of transcription (STAT) 3 is one of the most complex regulators of transcription. Constitutive activation of STAT3 has been reported in many types of tumors and depends on mechanisms such as hyperactivation of receptors for pro-oncogenic cytokines and growth factors, loss of negative regulation, and excessive cytokine stimulation. In contrast, somatic STAT3 mutations are less frequent in cancer. Several oncogenic targets of STAT3 have been recently identified such as c-myc, c-Jun, PLK-1, Pim1/2, Bcl-2, VEGF, bFGF, and Cten, and inhibitors of STAT3 have been developed for cancer prevention and treatment. However, despite the oncogenic role of STAT3 having been widely demonstrated, an increasing amount of data indicate that STAT3 functions are multifaced and not easy to classify. In fact, the specific cellular role of STAT3 seems to be determined by the integration of multiple signals, by the oncogenic environment, and by the alternative splicing into two distinct isoforms, STAT3α and STAT3β. On the basis of these different conditions, STAT3 can act both as a potent tumor promoter or tumor suppressor factor. This implies that the therapies based on STAT3 modulators should be performed considering the pleiotropic functions of this transcription factor and tailored to the specific tumor type.
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7
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Lu X, Zhang Y, Pan Y, Cao M, Zhou X, Zhang T. Overexpression of CTEN is associated with gefitinib resistance in non-small cell lung cancer. Oncol Lett 2020; 21:40. [PMID: 33262832 PMCID: PMC7693301 DOI: 10.3892/ol.2020.12301] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2020] [Accepted: 10/12/2020] [Indexed: 01/28/2023] Open
Abstract
COOH-terminus tensin-like molecule (CTEN) is a member of the tensin family, which is considered to be one of the novel proto-oncogenes involved in tumorigenesis and cancer progression. However, the mechanisms of CTEN in acquired resistance of non-small cell lung cancer (NSCLC) remain relatively unknown. The aim of the present study was to understand the roles of CTEN in acquired gefitinib resistance of NSCLC. The present study investigated the expression level of CTEN using reverse transcription-quantitative polymerase chain reaction and Western blot analysis. Cell Counting kit-8 and colony-formation assays were performed to evaluate the proliferative and colony-formative abilities of PC9 and PC9/GR cells in vitro. Mouse xenograft models were used to assess the growth of PC9/GR cells in vivo. A gefitinib-resistant NSCLC cell line (PC9/GR) was established, and the protein and mRNA expression levels of CTEN were observed to be higher in PC9/GR cells than in PC9 cells. Notably, the sensitivity of PC9/GR cells to gefitinib was observed to be decreased when CTEN was overexpressed, while PC9/GR cells with CTEN-downregulation showed markedly enhanced sensitivity to gefitinib. In vitro proliferation and colony formation assays revealed that increased CTEN markedly promoted the cell proliferative and colony-forming capacities of PC9 and PC9/GR cells, and CTEN-silencing inhibited the cell proliferative and colony-forming abilities of the PC9 and PC9/GR cells. Notably, deficient expression of CTEN notably retarded the growth of PC9/GR xenografts in vivo. In addition, the plasma mRNA expression of CTEN was notably elevated in patients with NSCLC with acquired gefitinib resistance. Overexpression of CTEN is associated with acquired gefitinib resistance in NSCLC. CTEN may be investigated as a potential therapeutic target for the treatment of patients with NSCLC with acquired gefitinib resistance.
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Affiliation(s)
- Xiangdong Lu
- Department of Oncology, The Jiangyin Hospital Affiliated to Medical College of Southeast University, Jiangyin, Jiangsu 214400, P.R. China
| | - Yao Zhang
- Department of Oncology, The Jiangyin Hospital Affiliated to Medical College of Southeast University, Jiangyin, Jiangsu 214400, P.R. China
| | - Yukai Pan
- Department of Oncology, The Jiangyin Hospital Affiliated to Medical College of Southeast University, Jiangyin, Jiangsu 214400, P.R. China
| | - Minmin Cao
- Department of Oncology, The Jiangyin Hospital Affiliated to Medical College of Southeast University, Jiangyin, Jiangsu 214400, P.R. China
| | - Xie Zhou
- Department of Oncology, The Jiangyin Hospital Affiliated to Medical College of Southeast University, Jiangyin, Jiangsu 214400, P.R. China
| | - Tingrong Zhang
- Department of Oncology, The Jiangyin Hospital Affiliated to Medical College of Southeast University, Jiangyin, Jiangsu 214400, P.R. China
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8
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Fleming JC, Woo J, Moutasim K, Hanley CJ, Frampton SJ, Wood O, Ward M, Woelk CH, Ottensmeier CH, Hafizi S, Kim D, Thomas GJ. CTEN Induces Tumour Cell Invasion and Survival and Is Prognostic in Radiotherapy-Treated Head and Neck Cancer. Cancers (Basel) 2020; 12:E2963. [PMID: 33066224 PMCID: PMC7602105 DOI: 10.3390/cancers12102963] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2020] [Revised: 09/18/2020] [Accepted: 10/08/2020] [Indexed: 12/12/2022] Open
Abstract
Head and neck squamous cell carcinoma (HNSCC) is a heterogenous disease treated with surgery and/or (chemo) radiotherapy, but up to 50% of patients with late-stage disease develop locoregional recurrence. Determining the mechanisms underpinning treatment resistance could identify new therapeutic targets and aid treatment selection. C-terminal tensin-like (CTEN) is a member of the tensin family, upregulated in several cancers, although its expression and function in HNSCC are unknown. We found that CTEN is commonly upregulated in HNSCC, particularly HPV-ve tumours. In vitro CTEN was upregulated in HPV-ve (n = 5) and HPV+ve (n = 2) HNSCC cell lines. Stable shRNA knockdown of CTEN in vivo significantly reduced tumour growth (SCC-25), and functional analyses in vitro showed that CTEN promoted tumour cell invasion, colony formation and growth in 3D-culture (SCC-25, Detroit 562). RNA sequencing of SCC-25 cells following CTEN siRNA knockdown identified 349 differentially expressed genes (logFC > 1, p < 0.05). Gene ontology analysis highlighted terms relating to cell locomotion and apoptosis, consistent with in vitro findings. A membrane-based antibody array confirmed that CTEN regulated multiple apoptosis-associated proteins, including HSP60 and cleaved caspase-3. Notably, in a mixed cohort of HPV+ve and HPV-ve HNSCC patients (n = 259), we found a significant, independent negative association of CTEN with prognosis, limited to those patients treated with (chemo)radiotherapy, not surgery, irrespective of human papillomavirus (HPV) status. These data show that CTEN is commonly upregulated in HNSCC and exerts several functional effects. Its potential role in modulating apoptotic response to therapy suggests utility as a predictive biomarker or radio-sensitising target.
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Affiliation(s)
- Jason C. Fleming
- Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton SO17 1BJ, UK; (K.M.); (C.J.H.); (S.J.F.); (O.W.); (M.W.); (C.H.O.)
- Liverpool Head & Neck Centre, University of Liverpool, Liverpool L3 9GA, UK
- Liverpool University Hospitals NHS Foundation Trust, Liverpool L9 7AL, UK
| | - Jeongmin Woo
- Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton SO17 1BJ, UK; (J.W.); (C.H.W.)
| | - Karwan Moutasim
- Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton SO17 1BJ, UK; (K.M.); (C.J.H.); (S.J.F.); (O.W.); (M.W.); (C.H.O.)
| | - Christopher J. Hanley
- Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton SO17 1BJ, UK; (K.M.); (C.J.H.); (S.J.F.); (O.W.); (M.W.); (C.H.O.)
| | - Steven J. Frampton
- Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton SO17 1BJ, UK; (K.M.); (C.J.H.); (S.J.F.); (O.W.); (M.W.); (C.H.O.)
| | - Oliver Wood
- Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton SO17 1BJ, UK; (K.M.); (C.J.H.); (S.J.F.); (O.W.); (M.W.); (C.H.O.)
| | - Matthew Ward
- Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton SO17 1BJ, UK; (K.M.); (C.J.H.); (S.J.F.); (O.W.); (M.W.); (C.H.O.)
| | - Christopher H. Woelk
- Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton SO17 1BJ, UK; (J.W.); (C.H.W.)
- Exploratory Science Center, Merck & Co., Inc., Cambridge, MA 02141, USA
| | - Christian H. Ottensmeier
- Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton SO17 1BJ, UK; (K.M.); (C.J.H.); (S.J.F.); (O.W.); (M.W.); (C.H.O.)
- Liverpool Head & Neck Centre, University of Liverpool, Liverpool L3 9GA, UK
- Liverpool University Hospitals NHS Foundation Trust, Liverpool L9 7AL, UK
- Clatterbridge Cancer Centre NHS Foundation Trust, Liverpool CH63 4JY, UK
| | - Sassan Hafizi
- School of Pharmacy & Biomedical Sciences, University of Portsmouth, Portsmouth PO1 2DT, UK;
| | - Dae Kim
- St. George’s University Hospitals NHS Foundation Trust, Tooting, London SW17 0QT, UK;
| | - Gareth J. Thomas
- Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton SO17 1BJ, UK; (K.M.); (C.J.H.); (S.J.F.); (O.W.); (M.W.); (C.H.O.)
