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Xiao Y, Martinez L, Zigmond Z, Woltmann D, Singer DV, Singer HA, Vazquez-Padron RI, Salman LH. Functions for platelet factor 4 (PF4/CXCL4) and its receptors in fibroblast-myofibroblast transition and fibrotic failure of arteriovenous fistulas (AVFs). J Vasc Access 2024; 25:1911-1924. [PMID: 37589266 PMCID: PMC10998683 DOI: 10.1177/11297298231192386] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/18/2023] Open
Abstract
BACKGROUND Over 60% of End Stage Renal Disease (ESRD) patients are relying on hemodialysis (HD) to survive, and the arteriovenous fistula (AVF) is the preferred vascular access method for HD. However approximately half of all newly created AVF fail to mature and cannot be used without a salvage procedure. We have recently demonstrated an association between AVF maturation failure and post-operative fibrosis, while our RNA-seq study also revealed that veins that ultimately failed during AVF maturation had elevated levels of platelet factor 4 (PF4/CXCL4). However, a link between these two findings was yet to be established. METHODS In this study, we investigated potential mechanisms between PF4 levels and fibrotic remodeling in veins. We compared the local expression of PF4 and fibrosis marker integrin β6 (ITGB6) in veins that successfully underwent maturation with that in veins that ultimately failed to mature. We also measured the changes of expression level of α-smooth muscle actin (αSMA/ACTA2) and collagen (Col1/COL1A1) in venous fibroblasts upon various treatments, such as PF4 pharmacological treatment, alteration of PF4 expression, and blocking of PF4 receptors. RESULTS We found that PF4 is expressed in veins and co-localizes with αSMA. In venous fibroblasts, PF4 stimulates expression of αSMA and Col1 via different pathways. The former requires integrins αvβ5 and α5β1, while chemokine receptor CXCR3 is needed for the latter. Interestingly, we also discovered that the expression of PF4 is associated with that of ITGB6, the β subunit of integrin αvβ6. This integrin is critical for the activation of the major fibrosis factor TGFβ, and overexpression of PF4 promotes activation of the TGFβ pathway. CONCLUSIONS These results indicate that upregulation of PF4 may cause venous fibrosis both directly by stimulating fibroblast differentiation and expression of extracellular matrix (ECM) molecules and indirectly by facilitating the activation of the TGFβ pathway.
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Affiliation(s)
- Yuxuan Xiao
- Department of Molecular & Cellular Physiology, Albany Medical College, Albany, NY, USA
| | - Laisel Martinez
- DeWitt Daughtry Family Department of Surgery, Leonard M. Miller School of Medicine, University of Miami, Miami, FL, USA
| | - Zachary Zigmond
- DeWitt Daughtry Family Department of Surgery, Leonard M. Miller School of Medicine, University of Miami, Miami, FL, USA
| | - Daniel Woltmann
- Department of Molecular & Cellular Physiology, Albany Medical College, Albany, NY, USA
| | - Diane V Singer
- Department of Molecular & Cellular Physiology, Albany Medical College, Albany, NY, USA
| | - Harold A Singer
- Department of Molecular & Cellular Physiology, Albany Medical College, Albany, NY, USA
| | - Roberto I Vazquez-Padron
- DeWitt Daughtry Family Department of Surgery, Leonard M. Miller School of Medicine, University of Miami, Miami, FL, USA
| | - Loay H Salman
- Department of Molecular & Cellular Physiology, Albany Medical College, Albany, NY, USA
- Division of Nephrology & Hypertension, Albany Medical College, Albany, NY, USA
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Rashid ZA, Bardaweel SK. Novel Matrix Metalloproteinase-9 (MMP-9) Inhibitors in Cancer Treatment. Int J Mol Sci 2023; 24:12133. [PMID: 37569509 PMCID: PMC10418771 DOI: 10.3390/ijms241512133] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2023] [Revised: 07/25/2023] [Accepted: 07/26/2023] [Indexed: 08/13/2023] Open
Abstract
Matrix metalloproteinases (MMPs) belong to a family of zinc-dependent proteolytic metalloenzymes. MMP-9, a member of the gelatinase B family, is characterized as one of the most intricate MMPs. The crucial involvement of MMP-9 in extracellular matrix (ECM) remodeling underscores its significant correlation with each stage of cancer pathogenesis and progression. The design and synthesis of MMP-9 inhibitors is a potentially attractive research area. Unfortunately, to date, there is no effective MMP-9 inhibitor that passes the clinical trials and is approved by the FDA. This review primarily focuses on exploring the diverse strategies employed in the design and advancement of MMP-9 inhibitors, along with their anticancer effects and selectivity. To illuminate the essential structural characteristics necessary for the future design of novel MMP-9 inhibitors, the current narrative review highlights several recently discovered MMP-9 inhibitors exhibiting notable selectivity and potency.
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Affiliation(s)
| | - Sanaa K. Bardaweel
- Department of Pharmaceutical Sciences, School of Pharmacy, University of Jordan, Amman 11942, Jordan
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3
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Shen Q, Wang J, Zhao L. To investigate the internal association between SARS-CoV-2 infections and cancer through bioinformatics. MATHEMATICAL BIOSCIENCES AND ENGINEERING : MBE 2022; 19:11172-11194. [PMID: 36124586 DOI: 10.3934/mbe.2022521] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/15/2023]
Abstract
Severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2), also known as COVID-19, is currently prevalent worldwide and poses a significant threat to human health. Individuals with cancer may have an elevated risk for SARS-CoV-2 infections and adverse outcomes. Therefore, it is necessary to explore the internal relationship between these two diseases. In this study, transcriptome analyses were performed to detect mutual pathways and molecular biomarkers in three types of common cancers of the breast, liver, colon, and COVID-19. Such analyses could offer a valuable understanding of the association between COVID-19 and cancer patients. In an analysis of RNA sequencing datasets for three types of cancers and COVID-19, we identified a sum of 38 common differentially expressed genes (DEGs). A variety of combinational statistical approaches and bioinformatics techniques were utilized to generate the protein-protein interaction (PPI) network. Subsequently, hub genes and critical modules were found using this network. In addition, a functional analysis was conducted using ontologies keywords, and pathway analysis was also performed. Some common associations between cancer and the risk and prognosis of COVID-19 were discovered. The datasets also revealed transcriptional factors-gene interplay, protein-drug interaction, and a DEGs-miRNAs coregulatory network with common DEGs. The potential medications discovered in this investigation could be useful in treating cancer and COVID-19.
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Affiliation(s)
- Qinyan Shen
- Department of Surgical Oncology, Affiliated Dongyang Hospital of Wenzhou Medical University, Zhejiang 322100, China
| | - Jiang Wang
- Department of Surgical Oncology, Affiliated Dongyang Hospital of Wenzhou Medical University, Zhejiang 322100, China
| | - Liangying Zhao
- Department of Surgical Oncology, Affiliated Dongyang Hospital of Wenzhou Medical University, Zhejiang 322100, China
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Wang B, Wang S, Wang W, Liu E, Guo S, Zhao C, Niu J, Zhang Z. Hyperglycemia Promotes Liver Metastasis of Colorectal Cancer via Upregulation of Integrin αvβ6. Med Sci Monit 2021; 27:e930921. [PMID: 34408123 PMCID: PMC8383819 DOI: 10.12659/msm.930921] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Background Diabetes is related to higher risk of multiple cancers. This study aimed to explore the effect and mechanism of diabetes on liver metastasis of CRC. Material/Methods Overall and liver metastasis-free survival in diabetic and non-diabetic CRC patients were compared by Kaplan-Meier analysis. Expression of αvβ6 was detected by immunohistochemistry in clinical specimens. Effects of hyperglycemia on αvβ6 expression in colon cancer cells were assessed by western blot, real-time PCR, and flowcytometry. Effects of hyperglycemia on migration and invasion were demonstrated by Transwell assay. Expression and activity of MMP-9 and MMP-2 were determined by real-time PCR and gelatin zymography. Liver metastatic nodules were counted and β6 expression was detected by western blot in a liver metastasis mouse model. Results CRC patients with diabetes had poorer overall and liver metastasis-free survival, and diabetes was associated with higher αvβ6 expression in CRC specimens. Hyperglycemia promoted the invasion and migration of colon cancer cells, and upregulated the expression and activity of MMP-9, which were attenuated by inhibition of αvβ6. Hyperglycemia upregulated the expression of β6 and cell surface expression of αvβ6, which was reduced by ERK inhibitor. The in vitro results were confirmed in vivo in the mouse model. Conclusions Our study demonstrated the enhancing effect of hyperglycemia on liver metastasis of CRC, and showed that αvβ6 was involved in this process, suggesting that control of glucose levels and inhibition of αvβ6 can reduce the risk of liver metastasis in diabetic CRC patients.