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9
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Qi X, Sun L, Wan J, Xu R, He S, Zhu X. Tensin4 promotes invasion and migration of gastric cancer cells via regulating AKT/GSK-3β/snail signaling pathway. Pathol Res Pract 2020; 216:153001. [PMID: 32534709 DOI: 10.1016/j.prp.2020.153001] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/09/2020] [Revised: 04/06/2020] [Accepted: 05/07/2020] [Indexed: 12/24/2022]
Abstract
Gastric cancer (GC) remains one of the most lethal human malignancies, and exploring novel therapeutic targets for the treatment has been a major focus. The molecular mechanism of invasion and migration of GC cells remains unclear. The present study aimed to investigate the role of Tensin 4 and the associated molecular signaling pathways in the process of invasion and metastasis of GC. The expression of Tensin 4 protein and phosphorylated AKT (p-AKT) were evaluated in GC and normal adjacent tissues of 80 patients using immunohistochemistry staining. The expression of Tensin4 mRNA was analyzed in 10 GC tissues and 3 GC cell lines (SGC7901, MKN45, and MKN28) by qPCR. Cell proliferation, migration, and invasion were assessed using CCK-8 and Transwell assays in the Tensin 4 siRNA transfected SGC7901 cells and Tensin 4 plasmid transfected MKN28 cells. Additionally, protein expressions of Tensin 4, E-cadherin, vimentin, AKT, p-AKT, GSK-3β, p-GSK-3β, and Snail were analyzed by western blotting. The results demonstrated that the expression of Tensin 4 was significantly up-regulated in the GC tissues and cell lines, especially in the SGC7901 cells. The expression of Tensin 4 positively correlated with p-AKT in GC tissues and with GC progression, and was an independent risk factor for the prognosis of GC. Tensin 4 promoted the invasion and migration abilities of GC cells, but had no significant effect on GC cell proliferation. Tensin 4 promoted the occurrence of epithelial mesenchymal transition (EMT) through up-regulating the expression of p-AKT, p-GSK-3β, and snail. Overall, this study suggests that the activation of AKT/GSK-3β/Snail signaling pathway promoted by Tensin 4 plays an important role in the progression of GC. Therefore, Tensin 4 may serve as a potential target in GC treatment.
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Affiliation(s)
- Xiumin Qi
- Department of General Surgery, The First Affiliated Hospital of Soochow University, 188 ShiZi Street, Suzhou 215006, China; Department of Pathology, Nanjing Medical University Affiliated Wuxi Second Hospital, China
| | - Liang Sun
- Department of General Surgery, The First Affiliated Hospital of Soochow University, 188 ShiZi Street, Suzhou 215006, China
| | - Jiayi Wan
- Department of Pathology, Nanjing Medical University Affiliated Wuxi Second Hospital, China
| | - Rongrong Xu
- Department of Pathology, Nanjing Medical University Affiliated Wuxi Second Hospital, China
| | - Songbing He
- Department of General Surgery, The First Affiliated Hospital of Soochow University, 188 ShiZi Street, Suzhou 215006, China.
| | - Xinguo Zhu
- Department of General Surgery, The First Affiliated Hospital of Soochow University, 188 ShiZi Street, Suzhou 215006, China.
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10
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Raposo TP, Susanti S, Ilyas M. Investigating TNS4 in the Colorectal Tumor Microenvironment Using 3D Spheroid Models of Invasion. ACTA ACUST UNITED AC 2020; 4:e2000031. [PMID: 32390347 DOI: 10.1002/adbi.202000031] [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: 01/27/2020] [Revised: 04/07/2020] [Accepted: 04/15/2020] [Indexed: 12/30/2022]
Abstract
TNS4 (Tensin 4 or Cten) is a putative oncogene in colorectal cancer (CRC) with a role in regulating cell adhesion, motility, invasion, and epithelial to mesenchymal transition (EMT). The objective is to study the role of TNS4 in CRC using more realistic models of the tumor microenvironment. CRC cells expressing TdTomato protein and shTNS4/shLUC hairpin oligos are grown in 3D spheroids with and without cancer-associated fibroblasts (CAFs). Adhesiveness to collagen I and CAFs is assessed in 2D and cell proliferation, volume, and invasion are assessed in 3D conditions. The role of TNS4 knockdown in gefitinib chemosensitivity and epidermal growth factor receptor (EGFR) and Ras protein levels are also tested. In general, TNS4 knockdown increases cell proliferation in cell lines producing compact spheroids. The addition of CAFs in spheroids supports CRC cell proliferation, whereas CAFs themselves do not proliferate, but increases ECM degradation. TNS4 knockdown reduces adhesiveness and 3D invasion and disrupts EGFR signaling which results in increased sensitivity to Gefitinib. In conclusion, in a 3D spheroid model, TNS4 inhibits cell proliferation and promotes cell invasion into the ECM, possibly by adhesion to the ECM and stromal cells. TNS4 knockdown enhances sensitivity to the EGFR inhibitor gefitinib and may be helpful for Kirsten ras oncogene homolog mutant CRC patients.
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Affiliation(s)
- Teresa P Raposo
- Dr. T. P. Raposo, Dr. S. Susanti, Prof. M. Ilyas, Division of Cancer and Stem Cells, School of Medicine, University of Nottingham, Queen's Medical Centre, Nottingham, NG7 2UH, UK.,Dr. T. P. Raposo, Dr. S. Susanti, Prof. M. Ilyas, Nottingham Molecular Pathology Node, University of Nottingham, UK
| | - Susanti Susanti
- Dr. T. P. Raposo, Dr. S. Susanti, Prof. M. Ilyas, Division of Cancer and Stem Cells, School of Medicine, University of Nottingham, Queen's Medical Centre, Nottingham, NG7 2UH, UK.,Dr. T. P. Raposo, Dr. S. Susanti, Prof. M. Ilyas, Nottingham Molecular Pathology Node, University of Nottingham, UK.,Dr. S. Susanti, Deparment of Pharmacology and Clinical Pharmacy, Faculty of Pharmacy, University of Muhammadiyah Purwokerto, Banyumas, Central Java, 53182, Indonesia
| | - Mohammad Ilyas
- Dr. T. P. Raposo, Dr. S. Susanti, Prof. M. Ilyas, Division of Cancer and Stem Cells, School of Medicine, University of Nottingham, Queen's Medical Centre, Nottingham, NG7 2UH, UK.,Dr. T. P. Raposo, Dr. S. Susanti, Prof. M. Ilyas, Nottingham Molecular Pathology Node, University of Nottingham, UK
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11
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Asiri A, Toss MS, Raposo TP, Akhlaq M, Thorpe H, Alfahed A, Asiri A, Ilyas M. Cten promotes Epithelial–Mesenchymal Transition (EMT) in colorectal cancer through stabilisation of Src. Pathol Int 2019; 69:381-391. [DOI: 10.1111/pin.12811] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2019] [Accepted: 05/03/2019] [Indexed: 12/28/2022]
Affiliation(s)
- Abdulaziz Asiri
- Division of Cancer and Stem Cells, School of MedicineThe University of Nottingham Nottingham UK
- Nottingham Molecular Pathology Node, Queen's Medical CentreThe University of Nottingham Nottingham UK
- Medical Genomics Research Department, King Abdullah International Medical Research Center (KAIMRC), King Saud Bin Abdulaziz University for Health SciencesMinistry of National Guard Health Affairs (MNGH) Riyadh Saudi Arabia
| | - Michael S. Toss
- Division of Cancer and Stem Cells, School of MedicineThe University of Nottingham Nottingham UK
| | - Teresa Pereira Raposo
- Division of Cancer and Stem Cells, School of MedicineThe University of Nottingham Nottingham UK
- Nottingham Molecular Pathology Node, Queen's Medical CentreThe University of Nottingham Nottingham UK
| | - Maham Akhlaq
- Division of Cancer and Stem Cells, School of MedicineThe University of Nottingham Nottingham UK
| | - Hannah Thorpe
- Division of Cancer and Stem Cells, School of MedicineThe University of Nottingham Nottingham UK
- Nottingham Molecular Pathology Node, Queen's Medical CentreThe University of Nottingham Nottingham UK
| | - Abdulaziz Alfahed
- Division of Cancer and Stem Cells, School of MedicineThe University of Nottingham Nottingham UK
- Nottingham Molecular Pathology Node, Queen's Medical CentreThe University of Nottingham Nottingham UK
- Department of Medical Laboratory, College of Applied Medical SciencesPrince Sattam Bin Abdulaziz University Al‐Kharj Saudi Arabia
| | - Abutaleb Asiri
- Division of Cancer and Stem Cells, School of MedicineThe University of Nottingham Nottingham UK
- Nottingham Molecular Pathology Node, Queen's Medical CentreThe University of Nottingham Nottingham UK
| | - Mohammad Ilyas
- Division of Cancer and Stem Cells, School of MedicineThe University of Nottingham Nottingham UK
- Nottingham Molecular Pathology Node, Queen's Medical CentreThe University of Nottingham Nottingham UK
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12
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Asiri A, Raposo TP, Alfahed A, Ilyas M. TGFβ1-induced cell motility but not cell proliferation is mediated through Cten in colorectal cancer. Int J Exp Pathol 2019; 99:323-330. [PMID: 30648319 DOI: 10.1111/iep.12300] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2018] [Revised: 11/21/2018] [Accepted: 12/06/2018] [Indexed: 12/18/2022] Open
Abstract
Cten (C-terminal tensin-like) is a member of the tensin protein family found in complex with integrins at focal adhesions. It promotes epithelial-mesenchymal transition (EMT) and cell motility. The precise mechanisms regulating Cten are unknown, although we and others have shown that Cten could be under the regulation of several cytokines and growth factors. Since transforming growth factor beta 1 (TGF-β1) regulates integrin function and promotes EMT/cell motility, we were prompted to investigate whether TGF-β1 induces EMT and cell motility through Cten signalling in colorectal cancer. TGF-β1 signalling was modulated by either stimulation with TGF-β1 or knockdown of TGF-β1 in the CRC cell lines SW620 and HCT116. The effect of this modulation on expression of Cten, EMT markers and on cellular function was tested. The role of Cten as a direct mediator of TGF-β1 signalling was investigated in a CRC cell line in which the Cten gene had been deleted (SW620ΔCten ). When TGF-β1 was stimulated or inhibited, this resulted in, respectively, upregulation and downregulation of Cten expression and EMT markers (Snail, Rock, N-cadherin, Src). Cell migration and cell invasion were significantly increased following TGF-β1 stimulation and lost by TGF-β1 knockdown. TGF-β1 stimulation of the SW620ΔCten cell line resulted in selective loss of the effect of TGF-β1 signalling pathway on EMT and cell motility while the stimulatory effect on cell proliferation was retained. These data suggested Cten may play an essential role in mediating TGF-β1-induced EMT and cell motility and may therefore play a role in metastasis in CRC.