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Affiliation(s)
- Ben Wang
- Department of General Surgery, Qilu Hospital of Shandong University, Jinan, Shandong, China (mainland)
| | - Shanjie Wang
- Department of General Surgery, People's Hospital, Zhangqiu District, Jinan, Shandong, China (mainland)
| | - Wenke Wang
- Department of Cardiology, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China (mainland)
| | - Enyu Liu
- Department of General Surgery, Qilu Hospital of Shandong University, Jinan, Shandong, China (mainland)
| | - Sen Guo
- Department of General Surgery, Qilu Hospital of Shandong University, Jinan, Shandong, China (mainland)
| | - Chuanzong Zhao
- Department of General Surgery, Qilu Hospital of Shandong University, Jinan, Shandong, China (mainland)
| | - Jun Niu
- Department of General Surgery, Qilu Hospital of Shandong University, Jinan, Shandong, China (mainland)
| | - Zongli Zhang
- Department of General Surgery, Qilu Hospital of Shandong University, Jinan, Shandong, China (mainland)
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Urquiza M, Guevara V, Diaz-Sana E, Mora F. The Role of αvβ6 Integrin Binding Molecules in the Diagnosis and Treatment of Cancer. CURR ORG CHEM 2020. [DOI: 10.2174/1385272824999200528124936] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Peptidic and non-peptidic αvβ6 integrin-binding molecules have been used in
the clinic for detection and treatment of tumors expressing αvβ6 integrin, because this protein
is expressed in malignant epithelial cells of the oral cavity, pancreas, breast, ovary,
colon and stomach carcinomas but it is not expressed in healthy adult tissue except during
wound healing and inflammation. This review focuses on the landscape of αvβ6 integrinbinding
molecules and their use in cancer treatment and detection, and discusses recent
designs for tumor detection, treatment, and immunotherapy. In the last ten years, several
reviews abamp;#945;vβ6 integrin-binding molecules and their role in cancer detection and treatment.
Firstly, this review describes the role of the αvβ6 integrin in normal tissues, how the expression
of this protein is correlated with cancer severity and its role in cancer development. Taking into account
the potential of αvβ6 integrin-binding molecules in detection and treatment of specific tumors, special
attention is given to several high-affinity αvβ6 integrin-binding peptides used for tumor imaging; particularly,
the αvβ6-binding peptide NAVPNLRGDLQVLAQKVART [A20FMDV2], derived from the foot and mouth
disease virus. This peptide labeled with either 18F, 111In or with 68Ga has been used for PET imaging of αvβ6
integrin-positive tumors. Moreover, αvβ6 integrin-binding peptides have been used for photoacoustic and fluorescence
imaging and could potentially be used in clinical application in cancer diagnosis and intraoperative
imaging of αvβ6-integrin positive tumors. Additionally, non-peptidic αvβ6-binding molecules have been designed
and used in the clinic for the detection and treatment of αvβ6-expressing tumors. Anti-αvβ6 integrin antibodies
are another useful tool for selective identification and treatment of αvβ6 (+) tumors. The utility of
these αvβ6 integrin-binding molecules as a tool for tumor detection and treatment is discussed, considering
specificity, sensitivity and serum stability. Another use of the αvβ6 integrin-binding peptides is to modify the
Ad5 cell tropism for inducing oncolytic activity of αvβ6-integrin positive tumor cells by expressing
A20FMDV2 peptide within the fiber knob protein (Ad5NULL-A20). The newly designed oncolytic
Ad5NULL-A20 virotherapy is promising for local and systemic targeting of αvβ6-overexpressing cancers. Finally,
new evidence has emerged, indicating that chimeric antigen receptor (CAR) containing the αvβ6 integrin-
binding peptide on top of CD28+CD3 endodomain displays a potent therapeutic activity in a diverse
repertoire of solid tumor models.
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Affiliation(s)
- Mauricio Urquiza
- Grupo de Investigacion en Hormonas (GIH), Department of Chemistry, National University of Columbia, Cra 30 # 45-03, Bogota, zip code 111321, Colombia
| | - Valentina Guevara
- Grupo de Investigacion en Hormonas (GIH), Department of Chemistry, National University of Columbia, Cra 30 # 45-03, Bogota, zip code 111321, Colombia
| | - Erika Diaz-Sana
- Grupo de Investigacion en Hormonas (GIH), Department of Chemistry, National University of Columbia, Cra 30 # 45-03, Bogota, zip code 111321, Colombia
| | - Felipe Mora
- Grupo de Investigacion en Hormonas (GIH), Department of Chemistry, National University of Columbia, Cra 30 # 45-03, Bogota, zip code 111321, Colombia
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Baster Z, Li L, Rajfur Z, Huang C. Talin2 mediates secretion and trafficking of matrix metallopeptidase 9 during invadopodium formation. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH 2020; 1867:118693. [DOI: 10.1016/j.bbamcr.2020.118693] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/16/2019] [Revised: 02/21/2020] [Accepted: 03/03/2020] [Indexed: 12/18/2022]
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Mondal S, Adhikari N, Banerjee S, Amin SA, Jha T. Matrix metalloproteinase-9 (MMP-9) and its inhibitors in cancer: A minireview. Eur J Med Chem 2020; 194:112260. [PMID: 32224379 DOI: 10.1016/j.ejmech.2020.112260] [Citation(s) in RCA: 305] [Impact Index Per Article: 61.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2019] [Revised: 02/28/2020] [Accepted: 03/18/2020] [Indexed: 12/15/2022]
Abstract
Matrix metalloproteinases (MMPs) are zinc dependent proteolytic metalloenzyme. MMP-9 is one of the most complex forms of matrix metalloproteinases. MMP-9 has the ability to degrade the extracellular matrix (ECM) components and has important role in the pathophysiological functions. Overexpression and dysregulation of MMP-9 is associated with various diseases. Thus, regulation and inhibition of MMP-9 is an important therapeutic approach for combating various diseases including cancer. Inhibitors of MMP-9 can be used as anticancer agents. Till date no selective MMP-9 inhibitors passed the clinical trials. In this review the structure, activation, function and inhibitors of MMP-9 are mainly focused. Some highly active and/or selective MMP-9 inhibitors have been discussed which may be helpful to explore the structural significance of MMP-9 inhibitors. This study may be useful to design new potent and selective MMP-9 inhibitors against cancer in future.
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Affiliation(s)
- Subha Mondal
- Natural Science Laboratory, Division of Medicinal and Pharmaceutical Chemistry, Department of Pharmaceutical Technology, P. O. Box 17020, Jadavpur University, Kolkata, 700032, India
| | - Nilanjan Adhikari
- Natural Science Laboratory, Division of Medicinal and Pharmaceutical Chemistry, Department of Pharmaceutical Technology, P. O. Box 17020, Jadavpur University, Kolkata, 700032, India
| | - Suvankar Banerjee
- Natural Science Laboratory, Division of Medicinal and Pharmaceutical Chemistry, Department of Pharmaceutical Technology, P. O. Box 17020, Jadavpur University, Kolkata, 700032, India
| | - Sk Abdul Amin
- Natural Science Laboratory, Division of Medicinal and Pharmaceutical Chemistry, Department of Pharmaceutical Technology, P. O. Box 17020, Jadavpur University, Kolkata, 700032, India
| | - Tarun Jha
- Natural Science Laboratory, Division of Medicinal and Pharmaceutical Chemistry, Department of Pharmaceutical Technology, P. O. Box 17020, Jadavpur University, Kolkata, 700032, India.
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Transforming growth factor-β1 enhances proliferative and metastatic potential by up-regulating lymphoid enhancer-binding factor 1/integrin αMβ2 in human renal cell carcinoma. Mol Cell Biochem 2019; 465:165-174. [PMID: 31848806 DOI: 10.1007/s11010-019-03676-8] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2019] [Accepted: 12/07/2019] [Indexed: 12/12/2022]
Abstract
Renal cell carcinoma (RCC) is a kind of malignant tumor with high recurrence, and it is urgent to find molecular markers for diagnosis and prognosis of RCC. Our study investigated the expression and function of integrin αMβ2 in RCC cells, aiming to understand the role of integrin αMβ2 in RCC and develop new therapeutic target for RCC. Overexpression and knockdown of lymphoid enhancer-binding factor 1 (LEF1) were performed using vector containing full-length cDNA and via siRNA technology, respectively. The expressions of mRNA and protein were detected by RT-PCR and Western blot, respectively. Proliferation of RCC cell was analyzed using WST-1 assay, and metastasis of RCC cell was evaluated using the transwell system. Our results demonstrated that LEF1 and integrin αMβ2 were up-regulated in RCC cells via TGF-β1-dependent mechanism, and LEF1 together with β-catenin directly increased integrin αMβ2 level. On the other hand, TGF-β1-induced proliferation, migration and invasion were suppressed by function-blocking antibody against integrin αMβ2 in RCC cells. In addition, integrin αMβ2 is crucial for LEF1 mediated cell invasion by regulating MMP-2, MMP-9 and calpain-2 secretion in RCC cells. LEF1/integrin αMβ2 expression was regulated by TGF-β1, and LEF1/integrin αMβ2 was involved in TGF-β1's improvement effects on the proliferation and metastasis of RCC. Blocking integrin αMβ2 activity could be a therapeutic option for patients with advanced RCC.
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Ahmadpour S, Hosseinimehr SJ. Recent developments in peptide-based SPECT radiopharmaceuticals for breast tumor targeting. Life Sci 2019; 239:116870. [DOI: 10.1016/j.lfs.2019.116870] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2019] [Revised: 09/09/2019] [Accepted: 09/10/2019] [Indexed: 12/31/2022]
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10
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Liang B, Li L, Miao R, Wang J, Chen Y, Li Z, Zou X, Zhou M. Expression of Interleukin-6 and Integrin ανβ6 in Colon Cancer: Association with Clinical Outcomes and Prognostic Implications. Cancer Invest 2019; 37:174-184. [PMID: 30982362 DOI: 10.1080/07357907.2019.1597103] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
As important factors in the tumor microenvironment, interleukin-6 (IL-6) and integrin ανβ6 play significant roles in accumulating mutations that drive the progression and metastatic capacities of cancer. The aim of this study was to investigate the expression of IL-6 and integrin ανβ6, their clinical significance, as well as their correlation in the colon cancer tissues of 145 cases using immunohistochemistry. Our results showed that IL-6 and integrin ανβ6 are indicators of cancer progression and poor prognosis in patients with colon cancer. Moreover, their relationship may provide clues for further studies on how the tumor microenvironment mediates the development of colon cancer, as well as strategies for the identification of novel therapeutic targets in the prevention and treatment of colon cancer.
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Affiliation(s)
- Benjia Liang
- a Department of Gastrointestinal Surgery , Provincial Hospital Affiliated to Shandong University , Jinan , China
| | - Leping Li
- a Department of Gastrointestinal Surgery , Provincial Hospital Affiliated to Shandong University , Jinan , China
| | - Ruizheng Miao
- a Department of Gastrointestinal Surgery , Provincial Hospital Affiliated to Shandong University , Jinan , China
| | - Jinshen Wang
- a Department of Gastrointestinal Surgery , Provincial Hospital Affiliated to Shandong University , Jinan , China
| | - Yuezhi Chen
- a Department of Gastrointestinal Surgery , Provincial Hospital Affiliated to Shandong University , Jinan , China
| | - Zequn Li
- b Key Laboratory of Cardiovascular Remodeling and Function Research Chinese Ministry of Education and Public Health , Jinan , China
| | - Xueqing Zou
- c Department of Hepatobiliary Surgery , Qilu Hospital Shandong University , Jinan , China
| | - Mingliang Zhou
- a Department of Gastrointestinal Surgery , Provincial Hospital Affiliated to Shandong University , Jinan , China
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Peng C, Li Z, Gao H, Zou X, Wang X, Zhou C, Niu J. Synchronous primary sigmoid colon cancer and primary thyroid cancer followed by a malignant tumor of the kidney: Case report of multiple primary cancer and review of the literature. Oncol Lett 2018; 17:2479-2484. [PMID: 30719116 DOI: 10.3892/ol.2018.9867] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2018] [Accepted: 11/13/2018] [Indexed: 12/12/2022] Open
Abstract
Multiple primary cancer (MPC) is relatively rare. With the development of diagnostic and anti-cancer therapeutic techniques, the incidence of MPC is rising annually. However, the incidence of triple or quadruple cancers in a single patient remains low. In this report, the case of a 58-year-old male with triple malignant cancer is outlined. Synchronous sigmoid colon cancer and thyroid cancer were diagnosed in May 2015; on subsequent re-examination, metastasis to the liver and a malignant kidney tumor were also identified. The diagnosis was established via computed tomography (CT), Positron emission tomography-CT (PET-CT) and other laboratory examination results, including analysis of tumor markers and liver function, and was confirmed by pathological diagnosis. The patient underwent radical surgery and standardized chemotherapy. Through literature review, the definition, characteristics, classification, incidence, possible causes of and treatment strategies for MPC were more clearly understood. In addition, immunohistochemical staining of integrin αvβ6 was performed on patient tissue specimens, where integrin αvβ6 expression was confirmed in cancer of the colon, thyroid and liver, as a result of colonic metastasis. Therefore, the involvement of integrin αvβ6 in the malignant progression of MPC was hypothesized, which may aid the investigation of MPC etiology in the future.
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Affiliation(s)
- Cheng Peng
- Department of Hepatobiliary Surgery, Qilu Hospital of Shandong University, Jinan, Shandong 250012, P.R. China.,The Institute of Laparoscopic Minimally Invasive Surgery, Department of Hepatobiliary Surgery, Shandong University, Jinan, Shandong 250012, P.R. China
| | - Zequn Li
- Department of Hepatobiliary Surgery, Qilu Hospital of Shandong University, Jinan, Shandong 250012, P.R. China.,The Institute of Laparoscopic Minimally Invasive Surgery, Department of Hepatobiliary Surgery, Shandong University, Jinan, Shandong 250012, P.R. China
| | - Huijie Gao
- Department of Hepatobiliary Surgery, Qilu Hospital of Shandong University, Jinan, Shandong 250012, P.R. China.,The Institute of Laparoscopic Minimally Invasive Surgery, Department of Hepatobiliary Surgery, Shandong University, Jinan, Shandong 250012, P.R. China
| | - Xueqing Zou
- Department of Hepatobiliary Surgery, Qilu Hospital of Shandong University, Jinan, Shandong 250012, P.R. China.,The Institute of Laparoscopic Minimally Invasive Surgery, Department of Hepatobiliary Surgery, Shandong University, Jinan, Shandong 250012, P.R. China
| | - Xiao Wang
- Department of Pathology, Qilu Hospital of Shandong University, Jinan, Shandong 250012, P.R. China
| | - Changkuo Zhou
- Department of Urology Surgery, Hospital of Shandong University, Jinan, Shandong 250012, P.R. China
| | - Jun Niu
- Department of Hepatobiliary Surgery, Qilu Hospital of Shandong University, Jinan, Shandong 250012, P.R. China.,The Institute of Laparoscopic Minimally Invasive Surgery, Department of Hepatobiliary Surgery, Shandong University, Jinan, Shandong 250012, P.R. China
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Song L, Fan Z, Jun N, Benjia L, Zequn L, Xilong W, Zhongming J, Yong H, Xiaohong W, Kai C, Zhenlin Y. Tumor specific delivery and therapy mediate by integrin β6-target immunoliposomes for β6-siRNA in colon carcinoma. Oncotarget 2018; 7:85163-85175. [PMID: 27835891 PMCID: PMC5356726 DOI: 10.18632/oncotarget.13209] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2016] [Accepted: 10/21/2016] [Indexed: 11/25/2022] Open
Abstract
Adjuvant chemotherapy does not achieve the desired therapeutic efficacy in colon cancer as a result of the deficient reaction. Gene therapy using small interfering RNAs (siRNAs) delivered by target delivering system represents a potent and specific strategy in tumor therapy. Integrinβ6 is exclusively expressed in malignant colonic epithelia, associated with the progression, metastasis, and chemotherapeutic resistance of colon cancer. Accordingly, designing an efficient and targeted delivery system for β6-siRNA could be a potential approach to improve therapeutic efficacy of colon cancer. Here, we designed the Integrinβ6 target immunoliposomes for highly efficient and selective delivery of β6-siRNA in colon cancer, which consequently resulted in greatly growth suppression, invasion and metastasis of colon cancer cells. Moreover, it was able to greatly inhibit the tumor growing in vivo.