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Affiliation(s)
- Abdulaziz Asiri
- Division of Cancer and Stem Cells, Queen's Medical Centre, School of Medicine, University of Nottingham, Nottingham, UK.,Nottingham Molecular Pathology Node, Queen's Medical Centre, University of Nottingham, Nottingham, UK
| | - Teresa Pereira Raposo
- Division of Cancer and Stem Cells, Queen's Medical Centre, School of Medicine, University of Nottingham, Nottingham, UK.,Nottingham Molecular Pathology Node, Queen's Medical Centre, University of Nottingham, Nottingham, UK
| | - Abdulaziz Alfahed
- Division of Cancer and Stem Cells, Queen's Medical Centre, School of Medicine, University of Nottingham, Nottingham, UK.,Nottingham Molecular Pathology Node, Queen's Medical Centre, University of Nottingham, Nottingham, UK.,Department of Medical Laboratory, College of Applied Medical Sciences, Prince Sattam Bin Abdulaziz University, Al-Kharj, 11942, Saudi Arabia
| | - Mohammad Ilyas
- Division of Cancer and Stem Cells, Queen's Medical Centre, School of Medicine, University of Nottingham, Nottingham, UK.,Nottingham Molecular Pathology Node, Queen's Medical Centre, University of Nottingham, Nottingham, UK
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13
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Lu X, Gao J, Zhang Y, Zhao T, Cai H, Zhang T. CTEN induces epithelial-mesenchymal transition (EMT) and metastasis in non small cell lung cancer cells. PLoS One 2018; 13:e0198823. [PMID: 29985912 PMCID: PMC6037349 DOI: 10.1371/journal.pone.0198823] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2018] [Accepted: 05/26/2018] [Indexed: 12/29/2022] Open
Abstract
To explore the effects and mechanism of CTEN (COOH-terminus tensin-like molecule) on EMT, cell migration and invasion of Human lung adenocarcinoma cells. The pCMV-vector, pCMV-CTEN, Control-shRNA, and CTEN-shRNA were transfected into A549 and NCI-H1299 cells by Lipofectamine 2000. Transforming growth factor-β1(TGF-β1)and epithelial-mesenchymal transition (EMT) -related biomarkers were detected by eliseand western blot. The migration and invasion ability of A549 cells and NCI-H1299 were examined by scratch-wound assay and transwell assay respectively. We found compare with control group, the expression of TGF-β and mesenchymal markers in CTEN overexpression group were increased, and the epithelial marker was decreased, which induced the EMT process. Meanwhile, scratch-woundassay showed that the migration efficiency of A549 and NCI-H1299 cells in CTEN overexpression group were higher than that in control group.Transwell assay demonstrated that the number of cells that migrated and invaded through the membrane were obviously more than those in control group.Furthermore, Knockdown of CTEN partially reversed transforming growth factor-β1(TGF-β1)-induced changes in EMT markers. In conclusion, CTEN activated the expression of TGF-β1, thereby prompting EMT in lung adenocareinma cancer cells.
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Affiliation(s)
- Xiangdong Lu
- Department of Oncology, The Jiangyin Hospital Affiliated to Medical College of Southeast University, Jiangyin, P.R.China
| | - Juan Gao
- Department of Obstetrics and Gynecology, Jiangyin Hospital of Traditional Chinese Medicine, Jiangyin, P.R.China
| | - Yao Zhang
- Department of Oncology, The Jiangyin Hospital Affiliated to Medical College of Southeast University, Jiangyin, P.R.China
| | - Tao Zhao
- Department of Oncology, The Jiangyin Hospital Affiliated to Medical College of Southeast University, Jiangyin, P.R.China
| | | | - Tingrong Zhang
- Department of Oncology, The Jiangyin Hospital Affiliated to Medical College of Southeast University, Jiangyin, P.R.China
- * E-mail:
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Sawazaki S, Oshima T, Sakamaki K, Aoyama T, Sato T, Shiozawa M, Yoshikawa T, Rino Y, Imada T, Masuda M. Clinical Significance of Tensin 4 Gene Expression in Patients with Gastric Cancer. ACTA ACUST UNITED AC 2018; 31:1065-1071. [PMID: 29102927 DOI: 10.21873/invivo.11171] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2017] [Revised: 08/14/2017] [Accepted: 08/22/2017] [Indexed: 12/15/2022]
Abstract
BACKGROUND Overall survival remains unsatisfactory in stage II/III gastric cancer, even after curative resection and adjuvant chemotherapy. Tensin 4 (TNS4), a cell adhesion factor, is associated with cancer-cell motility and migration. PATIENTS AND METHODS We examined the clinical significance of TNS4 gene expression in 134 patients with stage II/III gastric cancer who underwent adjuvant chemotherapy with S-1. TNS4 gene expression in surgical specimens was measured by quantitative reverse-transcription polymerase chain reaction (RT-PCR). RESULTS TNS4 gene expression levels were significantly higher in cancer tissue than in adjacent normal mucosa. High TNS4 gene expression was associated with significantly poorer 5-year overall survival than was low expression. On multivariate analysis, TNS4 gene expression was an independent prognostic factor. CONCLUSION Overexpression of the TNS4 gene is a useful independent predictor of outcomes in patients with stage II/III gastric cancer who undergo surgery and receive adjuvant chemotherapy with S-1.
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Affiliation(s)
- Sho Sawazaki
- Department of Surgery, Yokohama City University, Yokohama, Japan
| | - Takashi Oshima
- Department of Surgery, Yokohama City University, Yokohama, Japan
| | - Kentaro Sakamaki
- Department of Biostatistics, Yokohama City University Medical Center, Yokohama, Japan
| | - Toru Aoyama
- Department of Surgery, Yokohama City University, Yokohama, Japan
| | - Tsutomu Sato
- Department of Surgery, Yokohama City University, Yokohama, Japan
| | - Manabu Shiozawa
- Department of Gastrointestinal Surgery, Kanagawa Cancer Center, Yokohama, Japan
| | - Takaki Yoshikawa
- Department of Gastrointestinal Surgery, Kanagawa Cancer Center, Yokohama, Japan
| | - Yasushi Rino
- Department of Surgery, Yokohama City University, Yokohama, Japan
| | - Toshio Imada
- Department of Surgery, Saiseikai Yokohama-shi Nanbu Hospital, Yokohama, Japan
| | - Munetaka Masuda
- Department of Surgery, Yokohama City University, Yokohama, Japan
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15
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Integrated MicroRNA-mRNA Analysis Reveals miR-204 Inhibits Cell Proliferation in Gastric Cancer by Targeting CKS1B, CXCL1 and GPRC5A. Int J Mol Sci 2017; 19:ijms19010087. [PMID: 29283424 PMCID: PMC5796037 DOI: 10.3390/ijms19010087] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2017] [Revised: 12/23/2017] [Accepted: 12/25/2017] [Indexed: 01/07/2023] Open
Abstract
Gastric cancer (GC) is the second most frequent cause of cancer-related deaths worldwide. MicroRNAs are single-stranded RNA molecules of 21–23 nucleotides that regulate target gene expression through specific base-pairing interactions between miRNA and untranslated regions of targeted mRNAs. In this study, we generated a multistep approach for the integrated analysis of miRNA and mRNA expression. First, both miRNA and mRNA expression profiling datasets in gastric cancer from the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) identified 79 and 1042 differentially expressed miRNAs and mRNAs, respectively, in gastric cancer. Second, inverse correlations between miRNA and mRNA expression levels identified 3206 miRNA–mRNA pairs combined with 79 dysregulated miRNAs and their 774 target mRNAs predicted by three prediction tools, miRanda, PITA, and RNAhybrid. Additionally, miR-204, which was found to be down-regulated in gastric cancer, was ectopically over-expressed in the AGS gastric cancer cell line and all down-regulated targets were identified by RNA sequencing (RNA-seq) analysis. Over-expression of miR-204 reduced the gastric cancer cell proliferation and suppressed the expression of three targets which were validated by qRT-PCR and luciferase assays. For the first time, we identified that CKS1B, CXCL1, and GPRC5A are putative targets of miR-204 and elucidated that miR-204 acted as potential tumor suppressor and, therefore, are useful as a promising therapeutic target for gastric cancer.
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16
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Overexpression of CTEN relates to tumor malignant potential and poor outcomes of adenocarcinoma of the esophagogastric junction. Oncotarget 2017; 8:84112-84122. [PMID: 29137409 PMCID: PMC5663581 DOI: 10.18632/oncotarget.21109] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2017] [Accepted: 09/04/2017] [Indexed: 01/14/2023] Open
Abstract
Background To detect a novel treatment target for adenocarcinoma of the esophagogastric junction (AEG), we tested whether C-terminal tensin-like (CTEN), a member of the tensin gene family and frequently overexpressed in various cancers, acts as a cancer-promoting gene through overexpression in AEG. Materials and Methods We analyzed 5 gastric adenocarcinoma (GC) cell lines and 104 primary AEG tumors curatively resected in our hospital between 2000 and 2010. Results CTEN overexpression was detected in GC cell lines (2/5 cell lines; 40%) and primary AEG tumor samples (35/104 cases; 34%). CTEN knockdown using several specific siRNAs inhibited the proliferation, migration, and invasion of CTEN-overexpressing cells. CTEN overexpression was significantly correlated with more aggressive venous and lymphatic invasion, deeper tumor depth, and higher rates of lymph node metastasis and recurrence. Patients with CTEN-overexpressing tumors had a worse overall rate of survival than those with non-expressing tumors (P < 0.0001, log-rank test) in an expression-dependent manner. CTEN positivity was independently associated with a worse outcome in the multivariate analysis (P = 0.0423, hazard ratio 3.54 [1.04-16.4]). Conclusions CTEN plays a crucial role in tumor cell proliferation, migration, and invasion through its overexpression, which highlights its usefulness as a prognosticator and potential therapeutic target in AEG.
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17
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Tensin4 is up-regulated by EGF-induced ERK1/2 activity and promotes cell proliferation and migration in hepatocellular carcinoma. Oncotarget 2016; 6:20964-76. [PMID: 26035355 PMCID: PMC4673243 DOI: 10.18632/oncotarget.4122] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2014] [Accepted: 05/02/2015] [Indexed: 12/16/2022] Open
Abstract
The focal adhesion protein Tensin4, also known as cten (c-terminal tensin like), is structurally distinct from the three other members in the Tensin family. Its expression and potential functions in cancers including hepatocellular carcinoma (HCC) are not well understood. With immunohistochemistry, 43% (13/30) of our human HCC cases showed up-regulation of Tensin4 as compared with their corresponding non-tumorous livers. In HCC cells, treatment with epidermal growth factor (EGF) significantly induced Tensin4 transcript and protein expression, while treatment with pharmacological inhibitors against the MEK1/2 kinases abolished such induction, suggesting that Tensin4 expression was dependent on Ras/MAPK signaling. With immunofluorescence microscopy, the focal adhesion localization of Tensin4 was confirmed in HCC cells. Significantly, detailed examination using a panel of Tensin4 deletion constructs revealed that this specific focal adhesion localization required the N-terminal region together with the C-terminal SH2 domain. Up-regulation of ERK signaling by EGF in the HCC cells resulted in a change to a mesenchymal cell-like morphology through modulation of the actin cytoskeleton. Functionally, stable Tensin4 knockdown in SMMC-7721 HCC cells resulted in reduced cell proliferation and migration in vitro. Taken together, our data suggest that Tensin4 may play a pro-oncogenic role in HCC, possibly functioning as a downstream effector of Ras/MAPK signaling.
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18
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Thorpe H, Akhlaq M, Jackson D, Al Ghamdi S, Storr S, Martin S, Ilyas M. Multiple pathways regulate Cten in colorectal cancer without a Tensin switch. Int J Exp Pathol 2016; 96:362-9. [PMID: 26852686 DOI: 10.1111/iep.12154] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2015] [Accepted: 08/28/2015] [Indexed: 02/07/2023] Open
Abstract
CTEN/TNS4 is a member of the Tensin gene family. It localizes to focal adhesions and induces cell motility. The mechanisms regulating Cten expression are unclear although we have shown regulation by Kras in the colon and pancreas. In normal mammary cell lines, it is reportedly upregulated by epidermal growth factor receptor (EGFR) and STAT3 signalling and upregulation is accompanied by downregulation of Tensin 3 (Tensin switch). In this study, we investigated the roles of EGFR and STAT3 signalling in the regulation of Cten in colorectal cancer (CRC). In addition, we investigated calpain--a regulator of focal adhesion-associated proteins whose relevance to Cten has not been investigated. CRC cell lines were stimulated with epidermal growth factor (EGF). This resulted in an increase in Cten and Tensin 3 protein. Kras was knocked down and this resulted in downregulation of Cten and Tensin 3. We next investigated the role of STAT3 signalling. Activation and knockdown of STAT3 resulted in downregulation and upregulation, respectively, of Cten. Inhibition of calpain resulted in upregulation of both Cten and Tensin 3. As the regulators of Cten also seemed to regulate Tensin 3, we tested the interaction between Cten and Tensin 3. Cten was forcibly expressed or knocked down resulting, respectively, in upregulation and downregulation of Tensin 3. We conclude that in CRC, Cten is upregulated by EGFR and Kras but downregulated by STAT3. We show that calpain may be a negative regulator of Cten and that a Tensin switch does not occur and, if anything, Cten stabilizes Tensin 3.
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Affiliation(s)
- Hannah Thorpe
- School of Medicine, University of Nottingham, Nottingham, UK
| | - Maham Akhlaq
- School of Medicine, University of Nottingham, Nottingham, UK
| | - Darryl Jackson
- School of Medicine, University of Nottingham, Nottingham, UK
| | - Saleh Al Ghamdi
- King Abdullah International Medical Research Center, KSAU-HS, Riyadh, Saudi Arabia
| | - Sarah Storr
- School of Medicine, University of Nottingham, Nottingham, UK
| | - Stewart Martin
- School of Medicine, University of Nottingham, Nottingham, UK
| | - Mohammad Ilyas
- School of Medicine, University of Nottingham, Nottingham, UK
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19
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C-terminal tensin-like protein mediates invasion of human lung cancer cells and is regulated by signal transducer and activator of transcription 3. J Thorac Cardiovasc Surg 2014; 149:369-75. [PMID: 25439778 DOI: 10.1016/j.jtcvs.2014.08.087] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/25/2014] [Revised: 08/04/2014] [Accepted: 08/24/2014] [Indexed: 02/02/2023]
Abstract
OBJECTIVES C-terminal tensin-like (Cten) protein, a component of focal adhesions, contributes to cell motility and invasion in multiple human cancers. Epidermal growth factor can activate signal transducer and activator of transcription 3, and both contribute to invasion through focal adhesion interactions. We hypothesize that Cten may mediate invasion of lung cancer cells provided by epidermal growth factor via signal transducer and activator of transcription 3. METHODS Four human non-small cell lung cancer cell lines were treated with epidermal growth factor to evaluate activation of the signal transducer and activator of transcription 3 pathway and induction of Cten expression. Chemical inhibition of signal transducer and activator of transcription 3 was used to evaluate the effect on epidermal growth factor-induced Cten expression. Protein expression was quantified by Western blot. H125 and A549 cells were transduced with short-hairpin RNA via lentiviral vector to knockdown expression of Cten. An in vitro transwell invasion assay was used to assess the effects of Cten knockdown on cell invasion (n = 3 for all experiments). RESULTS Stimulation of lung cancer cells with epidermal growth factor activated the signal transducer and activator of transcription 3 pathway and induced expression of Cten in all cell lines. Signal transducer and activator of transcription 3 inhibition significantly reduced epidermal growth factor-induced expression of Cten in H125 (P < .0001), H358 (P = .006), and H441 (P = .014) cells in a dose-dependent manner. Knockdown of Cten expression resulted in significant decreases in cellular invasion in both H125 (P = .0036) and A549 (P = .0006) cells. CONCLUSIONS These are the first findings in lung cancer to demonstrate that Cten expression mediates invasion of human lung cancer cells and is upregulated by epidermal growth factor via signal transducer and activator of transcription 3 pathway. Cten should be considered a potential therapeutic target for lung cancer.
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20
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Muharram G, Sahgal P, Korpela T, De Franceschi N, Kaukonen R, Clark K, Tulasne D, Carpén O, Ivaska J. Tensin-4-dependent MET stabilization is essential for survival and proliferation in carcinoma cells. Dev Cell 2014; 29:421-36. [PMID: 24814316 PMCID: PMC4118019 DOI: 10.1016/j.devcel.2014.03.024] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2013] [Revised: 02/05/2014] [Accepted: 03/31/2014] [Indexed: 12/25/2022]
Abstract
Inappropriate MET tyrosine kinase receptor signaling is detected in almost all types of human cancer and contributes to malignant growth and MET dependency via proliferative and antiapoptotic activities. Independently, Tensin-4 (TNS4) is emerging as a putative oncogene in many cancer types, but the mechanisms of TNS4 oncogenic activity are not well established. Here, we demonstrate that TNS4 directly interacts with phosphorylated MET via the TNS4 SH2-domain to positively regulate cell survival, proliferation, and migration, through increased MET protein stability. In addition, TNS4 interaction with β1-integrin cytoplasmic tail positively regulates β1-integrin stability. Loss of TNS4 or disruption of MET-TNS4 interaction triggers MET trafficking toward the lysosomal compartment that is associated with excessive degradation of MET and triggers MET-addicted carcinoma cell death in vitro and in vivo. Significant correlation between MET and TNS4 expression in human colon carcinoma and ovarian carcinoma suggests TNS4 plays a critical role in MET stability in cancer.