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Affiliation(s)
- Liu Song
- Department of Thyroid & Breast Surgery, Binzhou Medical College Affiliated Hospital, Binzhou 256600, Shandong, PR China
| | - Zhang Fan
- Department of Oncology, Binzhou Medical College Affiliated Hospital, Binzhou 256600, Shandong, PR China
| | - Niu Jun
- Department of Hepatobiliary Surgery, Qilu Hospital of Shandong University, Jinan 250012, Shandong, PR China
| | - Liang Benjia
- Department of Hepatobiliary Surgery, Qilu Hospital of Shandong University, Jinan 250012, Shandong, PR China
| | - Li Zequn
- Department of Hepatobiliary Surgery, Qilu Hospital of Shandong University, Jinan 250012, Shandong, PR China
| | - Wang Xilong
- Department of Thyroid & Breast Surgery, Binzhou Medical College Affiliated Hospital, Binzhou 256600, Shandong, PR China
| | - Jia Zhongming
- Department of Thyroid & Breast Surgery, Binzhou Medical College Affiliated Hospital, Binzhou 256600, Shandong, PR China
| | - Han Yong
- Department of Thyroid & Breast Surgery, Binzhou Medical College Affiliated Hospital, Binzhou 256600, Shandong, PR China
| | - Wang Xiaohong
- Department of Thyroid & Breast Surgery, Binzhou Medical College Affiliated Hospital, Binzhou 256600, Shandong, PR China
| | - Cheng Kai
- Department of Thyroid & Breast Surgery, Binzhou Medical College Affiliated Hospital, Binzhou 256600, Shandong, PR China
| | - Yang Zhenlin
- Department of Thyroid & Breast Surgery, Binzhou Medical College Affiliated Hospital, Binzhou 256600, Shandong, PR China
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14
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Li Z, Biswas S, Liang B, Zou X, Shan L, Li Y, Fang R, Niu J. Integrin β6 serves as an immunohistochemical marker for lymph node metastasis and promotes cell invasiveness in cholangiocarcinoma. Sci Rep 2016; 6:30081. [PMID: 27440504 PMCID: PMC4954992 DOI: 10.1038/srep30081] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2016] [Accepted: 06/29/2016] [Indexed: 12/14/2022] Open
Abstract
Cholangiocarcinoma is a devastating malignancy that is notoriously difficult to diagnose and is associated with a high mortality. Despite extensive efforts to improve the diagnosis and treatment of this neoplasm, limited progress has been made. Integrin β6 is a subtype of integrin that is expressed exclusively on the surfaces of epithelial cells and is associated with a variety of tumors. In the present study, we investigated the expression and roles of integrin β6 in cholangiocarcinoma. β6 upregulation in cholangiocarcinoma was correlated with lymph node metastasis and distant metastasis. Moreover, integrin β6 was identified as a biomarker for the diagnosis of cholangiocarcinoma and an indicator of lymph node metastasis. Integrin β6 significantly promoted the proliferation, migration and invasion of cholangiocarcinoma cells. Furthermore, integrin β6 increased Rac1-GTPase, resulting in the upregulation of metalloproteinase-9 (MMP9) and F-actin polymerization. Taken together, our results indicate that integrin β6 promotes tumor invasiveness in a Rac1-dependent manner and is a potential biomarker for tumor metastasis. Integrin β6 may help to improve the diagnostic accuracy, and targeting β6 may be a novel strategy for the treatment of cholangiocarcinoma.
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Affiliation(s)
- Zequn Li
- Department of General Surgery, Qilu Hospital of Shandong University, Jinan 250012, Shandong, China.,Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Public Health, Jinan 250012, Shandong, China
| | - Siddhartha Biswas
- Department of General Surgery, Qilu Hospital of Shandong University, Jinan 250012, Shandong, China.,Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Public Health, Jinan 250012, Shandong, China
| | - Benjia Liang
- Department of General Surgery, Qilu Hospital of Shandong University, Jinan 250012, Shandong, China.,Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Public Health, Jinan 250012, Shandong, China
| | - Xueqing Zou
- Department of General Surgery, Qilu Hospital of Shandong University, Jinan 250012, Shandong, China.,Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Public Health, Jinan 250012, Shandong, China
| | - Liqun Shan
- Department of General Surgery, Qilu Hospital of Shandong University, Jinan 250012, Shandong, China.,Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Public Health, Jinan 250012, Shandong, China
| | - Yang Li
- Department of General Surgery, Qilu Hospital of Shandong University, Jinan 250012, Shandong, China.,Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Public Health, Jinan 250012, Shandong, China
| | - Ruliang Fang
- Department of General Surgery, Qilu Hospital of Shandong University, Jinan 250012, Shandong, China
| | - Jun Niu
- Department of General Surgery, Qilu Hospital of Shandong University, Jinan 250012, Shandong, China
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15
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Lian PL, Liu Z, Yang GY, Zhao R, Zhang ZY, Chen YG, Zhuang ZN, Xu KS. Integrin αvβ6 and matrix metalloproteinase 9 correlate with survival in gastric cancer. World J Gastroenterol 2016; 22:3852-3859. [PMID: 27076771 PMCID: PMC4814749 DOI: 10.3748/wjg.v22.i14.3852] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/06/2015] [Revised: 01/22/2016] [Accepted: 02/22/2016] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the expression of integrin αvβ6 and matrix metalloproteinase 9 (MMP-9), their association with prognostic factors and to assess their predictive role in gastric cancer patients.
METHODS: Immunohistochemistry was used to determine the expressions of integrin αvβ6 and MMP-9 in 126 specimens from patients with primary gastric carcinoma. Associations between immunohistochemical staining and various clinic pathologic variables of tissue specimens were evaluated by the χ2 test and Fisher’s exact test. Expression correlation of αvβ6 and MMP-9 was assessed using bivariate correlation analysis. The patients were followed-up every 3 mo in the first two years and at least every 6 mo afterwards, with a median follow-up of 56 mo (ranging from 2 mo to 94 mo). Four different combinations of αvβ6 and MMP-9 levels (that is, both markers positive, both markers negative, αvβ6 positive with MMP-9 negative, and αvβ6 negative with MMP-9 positive) were evaluated for their relative effect on survival. The difference in survival curves was evaluated with a log-rank test. Survival analysis was conducted using the Kaplan-Meier survival and Cox proportional hazards model analysis.
RESULTS: The expressions of integrin αvβ6 and MMP-9 were investigated in 126 cases, among which 34.92% were positive for αvβ6 expression, and 42.06% for MMP-9 expression. The expression of αvβ6 was associated with Lauren type, differentiation, N stage, and TNM stage (the P values were 0.006, 0.038, 0.016, and 0.002, respectively). While MMP-9 expression was associated with differentiation, T stage, N stage, and TNM stage (the P values were 0.039, 0.014, 0.033, and 0.008, respectively). The positive correlation between αvβ6 and MMP-9 in gastric cancer was confirmed by a correlation analysis. The Kaplan-Meier survival analysis showed that patients with expression of αvβ6 or MMP-9 alone died earlier than those with negative expression and that patients who were both αvβ6 and MMP-9 positive had a shorter overall survival than those with the opposite pattern (both αvβ6 and MMP-9 negative) (P = 0.000). A Cox model indicated that positive expression of αvβ6 and MMP-9, diffuse Lauren type, as well as a senior grade of N stage, M stage, and TNM stage were predictors of a poor prognosis in univariate analysis. Only αvβ6 and MMP-9 retained their significance when adjustments were made for other known prognostic factors in multivariate analysis (RR = 2.632, P = 0.003 and RR = 1.813, P = 0.007).
CONCLUSION: The expression of αvβ6 and MMP-9 are closely correlated, and the combinational pattern of αvβ6 and MMP-9 can serve as a more effective prognostic index for gastric cancer patients.
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Peng C, Li Z, Niu Z, Niu W, Xu Z, Gao H, Niu W, Wang J, He Z, Gao C, Lin P, Agrez M, Zhang Z, Niu J. Norcantharidin Suppresses Colon Cancer Cell Epithelial-Mesenchymal Transition by Inhibiting the αvβ6-ERK-Ets1 Signaling Pathway. Sci Rep 2016; 6:20500. [PMID: 26846153 PMCID: PMC4742802 DOI: 10.1038/srep20500] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2015] [Accepted: 01/05/2016] [Indexed: 12/30/2022] Open
Abstract
Norcantharidin (NCTD) is an efficacious anti-cancer drug that has been used in China for many years, but its underlying mechanism of action is still not fully understood. In the present study, we found that NCTD could induce morphological changes in colon cancer cells, causing a transition from a spindle-shaped morphology to a typical round or oval shape, which was indicative of a mesenchymal-epithelial transition (MET) process. Next, we investigated the mechanism by which NCTD induced the MET process. Using a transwell assay, we found that NCTD could suppress the migratory and invasive ability of colon cancer cells in a dose-dependent manner. Moreover, NCTD suppressed the expression of integrin αvβ6, MMP-3, and MMP-9 as well as the polymerization of F-actin, further supporting its suppressive effect on migratory and invasive ability. Furthermore, the expression of αvβ6, N-cadherin, vimentin and phosphorylated ERK was decreased, while the expression of E-cadherin was up-regulated. We verified that phosphorylated Ets1 was down-regulated substantially after treatment with NCTD. Taken together, our data demonstrated that NCTD could inhibit the EMT process of colon cancer cells by inhibiting the αvβ6-ERK-Ets1 signaling pathway. This study revealed part of the mechanism through which NCTD could reverse the EMT process in colon cancer.