A direct interaction is identified between MET and Tensin-4 TNS4 protects MET from degradation, thus promoting its oncogenic activity TNS4 and MET are significantly coexpressed in human carcinomas Loss of TNS4 inhibits survival of MET-dependent tumors
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Affiliation(s)
- Ghaffar Muharram
- Turku Centre for Biotechnology, University of Turku, Turku, 20520, Finland; VTT Technical Research Centre of Finland, Turku, 20521, Finland
| | - Pranshu Sahgal
- Turku Centre for Biotechnology, University of Turku, Turku, 20520, Finland; VTT Technical Research Centre of Finland, Turku, 20521, Finland
| | - Taina Korpela
- Department of Pathology, University of Turku, Turku, 20520, Finland; Department of Pathology, Turku University Hospital, Turku, 20520, Finland
| | - Nicola De Franceschi
- Turku Centre for Biotechnology, University of Turku, Turku, 20520, Finland; VTT Technical Research Centre of Finland, Turku, 20521, Finland
| | - Riina Kaukonen
- Turku Centre for Biotechnology, University of Turku, Turku, 20520, Finland; VTT Technical Research Centre of Finland, Turku, 20521, Finland
| | - Katherine Clark
- Department of Biochemistry, University of Leicester, Leicester LE1 9HN, UK
| | - David Tulasne
- Institut de Biologie de Lille-UMR8161, CNRS, 59021 Lille, France
| | - Olli Carpén
- Department of Pathology, University of Turku, Turku, 20520, Finland; Department of Pathology, Turku University Hospital, Turku, 20520, Finland
| | - Johanna Ivaska
- Turku Centre for Biotechnology, University of Turku, Turku, 20520, Finland; VTT Technical Research Centre of Finland, Turku, 20521, Finland; Department of Biochemistry and Food Chemistry, University of Turku, 20520, Finland.
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21
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Lo SH. C-terminal tensin-like (CTEN): a promising biomarker and target for cancer. Int J Biochem Cell Biol 2014; 51:150-4. [PMID: 24735711 DOI: 10.1016/j.biocel.2014.04.003] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2014] [Revised: 04/02/2014] [Accepted: 04/04/2014] [Indexed: 11/17/2022]
Abstract
C-terminal tensin-like (cten, also known as tensin4, TNS4) is a member of the tensin family. Cten protein, like the other three tensin family members, localizes to focal adhesion sites but only shares sequence homology with other tensins at its C-terminal region, which contains the SH2 and PTB domains. Cten is abundantly expressed in normal prostate and placenta and is down-regulated in prostate cancer. However, overexpression of cten frequently associates with tumors derived from breast, colon, lung, stomach, skin and pancreas. A variety of cancer-associated growth factors and cytokines induce cten expression. Up-regulated cten promotes cell motility, prolongs epidermal growth factor receptor signaling, and enhances tumorigenicity. Emerging findings suggest that cten is a promising biomarker and therapeutic target for various cancers.
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Affiliation(s)
- Su Hao Lo
- Department of Biochemistry and Molecular Medicine, University of California-Davis, Sacramento, CA 95817, United States.
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22
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Haynie DT. Molecular physiology of the tensin brotherhood of integrin adaptor proteins. Proteins 2014; 82:1113-27. [PMID: 24634006 DOI: 10.1002/prot.24560] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2013] [Revised: 02/24/2014] [Accepted: 03/07/2014] [Indexed: 01/08/2023]
Abstract
Numerous proteins have been identified as constituents of the adhesome, the totality of molecular components in the supramolecular assemblies known as focal adhesions, fibrillar adhesions and other kinds of adhesive contact. The transmembrane receptor proteins called integrins are pivotal adhesome members, providing a physical link between the extracellular matrix (ECM) and the actin cytoskeleton. Tensins are ever more widely investigated intracellular adhesome constituents. Involved in cell attachment and migration, cytoskeleton reorganization, signal transduction and other processes relevant to cancer research, tensins have recently been linked to functional properties of deleted in liver cancer 1 (DLC1) and a mitogen-activated protein kinases (MAPK), to cell migration in breast cancer, and to metastasis suppression in the kidney. Tensins are close relatives of phosphatase homolog/tensin homolog (PTEN), an extensively studied tumor suppressor. Such findings are recasting the earlier vision of tensin (TNS) as an actin-filament (F-actin) capping protein in a different light. This critical review aims to summarize current knowledge on tensins and thus to highlight key points concerning the expression, structure, function, and evolution of the various members of the TNS brotherhood. Insight is sought by comparisons with homologous proteins. Some historical points are added for perspective.
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Affiliation(s)
- Donald T Haynie
- Department of Physics, Nanomedicine and Nanobiotechnology Laboratory and Center for Integrated Functional Materials, University of South Florida, Tampa, Florida, 33620
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23
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Sjoestroem C, Khosravi S, Zhang G, Martinka M, Li G. C-terminal tensin-like protein is a novel prognostic marker for primary melanoma patients. PLoS One 2013; 8:e80492. [PMID: 24244691 PMCID: PMC3820571 DOI: 10.1371/journal.pone.0080492] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2013] [Accepted: 10/03/2013] [Indexed: 02/04/2023] Open
Abstract
Background C-terminal tensin-like protein (Cten) is a focal adhesion protein originally identified as a tumor suppressor in prostate cancer. It has since been found to be overexpressed and function as an oncogene in numerous other cancers, but the expression status of Cten in melanoma is still unknown. Methods Using tissue microarrays containing 562 melanocytic lesions, we evaluated Cten protein expression by immunohistochemistry. The association between Cten expression and patient survival was examined using Kaplan-Meier survival analysis, and univariate and multivariate Cox regression analyses were used to estimate the crude and adjusted hazard ratios. Results Strong Cten expression was detected in 7%, 24%, 41%, and 46% of normal nevi, dysplastic nevi, primary melanoma, and metastatic melanoma samples, respectively, and Cten expression was found to be significantly higher in dysplastic nevi compared to normal nevi (P = 0.046), and in primary melanoma compared to dysplastic nevi (P = 0.003), but no difference was observed between metastatic and primary melanoma. Cten staining also correlated with AJCC stages (P = 0.015) and primary tumor thickness (P = 0.002), with Cten expression being induced in the transition from thin (<1mm) to thick (≥1mm) melanomas. Strong Cten expression was significantly associated with a worse 5-year overall (P = 0.008) and disease-specific survival (P = 0.004) for primary melanoma patients, and multivariate Cox regression analysis revealed that Cten expression was an independent prognostic marker for these patients (P = 0.038 for overall survival; P = 0.021 for disease-specific survival). Conclusion Our findings indicate that induction of Cten protein expression is a relatively early event in melanoma progression, and that Cten has the potential to serve as a prognostic marker for primary melanoma patients.
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Affiliation(s)
- Cecilia Sjoestroem
- Department of Dermatology and Skin Science, Vancouver Coastal Health Research Institute, University of British Columbia, Vancouver, British Columbia, Canada
- * E-mail:
| | - Shahram Khosravi
- Department of Dermatology and Skin Science, Vancouver Coastal Health Research Institute, University of British Columbia, Vancouver, British Columbia, Canada
| | - Guohong Zhang
- Department of Dermatology and Skin Science, Vancouver Coastal Health Research Institute, University of British Columbia, Vancouver, British Columbia, Canada
| | - Magdalena Martinka
- Department of Pathology, Vancouver General Hospital, Vancouver, British Columbia, Canada
| | - Gang Li
- Department of Dermatology and Skin Science, Vancouver Coastal Health Research Institute, University of British Columbia, Vancouver, British Columbia, Canada
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Koringa PG, Jakhesara SJ, Bhatt VD, Patel AB, Dash D, Joshi CG. Transcriptome analysis and SNP identification in SCC of horn in (Bos indicus) Indian cattle. Gene 2013; 530:119-26. [PMID: 23978612 DOI: 10.1016/j.gene.2013.07.061] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2013] [Revised: 07/01/2013] [Accepted: 07/16/2013] [Indexed: 01/05/2023]
Abstract
Single Nucleotide Polymorphisms (SNPs) have become the marker of choice for genome wide association studies. In order to provide the best genome coverage for the analysis of disease, production and performance traits, a large number of relatively evenly distributed SNPs are needed. The main objective of present work was to identify large numbers of gene-associated SNPs using high-throughput sequencing in squamous cell carcinoma of horn. RNA-seq analysis was conducted on 2 tissues viz. Horn Cancer (HC) and Horn Normal (HN) in Kankrej breed of cattle. A total of 909,362 reads with average read length of 405 bp for HC and 583,491 reads with average read length of 411 bp for HN were obtained. We found 9532 and 7065 SNPs as well as 1771 and 1172 Indels in HC and HN, respectively, from which, 7889 SNPs and 1736 Indels were uniquely present in HC, 5886 SNPs and 1146 Indels were uniquely present in HN and reported first time in Bos indicus, whereas the rest are already reported in Bos taurus dbSNP database. The gene-associated SNPs and Indels were high in upregulated genes of HC as compared to HN. Analysis of differentially expressed genes was identified, these genes are involved in regulation of cell proliferation, apoptosis, gene transcription, cell survival and metabolism through various metabolic pathways. The result of transcriptome expression profiling was validated using Real Time quantitative PCR in nine randomly selected genes. We identified numbers aberrant signaling pathways responsible for carcinogenesis in HC which are also commonly altered in squamous cell carcinoma (SCC) of lung in human being. We conclude that a large number of altered genes and dysfunction of multiple pathways are involved in the development of Horn Cancer. The present findings contribute to theoretical information for further screening of genes and identification of markers for early diagnosis of HC as well as SNPs identified in this report provide a much needed resource for genetic studies in B. indicus and shall contribute to the development of a high density SNP array. Validation and testing of these SNPs using SNP arrays will form the material basis for gene associated SNPs in HC.
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Affiliation(s)
- Prakash G Koringa
- College of Veterinary Science and Animal Husbandry, Anand Agricultural University, Anand 388001, Gujarat, India.
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Hong SY, Shih YP, Li T, Carraway KL, Lo SH. CTEN prolongs signaling by EGFR through reducing its ligand-induced degradation. Cancer Res 2013; 73:5266-76. [PMID: 23774213 DOI: 10.1158/0008-5472.can-12-4441] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
Activation of EGF receptor (EGFR) triggers signaling pathways regulating various cellular events that contribute to tissue development and function. Aberrant activation of EGFR contributes to tumor progression as well as therapeutic resistance in patients with cancer. C-terminal tensin-like (CTEN; TNS4) is a focal adhesion molecule that is a member of the tensin family. Its expression is upregulated by EGF and elevated CTEN mediates EGF-induced cell migration. In the presence of CTEN, we found that EGF treatment elevated the level of EGFR protein but not mRNA. The extended half-life of activated EGFR sustained its signaling cascades. CTEN reduced ligand-induced EGFR degradation by binding to the E3 ubiquitin ligase c-Cbl and decreasing the ubiquitination of EGFR. The Src homology 2 domain of CTEN is not only required for binding to the phosphorylated tyrosine residue at codon 774 of c-Cbl, but is also essential for the tumorigenicity observed in the presence of CTEN. Public database analyses indicated that CTEN mRNA levels are elevated in breast, colon, lung, and pancreas cancers, but not correlated with EGFR mRNA levels in these cancers. In contrast, immunohistochemistry analyses of lung cancer specimens showed that CTEN and EGFR protein levels were positively associated, in support of our finding that CTEN regulates EGFR protein levels through a posttranslational mechanism. Overall, this work defines a function for CTEN in prolonging signaling from EGFR by reducing its ligand-induced degradation.
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Affiliation(s)
- Shiao-Ya Hong
- Department of Biochemistry and Molecular Medicine, School of Medicine, University of California-Davis, Sacramento, CA 95817, USA
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Carter JA, Górecki DC, Mein CA, Ljungberg B, Hafizi S. CpG dinucleotide-specific hypermethylation of the TNS3 gene promoter in human renal cell carcinoma. Epigenetics 2013; 8:739-47. [PMID: 23803643 DOI: 10.4161/epi.25075] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Tensin3 is a cytoskeletal regulatory protein that inhibits cell motility. Downregulation of the gene encoding Tensin3 (TNS3) in human renal cell carcinoma (RCC) may contribute to cancer cell metastatic behavior. We speculated that epigenetic mechanisms, e.g., gene promoter hypermethylation, might account for TNS3 downregulation. In this study, we identified and validated a TNS3 gene promoter containing a CpG island, and quantified the methylation level within this region in RCC. Using a luciferase reporter assay we demonstrated a functional minimal promoter activity for a 500-bp sequence within the TNS3 CpG island. Pyrosequencing enabled quantitative determination of DNA methylation of each CpG dinucleotide (a total of 43) in the TNS3 gene promoter. Across the entire analyzed CpG stretch, RCC DNA showed a higher methylation level than both non-tumor kidney DNA and normal control DNA. Out of all the CpGs analyzed, two CpG dinucleotides, specifically position 2 and 8, showed the most pronounced increases in methylation levels in tumor samples. Furthermore, CpG-specific higher methylation levels were correlated with lower TNS3 gene expression levels in RCC samples. In addition, pharmacological demethylation treatment of cultured kidney cells caused a 3-fold upregulation of Tensin3 expression. In conclusion, these results reveal a differential methylation pattern in the TNS3 promoter occurring in human RCC, suggesting an epigenetic mechanism for aberrant Tensin downregulation in human kidney cancer.
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Affiliation(s)
- Jessica A Carter
- Institute of Biomedical and Biomolecular Science (IBBS), School of Pharmacy and Biomedical Sciences, University of Portsmouth, Portsmouth, UK
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Hung SY, Shih YP, Chen M, Lo SH. Up-regulated cten by FGF2 contributes to FGF2-mediated cell migration. Mol Carcinog 2013; 53:787-92. [PMID: 23625726 DOI: 10.1002/mc.22034] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2012] [Revised: 02/25/2013] [Accepted: 03/12/2013] [Indexed: 12/28/2022]
Abstract
Cten is a focal adhesion molecule that is expressed at very low levels in most normal tissues. Nonetheless, its expression has been found to increase dramatically in many types of cancer including colorectal, breast, gastric, and pancreatic cancer, suggesting that cten may play a critical role during tumorigenesis. To study the mechanisms that induce cten expression and the function of up-regulated cten, we examined the effects of several cancer-associated growth factors and cytokines on cten expression. We found that EGF, FGF2, NGF, PDGF, TGF-β, IGF-1, IL-6, and IL-13 were able to induce cten expression in a dose- and time-dependent manner. The Mek-Erk and PI3K-Akt pathways were two main signaling cascades responsible for cten up-regulation, whereas the Jak-Stat pathway could contribute to the increase in some conditions. Since many of these factors are known to promote cell migration, we hypothesized that up-regulated cten might contribute to this process. This hypothesis was investigated in FGF2-mediated cell migration. Silencing of cten not only reduced regular cell motility but also FGF2-mediated cell migration. Overexpression of cten promoted cell migration and FGF2 treatment failed to further enhance cell migration. Our findings that (1) cten is a common downstream molecule of these cancer-associated growth factors and cytokines; and that (2) up-regulated cten modulates cell migration induced by FGF2 and likely other growth factors as well, strongly suggest that cten could be a potential downstream therapeutic target for treating cancers associated with aberrant signaling of these growth factors and cytokines.
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Affiliation(s)
- Shih-Ya Hung
- Center for Tissue Regeneration and Repair, Department of Biochemistry and Molecular Medicine, University of California-Davis, Sacramento, California
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Chen NT, Kuwabara Y, Conley C, Liao YC, Hong SY, Chen M, Shih YP, Chen HW, Hsieh F, Lo SH. Phylogenetic analysis, expression patterns, and transcriptional regulation of human CTEN gene. Gene 2013; 520:90-7. [PMID: 23500447 DOI: 10.1016/j.gene.2013.02.041] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2012] [Revised: 02/21/2013] [Accepted: 02/23/2013] [Indexed: 10/27/2022]
Abstract
Cten is a focal adhesion molecule and a member of the tensin family. Its expression is highly enriched in the prostate and placenta, suggesting that cten gene might be closely associated with mammalian species. Recent studies have reported that cten expression is frequently up-regulated in a variety of cancers and its levels appear to correlate with tumorigenicity. Here, we have (1) analyzed cten sequences of various species to build a phylogenetic tree, (2) examined cten mRNA levels in human and mouse tissues to establish its expression profiles, and (3) determined the promoter region of human CTEN gene in cell lines and in a mouse model to understand its transcriptional regulation. Our analyses indicate that all currently known cten genes are present in mammals. The prostate and placenta are the two most cten abundant tissues in human and mouse, meanwhile brain and lung also express low levels of cten. Results from cell culture reporter assays demonstrate that a 327-bp fragment is the shortest functional promoter. All functional promoter constructs produce 40- to 160-fold increases in luciferase reporter activities in normal prostate cells, whereas lower activities (<40-fold) are detected in non-prostatic cell lines. To evaluate CTEN promoter activity in mice and develop a new tissue specific Cre recombinase mouse model, we have established pCTEN-Cre:R26R mice by crossing R26R β-galactosidase reporter mice with pCTEN-Cre transgenic mice, in which the 327-bp cten promoter drives the expression of Cre recombinase. X-gal analysis has shown strong β-galactosidase activities in the prostate, brain, and few other tissues in pCTEN-Cre:R26R mice. Altogether, we have identified the promoter region of human cten gene and provided a useful tool for investigating cell lineages and generating tissue-specific knockout or knockin mice.
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Affiliation(s)
- Nien-Tsu Chen
- Department of Biochemistry and Molecular Medicine, University of California-Davis, Sacramento, CA 95817, USA
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Differential regulation of the activity of deleted in liver cancer 1 (DLC1) by tensins controls cell migration and transformation. Proc Natl Acad Sci U S A 2012; 109:1455-60. [PMID: 22307599 DOI: 10.1073/pnas.1114368109] [Citation(s) in RCA: 62] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
Abstract
The epithelial growth factor receptor plays an important role in cell migration and cancer metastasis, but the underlying molecular mechanism is not fully understood. We show here that differential regulation of the Ras-homology-GTPase-activating protein [corrected] (Rho-GAP) activity of deleted in liver cancer 1 (DLC1) by tensin3 and COOH-terminal tensin-like protein (cten) controls EGF-driven cell migration and transformation. Tensin3 binds DLC1 through its actin-binding domain, a region that is missing in cten, and thereby releases an autoinhibitory interaction between the sterile alpha motif and Rho-GAP domains of DLC1. Consequently, tensin3, but not cten, promotes the activation of DLC1, which, in turn, leads to inactivation of RhoA and decreased cell migration. Depletion of endogenous tensin3, but not cten, augmented the formation of actin stress fibers and focal adhesions and enhanced cell motility. These effects were, however, ablated by an inhibitor of the Rho-associated protein kinase. Importantly, activation of DLC1 by tensin3 or its actin-binding domain drastically reduced the anchorage-independent growth of transformed cells. Our study therefore links dynamic regulation of tensin family members by EGF to Rho-GAP through DLC1 and suggests that the tensin-DLC1-RhoA signaling axis plays an important role in tumorigenesis and cancer metastasis, and may be explored for cancer intervention.