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Affiliation(s)
- Cheng Peng
- Department of General Surgery, Qilu Hospital, Shandong University, Jinan, Shandong, China
| | - Zequn Li
- Department of General Surgery, Qilu Hospital, Shandong University, Jinan, Shandong, China
| | - Zhengchuan Niu
- Department of General Surgery, Qilu Hospital, Shandong University, Jinan, Shandong, China
| | - Wei Niu
- Department of General Surgery, Qilu Hospital, Shandong University, Jinan, Shandong, China
| | - Zongquan Xu
- Department of Hepatic Oncology, Jiangxi Provincial Cancer Hospital, Nanchang, Jiangxi, China
| | - Huijie Gao
- Department of General Surgery, Qilu Hospital, Shandong University, Jinan, Shandong, China
| | - Weibo Niu
- Department of General Surgery, Qilu Hospital, Shandong University, Jinan, Shandong, China
| | - JiaYong Wang
- Department of General Surgery, Qilu Hospital, Shandong University, Jinan, Shandong, China
| | - Zhaobin He
- Department of General Surgery, Qilu Hospital, Shandong University, Jinan, Shandong, China
| | - Chao Gao
- Department of General Surgery, Qilu Hospital, Shandong University, Jinan, Shandong, China
| | - Pengfei Lin
- Department of General Surgery, Qilu Hospital, Shandong University, Jinan, Shandong, China
| | - Michael Agrez
- Newcastle Bowel Cancer Research Collaborative, The University of Newcastle, Callaghan, New South Wales, Australia
| | - Zongli Zhang
- Department of General Surgery, Qilu Hospital, Shandong University, Jinan, Shandong, China
| | - Jun Niu
- Department of General Surgery, Qilu Hospital, Shandong University, Jinan, Shandong, China
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17
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Yang GY, Guo S, Dong CY, Wang XQ, Hu BY, Liu YF, Chen YW, Niu J, Dong JH. Integrin αvβ6 sustains and promotes tumor invasive growth in colon cancer progression. World J Gastroenterol 2015; 21:7457-7467. [PMID: 26139991 PMCID: PMC4481440 DOI: 10.3748/wjg.v21.i24.7457] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2014] [Revised: 11/27/2014] [Accepted: 01/21/2015] [Indexed: 02/06/2023] Open
Abstract
AIM: To detect the mechanism by which colon tumor escapes the growth constraints imposed on normal cells by cell crowding and dense pericellular matrices.
METHODS: An immunohistochemical study of integrin αvβ6 and matrix metalloproteinase-9 (MMP-9) was performed on tissue microarrays of 200 spots, including 100 cases of colon tumors.
RESULTS: High immunoreactivity for αvβ6 (73.7%; 28/38) and MMP-9 (76.5%; 52/68) was observed in invasive tumor portions. Furthermore, the effects of integrin αvβ6 on tumor invasive growth in nude mice were detected. Tumor invasive growth and high expression of both αvβ6 and MMP-9 were only seen in tumors resulting from WiDr cells expressing αvβ6 in the tumorigenicity assay. Flow cytometry was applied to analyze αvβ6 expression in colon cancer WiDr and SW480 cells. The effects of cell density on αvβ6 expression and MMP-9 secretion were also detected by Biotrak MMP-9 activity assay and gelatin zymography assay. High cell density evidently enhanced αvβ6 expression and promoted MMP-9 secretion compared with low density.
CONCLUSION: Integrin αvβ6 sustains and promotes tumor invasive growth in tumor progression via a self-perpetuating mechanism. Integrin ανβ6-mediated MMP-9 secretion facilitates pericellular matrix degradation at high cell density, which provides the basis of invasive growth.
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18
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Integrin β6 can be translationally regulated by eukaryotic initiation factor 4E: Contributing to colonic tumor malignancy. Tumour Biol 2015; 36:6541-50. [PMID: 25982998 DOI: 10.1007/s13277-015-3348-8] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2014] [Accepted: 03/16/2015] [Indexed: 01/09/2023] Open
Abstract
It is well known that both eukaryotic initiation factor 4E (eIF4E) and integrin αvβ6 can contribute to malignant behavior of colon cancer. We have found that integrin αvβ6 and eIF4E were co-expressed and positively correlated in colon cancer tissues. Recently, deregulation of the protein synthesis apparatus has begun to gain attention as a major participant in cancer development and progression. However, the regulation of integrin β6 expression at translational level has never been investigated before. In present study, gene-silencing technique for eIF4E by small interfering RNA (siRNA) was used in all the subsequent experiments, in order to investigate whether eIF4E could translationally regulate expression of integrin β6 in colon cancer SW480 and HT-29 cell lines. Additionally, the subsequent effects of eIF4E knockdown on cellular malignant behavior were observed. siRNA in SW480 and HT-29 transfectants. Subsequently, protein expression of β6 was markedly suppressed, while mRNA expression of β6 showed no significant variation before and after eIF4E RNA interfering. Therefore, it could be seen that eIF4E could upregulate the expression of β6, without effect on β6 mRNA expression. More importantly, after treated with eIF4E siRNA, cellular migratory capacity on fibronectin of HT-29 and β6-transfected SW480 as well as their survival to 5-FU was decreased distinctly. Expression of integrin β6 could be translationally regulated by eIF4E, which subsequently contributed to tumor malignancy through enhancing cellular migration, survival, anti-apoptosis, and chemoresistance of colon cancer in vitro. Thus, targeting eIF4E in integrin αvβ6 expressing tumors can be a potential therapeutic strategy for patients with colon cancer.
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19
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Abstract
Transforming growth factor (TGF) β1 activity depends on a complex signalling cascade that controls expression of several genes. Among others, TGFβ1 regulates expression of matrix metalloproteinases (MMPs) through activation of Smads. In the present study, we demonstrate for the first time that the αvβ6 integrin interacts with TGFβ receptor II (TβRII) through the β6 cytoplasmic domain and promotes Smad3 activation in prostate cancer (PrCa) cells. Another related αv integrin, αvβ5, as well as the αvβ6/3 integrin, which contains a chimeric form of β6 with a β3 cytoplasmic domain, do not associate with TβRII and fail to show similar responses. We provide evidence that αvβ6 is required for up-regulation of MMP2 by TGFβ1 through a Smad3-mediated transcriptional programme in PrCa cells. The functional relevance of these results is underscored by the finding that αvβ6 modulates cell migration in an MMP2-dependent manner on an αvβ6-specific ligand, latency-associated peptide (LAP)-TGFβ. Overall, these mechanistic studies establish that expression of a single integrin, αvβ6, is sufficient to promote activation of Smad3, regulation of MMP2 levels and consequent catalytic activity, as well as cell migration. Our study describes a new TGFβ1-αvβ6-MMP2 signalling pathway that, given TGFβ1 pro-metastatic activity, may have profound implications for PrCa therapy.
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20
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Switch from αvβ5 to αvβ6 integrin is required for CD9-regulated keratinocyte migration and MMP-9 activation. FEBS Lett 2014; 588:4044-52. [PMID: 25265322 DOI: 10.1016/j.febslet.2014.09.027] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2014] [Revised: 09/15/2014] [Accepted: 09/17/2014] [Indexed: 01/12/2023]
Abstract
Our previous research found that tetraspanin CD9 is downregulated in migrating epidermis during wound healing, and CD9 downregulation contributes to keratinocyte migration via matrix metalloproteinase-9 (MMP-9) activation. However, little is known about the mechanisms involved in CD9-regulated keratinocyte migration and MMP-9 activation. In this study, we revealed that the expressions of integrin subunits β5 and β6 were regulated by CD9. Furthermore, CD9 silencing triggered the switch from αvβ5 to αvβ6 integrin in HaCaT keratinocytes and CD9 overexpression reversed the switch. Importantly, integrin αvβ6 functional blocking antibody 10D5 significantly inhibited CD9 silencing-induced keratinocyte migration and MMP-9 activation, suggesting that the switch from αvβ5 to αvβ6 integrin plays a key role in CD9-regulated cell migration and MMP-9 activation in keratinocytes.