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Al-Ghamdi S, Albasri A, Cachat J, Ibrahem S, Muhammad BA, Jackson D, Nateri AS, Kindle KB, Ilyas M. Cten is targeted by Kras signalling to regulate cell motility in the colon and pancreas. PLoS One 2011; 6:e20919. [PMID: 21698197 PMCID: PMC3116852 DOI: 10.1371/journal.pone.0020919] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2010] [Accepted: 05/16/2011] [Indexed: 11/18/2022] Open
Abstract
CTEN/TNS4 is an oncogene in colorectal cancer (CRC) which enhances cell motility although the mechanism of Cten regulation is unknown. We found an association between high Cten expression and KRAS/BRAF mutation in a series of CRC cell lines (p = 0.03) and hypothesised that Kras may regulate Cten. To test this, Kras was knocked-down (using small interfering (si)RNA) in CRC cell lines SW620 and DLD1 (high Cten expressors and mutant for KRAS). In each cell line, Kras knockdown was mirrored by down-regulation of Cten Since Kras signals through Braf, we tested the effect of Kras knockdown in CRC cell line Colo205 (which shows high Cten expression and is mutant for BRAF but wild type for KRAS). Cten levels were unaffected by Kras knockdown whilst Braf knockdown resulted in reduced Cten expression suggesting that Kras signals via Braf to regulate Cten. Quantification of Cten mRNA and protein analysis following proteasome inhibition suggested that regulation was of Cten transcription. Kras knockdown inhibited cell motility. To test whether this could be mediated through Cten, SW620 cells were co-transfected with Kras specific siRNAs and a Cten expression vector. Restoring Cten expression was able to restore cell motility despite Kras knockdown (transwell migration and wounding assay, p<0.001 for both). Since KRAS is mutated in many cancers, we investigated whether this relationship could be demonstrated in other tumour models. The experiments were repeated in the pancreatic cancer cell lines Colo357 & PSN-1(both high Cten expressors and mutant for KRAS). In both cell lines, Kras was shown to regulate Cten and forced expression of Cten was able to rescue loss of cell motility following Kras knockdown in PSN-1 (transwell migration assay, p<0.001). We conclude that, in the colon and pancreas, Cten is a downstream target of Kras and may be a mechanism through which Kras regulates of cell motility.
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Affiliation(s)
- Saleh Al-Ghamdi
- Division of Pathology, Nottingham University, Nottingham, United Kingdom
| | - Abdulkader Albasri
- Division of Pathology, Nottingham University, Nottingham, United Kingdom
| | - Julien Cachat
- Division of Pathology, Nottingham University, Nottingham, United Kingdom
| | - Salih Ibrahem
- Division of Pathology, Nottingham University, Nottingham, United Kingdom
| | - Belal A. Muhammad
- Division of Pathology, Nottingham University, Nottingham, United Kingdom
- Division of Pre-Clinical Oncology, Nottingham University, Nottingham, United Kingdom
| | - Darryl Jackson
- Division of Pathology, Nottingham University, Nottingham, United Kingdom
| | - Abdolrahman S. Nateri
- Division of Pre-Clinical Oncology, Nottingham University, Nottingham, United Kingdom
| | - Karin B. Kindle
- Division of Pathology, Nottingham University, Nottingham, United Kingdom
| | - Mohammad Ilyas
- Division of Pathology, Nottingham University, Nottingham, United Kingdom
- Nottingham Digestive Diseases Centre, NIHR Biomedical Research Unit, Queen's Medical Centre, Nottingham University Hospitals NHS Trust, Nottingham, United Kingdom
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Cten signals through integrin-linked kinase (ILK) and may promote metastasis in colorectal cancer. Oncogene 2011; 30:2997-3002. [PMID: 21339732 DOI: 10.1038/onc.2011.26] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
CTEN/TNS4 is an oncogene in colorectal cancer (CRC), which can induce cell motility although its mechanistic basis of activity and the clinical implications of Cten expression are unknown. As Cten is in complex with integrins at focal adhesions, we hypothesised that it may interact with integrin-linked kinase (ILK). Through forced expression and knockdown of Cten in HCT116 and SW620 (respectively, showing low and high Cten expression), we showed that Cten could regulate ILK. However, inhibition of ILK after forced expression of Cten abrogated the motility-inducing effects of Cten, thereby demonstrating that the Cten-ILK interaction was functionally relevant. Combined knockdown of Cten and ILK had no additive effects on cell motility compared with knockdown of each individually. In order to investigate the clinical implications of Cten expression, a series of 462 CRCs were evaluated by immunohistochemistry. High expression of Cten was associated with advanced Dukes' stage (P<0.001), poor prognosis (P<0.001) and distant metastasis (P=0.008). The role of Cten in metastasis was tested by (a) intrasplenic injection of CRC cells stably transfected with a Cten expression vector into nude mice and (b) testing a series of primary human CRCs and their metastases by immunohistochemistry. Compared with controls, mice injected with cells expressing Cten developed larger tumours in the spleen (P<0.05) and liver (P<0.05). In the human cases, compared with primary tumours, the metastatic deposits had a significantly higher frequency of nuclear localisation of Cten (P=0.002). We conclude that Cten expression is of prognostic significance in CRC, and we delineate a Cten-ILK pathway controlling cell motility and possibly promoting metastasis.
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Kwon SH, Nedvetsky PI, Mostov KE. Transcriptional profiling identifies TNS4 function in epithelial tubulogenesis. Curr Biol 2011; 21:161-6. [PMID: 21236678 PMCID: PMC3031161 DOI: 10.1016/j.cub.2010.12.037] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2010] [Revised: 11/22/2010] [Accepted: 12/16/2010] [Indexed: 12/21/2022]
Abstract
Hepatocyte growth factor (HGF) plays central roles in tubulogenesis and metastasis [1-4]. HGF treatment of Madin-Darby canine kidney (MDCK) cells grown as cysts in three-dimensional culture induces tubulogenesis [5, 6], which like most tubulogenic processes proceeds through distinct intermediate phases. Identification of genes associated with these phases is central to understanding the molecular mechanisms of tubulogensis; however, because of inefficient, asynchronous tubule formation, isolating such genes has been unfeasible. Here we developed a synchronous, efficient tubulogenesis system and used time-course transcriptional profiling to identify genes temporally regulated in developmental intermediates. Knockdown (KD) of tensin 4 (TNS4), a particularly highly upregulated gene, leads to a decrease in formation of extensions and tubules, two sequential intermediates in tubulogenesis. Exogenous expression of TNS4 marks invasive cells in an epithelial sheet. A mutation in the SH2 domain of TNS4 prevents the transition from extension formation to invasive migration during tubule formation and leads to increased basal activation of STAT3. Exogenous expression of a constitutively active STAT3 mimics the defect by the mutation. Our study highlights the role of the TNS4-STAT3 axis in epithelial sheet invasion and tubulogenesis.
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Affiliation(s)
- Sang-Ho Kwon
- Department of Anatomy, University of California, San Francisco, San Francisco, CA 94143-2140, USA
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Albasri A, Aleskandarany M, Benhasouna A, Powe DG, Ellis IO, Ilyas M, Green AR. CTEN (C-terminal tensin-like), a novel oncogene overexpressed in invasive breast carcinoma of poor prognosis. Breast Cancer Res Treat 2010; 126:47-54. [DOI: 10.1007/s10549-010-0890-3] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2010] [Accepted: 04/03/2010] [Indexed: 12/27/2022]
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Barbieri I, Pensa S, Pannellini T, Quaglino E, Maritano D, Demaria M, Voster A, Turkson J, Cavallo F, Watson CJ, Provero P, Musiani P, Poli V. Constitutively Active Stat3 Enhances Neu-Mediated Migration and Metastasis in Mammary Tumors via Upregulation of Cten. Cancer Res 2010; 70:2558-67. [DOI: 10.1158/0008-5472.can-09-2840] [Citation(s) in RCA: 119] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
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Li Y, Mizokami A, Izumi K, Narimoto K, Shima T, Zhang J, Dai J, Keller ET, Namiki M. CTEN/tensin 4 expression induces sensitivity to paclitaxel in prostate cancer. Prostate 2010; 70:48-60. [PMID: 19725034 DOI: 10.1002/pros.21037] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
BACKGROUND Recently, we established paclitaxel-resistant prostate cancer cell lines (PC-3-TxR and DU145-TxR). To determine the mechanisms of paclitaxel resistance in PC-3-TxR cells, we compared the gene expression profiles between PC-3 and PC-3-TxR cells. Our results indicated that expression of the C-terminal tensin like protein (CTEN, tensin 4) gene was down-regulated by 10-fold in PC-3-TxR cells. We investigated the possibility that CTEN overexpression restores paclitaxel sensitivity. METHODS We investigated how knockdown and overexpression of CTEN in androgen-independent cell lines affect paclitaxel sensitivity by colony formation assay and growth inhibition assay. To determine the mechanisms by which CTEN affects paclitaxel sensitivity, we investigated the relationships between CTEN and F-actin or epidermal growth factor receptor (EGFR) in PC-3 cells. We also examined the association between expression of CTEN and grade of prostate cancer by immunohistochemistry using tissue microarray analysis. RESULTS Down-regulation of CTEN, which is located in the cytoskeleton, played an important role in paclitaxel resistance in PC-3-TxR cells. Knockdown of CTEN expression in PC-3 cells induced paclitaxel resistance. Overexpression of CTEN in PC-3-TxR and DU145-TxR cells restored paclitaxel sensitivity. CTEN expression was inversely correlated with F-actin and EGFR expression. Then knockdown of actin and EGFR in PC-3-TxR cells recovered paclitaxel sensitivity, indicating that CTEN down-regulation mediates paclitaxel resistance through elevation of EGFR and actin expression. Moreover, CTEN expression was inversely correlated with Gleason score. CONCLUSIONS These results strongly suggested that CTEN plays an important role in paclitaxel sensitivity and that CTEN expression level may be a prognostic predictive factor for PCa patients.
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Affiliation(s)
- YouQiang Li
- Department of Integrative Cancer Therapy and Urology, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Japan
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Liao YC, Chen NT, Shih YP, Dong Y, Lo SH. Up-regulation of C-terminal tensin-like molecule promotes the tumorigenicity of colon cancer through beta-catenin. Cancer Res 2009; 69:4563-6. [PMID: 19487278 PMCID: PMC2692076 DOI: 10.1158/0008-5472.can-09-0117] [Citation(s) in RCA: 51] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
C-terminal tensin-like (cten) is a focal adhesion molecule belonging to the tensin family. Previous studies have suggested that cten may function as a prostate-specific tumor suppressor. Here, we show that although cten is expressed at a very low level in normal colon, its expression is significantly up-regulated in colon cancer. Furthermore, a high population of cten is found in the nucleus, where it interacts with beta-catenin, a critical player in the canonical Wnt pathway. This interaction may contribute to the role of cten in enhancing the colony formation, anchorage-independent growth, and invasiveness of colon cancer cells. Our studies have identified cten as a novel nuclear partner of beta-catenin, showed an oncogenic activity of cten in colon cancers, and revealed cten as a potential biomarker and target for colon cancers.
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Affiliation(s)
- Yi-Chun Liao
- Center for Tissue Regeneration and Repair, Department of Biochemistry and Molecular Medicine, University of California-Davis, Sacramento, California 95817, USA
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Albasri A, Seth R, Jackson D, Benhasouna A, Crook S, Nateri AS, Chapman R, Ilyas M. C-terminal Tensin-like (CTEN) is an oncogene which alters cell motility possibly through repression of E-cadherin in colorectal cancer. J Pathol 2009; 218:57-65. [PMID: 19214987 DOI: 10.1002/path.2508] [Citation(s) in RCA: 45] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2008] [Accepted: 12/10/2008] [Indexed: 01/06/2023]
Abstract
The Tensin gene family encodes proteins thought to modulate integrin function. C-terminal Tensin-like (CTEN) is a member of the Tensin gene family which lacks the N-terminus actin-binding domain. Cten is reported to have both oncogenic and tumour-suppressor functions. We investigated the role that Cten may play in colorectal cancer (CRC). By quantitative RT-PCR CTEN is up-regulated (i.e. > two-fold increase) in 62% of cell lines and 69% of tumours compared with normal mucosa, consistent with CTEN being a possible oncogene. Stable transfection of HCT116 and SW480 (CRC cell lines with low endogenous Cten expression) with a Cten expression vector gave identical results in both cell lines. Forced Cten expression did not cause change in cell numbers, although it did confer resistance to staurosporine-induced apoptosis (p < 0.005). Cten also induced epithelial-mesenchymal transition (EMT) in tumour cells accompanied by a significant increase in both cell migration (transwell migration and cell wounding assays, p < 0.001 and p < 0.05, respectively) and cell invasion (invasion through Matrigel, p < 0.001). Given the observed EMT, we investigated the levels of E-cadherin. Cten induction was associated with a reduction in E-cadherin protein expression but not levels of E-cadherin mRNA. These data suggest that CTEN is an oncogene in CRC which stimulates EMT, cell migration and invasion and may therefore have a role in tumour invasion/spread. Furthermore, Cten induction is associated with post-transcriptional repression of E-cadherin.
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Martuszewska D, Ljungberg B, Johansson M, Landberg G, Oslakovic C, Dahlbäck B, Hafizi S. Tensin3 is a negative regulator of cell migration and all four Tensin family members are downregulated in human kidney cancer. PLoS One 2009; 4:e4350. [PMID: 19194507 PMCID: PMC2632886 DOI: 10.1371/journal.pone.0004350] [Citation(s) in RCA: 53] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2008] [Accepted: 12/15/2008] [Indexed: 11/18/2022] Open
Abstract
Background The Tensin family of intracellular proteins (Tensin1, -2, -3 and -4) are thought to act as links between the extracellular matrix and the cytoskeleton, and thereby mediate signaling for cell shape and motility. Dysregulation of Tensin expression has previously been implicated in human cancer. Here, we have for the first time evaluated the significance of all four Tensins in a study of human renal cell carcinoma (RCC), as well as probed the biological function of Tensin3. Principal Findings Expression of Tensin2 and Tensin3 at mRNA and protein levels was largely absent in a panel of diverse human cancer cell lines. Quantitative RT-PCR analysis revealed mRNA expression of all four Tensin genes to be significantly downregulated in human kidney tumors (50–100% reduction versus normal kidney cortex; P<0.001). Furthermore, the mRNA expressions of Tensins mostly correlated positively with each other and negatively with tumor grade, but not tumor size. Immunohistochemical analysis revealed Tensin3 to be present in the cytoplasm of tubular epithelium in normal human kidney sections, whilst expression was weaker or absent in 41% of kidney tumors. A subset of tumor sections showed a preferential plasma membrane expression of Tensin3, which in clear cell RCC patients was correlated with longer survival. Stable expression of Tensin3 in HEK 293 cells markedly inhibited both cell migration and matrix invasion, a function independent of putative phosphatase activity in Tensin3. Conversely, siRNA knockdown of endogenous Tensin3 in human cancer cells significantly increased their migration. Conclusions Our findings indicate that the Tensins may represent a novel group of metastasis suppressors in the kidney, the loss of which leads to greater tumor cell motility and consequent metastasis. Moreover, tumorigenesis in the human kidney may be facilitated by a general downregulation of Tensins. Therefore, anti-metastatic therapies may benefit from restoring or preserving Tensin expression in primary tumors.
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Affiliation(s)
- Danuta Martuszewska
- Department of Laboratory Medicine, Section for Clinical Chemistry, Lund University, University Hospital Malmö, Malmö, Sweden
| | - Börje Ljungberg
- Department of Surgical and Perioperative Sciences, Umeå University, Umeå, Sweden
| | - Martin Johansson
- Department of Laboratory Medicine, Section for Pathology, Lund University, University Hospital Malmö, Malmö, Sweden
| | - Göran Landberg
- Department of Laboratory Medicine, Section for Pathology, Lund University, University Hospital Malmö, Malmö, Sweden
| | - Cecilia Oslakovic
- Department of Laboratory Medicine, Section for Clinical Chemistry, Lund University, University Hospital Malmö, Malmö, Sweden
| | - Björn Dahlbäck
- Department of Laboratory Medicine, Section for Clinical Chemistry, Lund University, University Hospital Malmö, Malmö, Sweden
| | - Sassan Hafizi
- Department of Laboratory Medicine, Section for Clinical Chemistry, Lund University, University Hospital Malmö, Malmö, Sweden
- * E-mail:
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Sakashita K, Mimori K, Tanaka F, Kamohara Y, Inoue H, Sawada T, Hirakawa K, Mori M. Prognostic Relevance of Tensin4 Expression in Human Gastric Cancer. Ann Surg Oncol 2008; 15:2606-13. [DOI: 10.1245/s10434-008-9989-8] [Citation(s) in RCA: 32] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2008] [Revised: 05/09/2008] [Accepted: 05/09/2008] [Indexed: 12/11/2022]
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Abstract
Epidermal Growth Factor (EGF) is an important regulator of normal epithelial and carcinoma cell migration. The mechanism by which EGF induces cell migration is not fully understood. A recent report in Nature Cell Biology (Katz et al., 2007) demonstrates that EGF regulates migration through a switch in the expression of two tensin isoforms, weakening the association of beta1 integrin with the actin cytoskeleton in focal adhesions.
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Affiliation(s)
- Ghassan Mouneimne
- Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
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Katz M, Amit I, Citri A, Shay T, Carvalho S, Lavi S, Milanezi F, Lyass L, Amariglio N, Jacob-Hirsch J, Ben-Chetrit N, Tarcic G, Lindzen M, Avraham R, Liao YC, Trusk P, Lyass A, Rechavi G, Spector NL, Lo SH, Schmitt F, Bacus SS, Yarden Y. A reciprocal tensin-3-cten switch mediates EGF-driven mammary cell migration. Nat Cell Biol 2007; 9:961-9. [PMID: 17643115 DOI: 10.1038/ncb1622] [Citation(s) in RCA: 146] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2007] [Accepted: 06/28/2007] [Indexed: 02/08/2023]
Abstract
Cell migration driven by the epidermal growth factor receptor (EGFR) propels morphogenesis and involves reorganization of the actin cytoskeleton. Although de novo transcription precedes migration, transcript identity remains largely unknown. Through their actin-binding domains, tensins link the cytoskeleton to integrin-based adhesion sites. Here we report that EGF downregulates tensin-3 expression, and concomitantly upregulates cten, a tensin family member that lacks the actin-binding domain. Knockdown of cten or tensin-3, respectively, impairs or enhances mammary cell migration. Furthermore, cten displaces tensin-3 from the cytoplasmic tail of integrin beta1, thereby instigating actin fibre disassembly. In invasive breast cancer, cten expression correlates not only with high EGFR and HER2, but also with metastasis to lymph nodes. Moreover, treatment of inflammatory breast cancer patients with an EGFR/HER2 dual-specificity kinase inhibitor significantly downregulated cten expression. In conclusion, a transcriptional tensin-3-cten switch may contribute to the metastasis of mammary cancer.
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Affiliation(s)
- Menachem Katz
- Department of Biological Regulation, The Weizmann Institute of Science, Rehovot 76100, Israel
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