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21
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Aparna M, Rao L, Kunhikatta V, Radhakrishnan R. The role of MMP-2 and MMP-9 as prognostic markers in the early stages of tongue squamous cell carcinoma. J Oral Pathol Med 2014; 44:345-52. [PMID: 25212455 DOI: 10.1111/jop.12245] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/08/2014] [Indexed: 12/14/2022]
Abstract
BACKGROUND Tongue cancer is the most common intra-oral malignancy with a high rate of morbidity and mortality owing to its increased propensity for tumor invasion and metastasis. These processes require a controlled degradation of the extracellular matrix. Matrix Metalloproteinase-2 (MMP-2) and Matrix Metalloproteinase-9 (MMP-9) are known to be important regulators of matrix lysis and play a significant role in the metastasis of malignancies. AIM AND OBJECTIVES To study the expression of MMP-2 and MMP-9 in the early stages of tongue squamous cell carcinoma and find the association between their expression and local recurrence, metastasis, and survival rates of the subjects. MATERIALS AND METHODS Fifty-nine tumor biopsy samples of tongue squamous cell carcinoma in T1 N0 M0 and T2 N0 M0 stages were immunostained with MMP-2 and MMP-9 antibodies. The immunohistochemical expression was compared with the patient characteristics and outcome. RESULTS Cytoplasmic expression of MMP-2 correlated with that of MMP-9 (r = 0.716, P < 0.001). Greater expression of MMP-2 and MMP-9 was observed in patients who subsequently developed local recurrence (P = 0.044 and P < 0.001, respectively), regional and/or distant metastasis (P < 0.001 and P = 0.001, respectively) of the tumor. Further, a higher expression of these biomarkers was associated with shorter survival. MMP-9 was found to have better specificity for local recurrence, metastasis and survival. CONCLUSION Our results showed that these biomarkers may serve as indicators of a patient's risk potential for poor prognosis and presage the need for more aggressive treatment measures.
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Affiliation(s)
- Manikkath Aparna
- Department of Oral Pathology and Microbiology, Manipal College of Dental Sciences, Manipal University, Manipal, Karnataka, India
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22
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Peng C, Gao H, Niu Z, Wang B, Tan Z, Niu W, Liu E, Wang J, Sun J, Shahbaz M, Agrez M, Niu J. Integrin αvβ6 and transcriptional factor Ets-1 act as prognostic indicators in colorectal cancer. Cell Biosci 2014; 4:53. [PMID: 25264483 PMCID: PMC4175281 DOI: 10.1186/2045-3701-4-53] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2014] [Accepted: 08/18/2014] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Both transcriptional factor Ets-1 and integrin αvβ6 play an important role in the development and progression of cancer. The aim of our study was to investigate the expression of Integrin αvβ6 and Ets-1, two proteins' correlation and their clinical significance in colorectal cancerous tissues. RESULTS The specimens were arranged into microarray using the immunohistochemistry method to investigate the expression of integrin αvβ6 and transcriptional factor Ets-1 in these tissues. Among the 158 tissue specimens, 36.07% were positive for αvβ6 expression, and 57.59% were positive for Ets-1 expression. There were obvious statistical differences existed regarding differentiation, N stage, M stage and TNM stage between αvβ6 and Ets-1 positively and negatively expressing tumors. The correlation analysis confirmed the expression of αvβ6 and Ets-1 were positively correlated in colorectal cancer. The Kaplan-Meier survival analysis showed that patients who were both αvβ6 and Ets-1 positive relapsed earlier than those who were both αvβ6 and Ets-1 negative; and the former group had much shorter survival time than the latter. And Cox model indicated that αvβ6 and Ets-1 were the independent prognostic factors (RR = 2.175, P = 0.012 and RR = 3.903, P < 0.001). CONCLUSIONS The expression of αvβ6 and Ets-1 were positively correlated, and their expression degrees were associated with the differentiation, N stage, M stage and TNM stage of the tumors. Hence, the combination of αvβ6 and Ets-1 can be used as a prognostic marker in colorectal cancer, especially for the early stage.
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Affiliation(s)
- Cheng Peng
- />Department of Hepatobiliary Surgery, QiLu Hospital, Shandong University, Jinan, Shandong China
| | - Huijie Gao
- />Department of Hepatobiliary Surgery, QiLu Hospital, Shandong University, Jinan, Shandong China
| | - Zhengchuan Niu
- />Department of Hepatobiliary Surgery, QiLu Hospital, Shandong University, Jinan, Shandong China
| | - Ben Wang
- />Department of Hepatobiliary Surgery, QiLu Hospital, Shandong University, Jinan, Shandong China
| | - Zhen Tan
- />Health Science College, The State University of New York -Stony Brook University, Stony Brook, NY USA
| | - Weibo Niu
- />Department of Hepatobiliary Surgery, QiLu Hospital, Shandong University, Jinan, Shandong China
| | - Enyu Liu
- />Department of Hepatobiliary Surgery, QiLu Hospital, Shandong University, Jinan, Shandong China
| | - Jiayong Wang
- />Department of Hepatobiliary Surgery, QiLu Hospital, Shandong University, Jinan, Shandong China
| | - Jiuzheng Sun
- />Department of General Surgery, Jinan Central Hospital, Shandong University, Jinan, Shandong China
| | - Muhammad Shahbaz
- />Department of Hepatobiliary Surgery, QiLu Hospital, Shandong University, Jinan, Shandong China
| | - Michael Agrez
- />Newcastle Bowel Cancer Research Collaborative, Hunter Medical Research Institute, John Hunter Hospital and Faculty of Medicine and Health Sciences, The University of Newcastle, Callaghan, NSW Australia
| | - Jun Niu
- />Department of Hepatobiliary Surgery, QiLu Hospital, Shandong University, Jinan, Shandong China
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23
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Sun Q, Sun F, Wang B, Liu S, Niu W, Liu E, Peng C, Wang J, Gao H, Liang B, Niu Z, Zou X, Niu J. Interleukin-8 promotes cell migration through integrin αvβ6 upregulation in colorectal cancer. Cancer Lett 2014; 354:245-53. [PMID: 25150782 DOI: 10.1016/j.canlet.2014.08.021] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2014] [Revised: 08/01/2014] [Accepted: 08/14/2014] [Indexed: 01/05/2023]
Abstract
Colorectal cancer (CRC), which is notorious for high morbidity and mortality around the world, shows a predilection for metastasis to liver. Interleukin-8 (IL-8), a chemokine with a defining CXC amino acid motif, has been reported to promote CRC cell migration and is associated with poor prognosis of CRC. However, the underlying molecular mechanism of IL-8-mediated migration remains obscure. In this study, we first demonstrated the cross talk between IL-8 and integrin αvβ6. We analyzed 139 human CRC samples, and found that the immunohistochemical expression of αvβ6 was significantly correlated with expression of IL-8. Furthermore, IL-8 increased the migration through integrin αvβ6 in human CRC cells, and both CXCR1 and CXCR2 were primarily involved during the process. IL-8 upregulated αvβ6 expression in a dose-dependent manner through activation of ERK and Ets-1 signaling pathway. Taken together, our results indicated that IL-8 enhances the migration of CRC cells by increasing αvβ6 integrin expression through the ERK/Ets-1 pathway. Targeting integrin αvβ6 in IL-8 expressing tumors might be a potential therapeutic strategy for CRC patients.
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Affiliation(s)
- Qi Sun
- Department of Hepatobiliary Surgery, Qilu Hospital of Shandong University, Jinan 250012, Shandong, China; Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Public Health, Qilu Hospital of Shandong University, Jinan 250012, Shandong, China
| | - Fengkai Sun
- Department of Hepatology, Qilu Hospital of Shandong University, Jinan 250012, Shandong, China
| | - Ben Wang
- Department of Hepatobiliary Surgery, Qilu Hospital of Shandong University, Jinan 250012, Shandong, China; Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Public Health, Qilu Hospital of Shandong University, Jinan 250012, Shandong, China
| | - Song Liu
- Department of Thyroid and Breast Surgery, Affiliated Hospital of Binzhou Medical College, Binzhou 256603, Shandong, China
| | - Weibo Niu
- Department of Hepatobiliary Surgery, Qilu Hospital of Shandong University, Jinan 250012, Shandong, China
| | - Enyu Liu
- Department of Hepatobiliary Surgery, Qilu Hospital of Shandong University, Jinan 250012, Shandong, China
| | - Cheng Peng
- Department of Hepatobiliary Surgery, Qilu Hospital of Shandong University, Jinan 250012, Shandong, China
| | - Jiayong Wang
- Department of Hepatobiliary Surgery, Qilu Hospital of Shandong University, Jinan 250012, Shandong, China
| | - Huijie Gao
- Department of Hepatobiliary Surgery, Qilu Hospital of Shandong University, Jinan 250012, Shandong, China; Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Public Health, Qilu Hospital of Shandong University, Jinan 250012, Shandong, China
| | - Benjia Liang
- Department of Hepatobiliary Surgery, Qilu Hospital of Shandong University, Jinan 250012, Shandong, China; Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Public Health, Qilu Hospital of Shandong University, Jinan 250012, Shandong, China
| | - Zhengchuan Niu
- Department of Hepatobiliary Surgery, Qilu Hospital of Shandong University, Jinan 250012, Shandong, China; Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Public Health, Qilu Hospital of Shandong University, Jinan 250012, Shandong, China
| | - Xueqing Zou
- Department of Hepatobiliary Surgery, Qilu Hospital of Shandong University, Jinan 250012, Shandong, China; Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Public Health, Qilu Hospital of Shandong University, Jinan 250012, Shandong, China
| | - Jun Niu
- Department of Hepatobiliary Surgery, Qilu Hospital of Shandong University, Jinan 250012, Shandong, China.
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β6 integrin induces the expression of metalloproteinase-3 and metalloproteinase-9 in colon cancer cells via ERK-ETS1 pathway. Cancer Lett 2014; 354:427-37. [PMID: 25135220 DOI: 10.1016/j.canlet.2014.08.017] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2014] [Revised: 08/12/2014] [Accepted: 08/12/2014] [Indexed: 01/09/2023]
Abstract
We previously reported that β6 integrin played an important role in the progression of colon cancer. In this study, we demonstrated that β6 integrin induced the expression of MMP-3/MMP-9 and the invasion of colon cancer cells. Moreover, that function was abolished by the inhibition of ERK/MAPK pathways or knockdown of ETS1, an important transcription factor of MMP genes. Here, we showed that β6 induced phosphorylation of ETS1 via the ERK/MAPK pathways, through which the MMP-3/MMP-9 promoters were stimulated, thereby leading to the up-regulation of MMP-3/MMP-9, and subsequent the invasion of colon cancer cells.
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25
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Wang B, Wang W, Niu W, Liu E, Liu X, Wang J, Peng C, Liu S, Xu L, Wang L, Niu J. SDF-1/CXCR4 axis promotes directional migration of colorectal cancer cells through upregulation of integrin αvβ6. Carcinogenesis 2013; 35:282-91. [PMID: 24085800 DOI: 10.1093/carcin/bgt331] [Citation(s) in RCA: 51] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023] Open
Abstract
Colorectal cancer (CRC) displays a predilection for metastasis to liver. Although stromal cell-derived factor-1 (SDF-1)/CXCR4 plays an important role in the liver metastasis, the molecular mechanism still remains obscure. We previously reported that integrin αvβ6 was implicated in the progression of CRC. However, no data are currently available on the cross talk between CXCR4 and αvβ6. In the present study, we first demonstrated the cross talk between CXCR4 and αvβ6 and their role in liver metastasis of CRC. We analyzed 159 human CRC samples and found that expression of CXCR4 and αvβ6 was significantly associated with liver metastasis, and interestingly expression of αvβ6 significantly correlated with expression of CXCR4. Both CXCR4 and αvβ6 were highly expressed in metastatic CRC cell lines HT-29 and WiDr, whereas both of them were exiguous in non-metastatic cell line Caco-2. Furthermore, inhibition of αvβ6 significantly decreased SDF-1α-induced cell migration in vitro. SDF-1/CXCR4 could upregulate αvβ6 expression through phosphorylation of ERK and activation of Ets-1 transcription factor. In conclusion, we demonstrate that SDF-1/CXCR4 induces directional migration and liver metastasis of CRC cells by upregulating αvβ6 through ERK/Ets-1 pathway. These data support combined inhibition of CXCR4 and αvβ6 to prevent development of liver metastasis of CRC.
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Affiliation(s)
- Ben Wang
- Department of Hepatobiliary Surgery
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27
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Liu S, Wang J, Niu W, Liu E, Wang J, Peng C, Lin P, Wang B, Khan AQ, Gao H, Liang B, Shahbaz M, Niu J. The β6-integrin-ERK/MAP kinase pathway contributes to chemo resistance in colon cancer. Cancer Lett 2012; 328:325-34. [PMID: 23073477 DOI: 10.1016/j.canlet.2012.10.004] [Citation(s) in RCA: 52] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2012] [Revised: 09/30/2012] [Accepted: 10/07/2012] [Indexed: 12/21/2022]
Abstract
5-Fluorouracil (5-FU) is the most widely used chemo drug for the treatment of colon cancer. However, a sub-population of colon cancer patients do not respond to 5-FU and this treatment does not provide survival benefit due to chemo resistance. The mechanisms involved in 5-FU resistance are not fully understood and multiple factors have been involved in the sensitivity of cancer cells to 5-FU. We previously reported that β6-integrin plays an important role in invasion, metastasis and degradation of extracellular matrix of colon cancer. In this study, we investigated whether β6-integrin is associated with chemo resistance in colon cancer. We found that over-expression of β6-integrin protected SW480 and HT-29 colon cancer cells from 5-FU-induced growth inhibition and apoptosis, which were accompanied by changes in cytochrome C released from the mitochondria and activity of caspase-3 and caspase-9. Moreover, β6-integrin resulted in up-regulation of Bcl-2 and down-regulation of Bax. We also found that β6-integrin induced 5-FU resistance through the ERK/MAP kinase pathway and the β6-ERK2 direct binding. The results indicate β6-integrin might be a novel therapeutic target in colon cancer therapy.
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Affiliation(s)
- Song Liu
- Department of Hepatobiliary Surgery, Qilu Hospital, Shandong University, Jinan 250012, Shandong, PR China
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Neutrophil gelatinase-associated lipocalin (NGAL) and matrix metalloproteinase-9 (MMP-9) prognostic value in stage I colorectal carcinoma. Pathol Res Pract 2011; 207:479-86. [PMID: 21726963 DOI: 10.1016/j.prp.2011.05.012] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/25/2011] [Revised: 05/11/2011] [Accepted: 05/30/2011] [Indexed: 01/25/2023]
Abstract
The expression of neutrophil gelatinase-associated lipocalin (NGAL) has been suggested to behave like a negative prognostic marker in stage I colorectal carcinoma. In the aim of clarifying whether its association with adverse outcome may descend from NGAL's ability to regulate matrix metallo-proteinase-9 (MMP-9), we analyzed the correlation, prognostic value, and association with neo-angiogenesis of NGAL and MMP-9 immunohistochemical expression in a series of stage I colorectal carcinomas. A variable NGAL immunoexpression was demonstrated in 17 of the 48 analyzed cases with a significantly higher frequency of positive cases among patients showing disease progression. NGAL expression was also positively correlated with VEGF expression detected in the same cases. MMP-9 immunostaining was present in the cytoplasm of the neoplastic cells in 30 cases; no significant correlations were evidenced with NGAL expression, as well as with the various clinico-pathological parameters or with progression of the colorectal carcinomas. By contrast, NGAL expression was confirmed as a significant independent negative prognostic marker related to a shorter disease-free survival in stage I colorectal carcinoma. Our preliminary results suggest that the association of NGAL with poor outcome might be independent from MMP-9 regulation, thus highlighting its prognostic value in this neoplasia. If our findings are confirmed in further analyses, NGAL assessment might be used in order to select those patients with a higher progression risk and to submit them to adjuvant therapies useful to prevent adverse outcome.
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Wang J, Wu J, Hong J, Chen R, Xu K, Niu W, Peng C, Liu E, Wang J, Liu S, Agrez M, Niu J. PKC promotes the migration of colon cancer cells by regulating the internalization and recycling of integrin αvβ6. Cancer Lett 2011; 311:38-47. [PMID: 21741165 DOI: 10.1016/j.canlet.2011.06.025] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2011] [Revised: 06/02/2011] [Accepted: 06/16/2011] [Indexed: 12/16/2022]
Abstract
Recently published studies have suggested that integrin trafficking is necessary to support cell migration, but the role of internalization and recycling of integrin αvβ6 in colon cancer cells remained unclear. In our study, we demonstrated the existence of the integrin cycle and found that inhibition of ERK2 phosphorylation by PD98059 or deletion of the ERK2 direct binding site on the β6 cytoplasmic domain could interrupt the internalization of integrin αvβ6, but had no effect on its recycling. Furthermore, integrin αvβ6 trafficking played a key role in the migration of colon cancer cells towards fibronectin. Activation of PKC significantly accelerated the internalization and recycling of integrin αvβ6, which could facilitate rapid redistribution of integrin αvβ6 and increase cell motility. When colon cancer cells became crowded, the increase in αvβ6 levels at the cell surface was not accompanied by a change in total αvβ6 expression in cell lysates. This change may be due to a redistribution of αvβ6 in cell microstructures and a rapid cellular response towards the demands of migration.
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Affiliation(s)
- Jian Wang
- Department of General Surgery, Qilu Hospital, Shandong University, Jinan 250012, Shandong, PR China
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Fernandez-Cadenas I, Mendioroz M, Domingues-Montanari S, Del Rio-Espinola A, Delgado P, Ruiz A, Hernandez-Guillamon M, Giralt D, Chacon P, Navarro-Sobrino M, Ribo M, Molina CA, Alvarez-Sabin J, Rosell A, Montaner J. Leukoaraiosis is associated with genes regulating blood-brain barrier homeostasis in ischaemic stroke patients. Eur J Neurol 2010; 18:826-35. [PMID: 21122033 DOI: 10.1111/j.1468-1331.2010.03243.x] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
BACKGROUND The biologic agents causing leukoaraiosis are unknown. Our aim was to study the genetic basis of leukoaraiosis. METHODS We analyzed 212 single nucleotide polymorphisms (SNPs) in 142 patients with ischaemic stroke, generating a total of 30,104 genotypes. Seventy-nine subjects (55.6%) presented leukoaraiosis measured by the Fazekas scale and 69 (48.6%) by ARWMC scale. We analyzed the presence of synergic associations between SNPs using the hfcc software. Finally, functional studies were performed in 56 subjects. The Ingenuity Pathways software (ipa) was used to examine the role of the identified genes. RESULTS Six SNPs were associated with leukoaraiosis using both measuring scales. After logistic regression adjusted for leukoaraiosis risk factors, the rs2252070 of MMP13 (OR = 4.9, 95%CI: 1.34-17.9, P = 0.016), rs662 of PON1 (OR = 0.37, 95%CI: 0.15-0.87, P = 0.024) and rs1800779 of NOS3 (OR = 3.9, 95%CI: 1.38-11.38, P = 0.01) were independently associated with leukoaraiosis under a dominant/recessive model and the rs2290608 of IL5RA (OR = 0.46, 95%CI: 0.25-0.85, P = 0.013) and rs669 of A2M (OR = 2.5, 95%CI: 1.36-4.83, P = 0.004) under an additive model. Computational analysis showed a synergic association of rs10497212-AA of ITGB6 and rs2290608-GG of IL5RA with leukoaraiosis using both scales. (i) ARWMC (P = 1.3 × 10(-4) ) and (ii) Fazekas (P = 4.5 × 10(-5) ). Functional studies showed that the rs669 SNP was associated with plasma levels of A2M (P = 0.012) and A2M levels with leukoaraiosis in Fazekas scale (P = 0.02). ipa analysis revealed that the genes associated with leukoaraiosis were involved in blood-brain barrier (BBB) homeostasis. CONCLUSIONS Amongst patients with ischaemic stroke, several genes associated with BBB homeostasis could be involved with a higher risk of leukoaraiosis.
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Affiliation(s)
- I Fernandez-Cadenas
- Department of Neurology, Neurovascular Research Laboratory and Neurovascular Unit, Vall d'Hebron University Hospital, Barcelona, Spain
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Saha A, Ellison D, Thomas GJ, Vallath S, Mather SJ, Hart IR, Marshall JF. High-resolution in vivo imaging of breast cancer by targeting the pro-invasive integrin alphavbeta6. J Pathol 2010; 222:52-63. [PMID: 20629113 DOI: 10.1002/path.2745] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
The integrin alphavbeta6 is expressed only on epithelia and then usually only during processes of tissue remodelling including cancer, where its high expression correlates with reduced survival. Thus, alphavbeta6 represents an important target for imaging and therapy of cancer and new molecular-specific targeting agents are required. We have developed A20FMDV2, a peptide derived from the VP1 coat protein of foot-and-mouth-disease virus that binds specifically and stably to alphavbeta6. Using a newly generated pair of isogenic human cell lines that differ only in alphavbeta6 expression, it was shown, using biodistribution and SPECT imaging, that indium-111-labelled A20FMDV2 locates specifically to alphavbeta6-expressing tissues in vivo, achieving at least seven-times higher retention in alphavbeta6-positive than in alphavbeta6-negative tumours. In further studies with MCF10.DCIS.COM and MCF10A.CA1a breast carcinoma cell lines, which express alphavbeta6 endogenously, the radiopeptide achieved similar levels of tumour retention and permitted excellent discriminatory imaging of tumours. Thus, A20FMDV2 can be used for molecular-specific targeting of alphavbeta6 for imaging in vivo the often more aggressive, alphavbeta6-positive cancers. In the future, A20FMDV2 could serve also to deliver therapy to these same cancers.
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Affiliation(s)
- Antonio Saha
- Centre for Tumour Biology, Queen Mary University of London, Barts and London School of Medicine & Dentistry, Institute of Cancer and CR-UK Clinical Centre, John Vane Science Centre, Charterhouse Square, London EC1M 6BQ, UK
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Prognostic significance of matrix metalloproteinase-9 (MMP-9) in stage II colorectal carcinoma. J Gastrointest Cancer 2010; 40:91-7. [PMID: 19921474 DOI: 10.1007/s12029-009-9091-x] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
BACKGROUND Approximately 30% of all colorectal cancer patients are diagnosed with stage II disease. Adjuvant therapy is not widely recommended. However, it is well-established that a subgroup of patients with stage II is at high risk for recurrence within their life time and should be considered for adjuvant chemotherapy. The present work was designed to assess the value of matrix metalloproteinase-9 (MMP-9) as a predictor of disease outcome in a series of 202 stage II colorectal cancer (CRC) patients with long-term follow-up. METHODS The present study comprises a series of 202 patients who underwent bowel resection for stage II CRC at Turku University Hospital. Archival paraffin-embedded CRC tissue samples were used to prepare tissue microarray blocks for immunohistochemical staining with MMP-9 antibody. RESULTS Forty-eight percent of all CRC samples were positive for MMP-9. There was no significant correlation between MMP-9 expression and age, depth of invasion, and lymph node status. However, MMP-9 expression was significantly related to histological grade (p = 0.03) and location of the tumor (p = 0.01), therefore, being lower in high-grade tumors and most intense in carcinomas of the descending colon and rectum. Tumors with high MMP-9 expression showed a higher recurrence rate than tumors with low expression (p = 0.02). MMP-9 negative tumors had a more favorable disease-free survival (DFS) than those expressing MMP-9 (p = 0.03). The same was true with disease-specific survival (DSS; p = 0.02) as well, high expression of MMP-9 being associated with shorter survival rates. In multivariate (Cox) survival analysis, MMP-9 expression proved to be an independent predictor of DFS, but not DSS, which was predicted by age and sex only. CONCLUSION Quantification of MMP-9 expression seems to provide valuable prognostic information in stage II CRC, particularly, in selecting the patients at high risk for recurrent disease who might benefit from adjuvant therapy.
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Peng C, Liu X, Liu E, Xu K, Niu W, Chen R, Wang J, Zhang Z, Lin P, Wang J, Agrez M, Niu J. Norcantharidin induces HT-29 colon cancer cell apoptosis through the alphavbeta6-extracellular signal-related kinase signaling pathway. Cancer Sci 2009; 100:2302-8. [PMID: 19744110 PMCID: PMC11159502 DOI: 10.1111/j.1349-7006.2009.01320.x] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Norcantharidin has been used as an efficacious anticancer drug in China for many years, but its true mechanism remains poorly understood. Intriguingly, in an in vitro series study of anticancer drugs, we found that norcantharidin can effectively inhibit epithelial tumor cells from expressing integrin alphavbeta6. Our previous studies have confirmed that integrin alphavbeta6 is closely relevant to malignant epithelial cell tumor biology behavior, and it can promote cancer cells to invade and metastasize through a special alphavbeta6-extracellular signal-related kinase (ERK) direct signaling pathway. In this study, we investigated the relationship between the norcantharidin anticancer mechanism and integrin alphavbeta6. After HT-29 colon cancer cells were treated with norcantharidin, cell apoptosis increased remarkably. The expression of alphavbeta6 and the amount of p-ERK decreased substantially; simultaneously, the linkage between alphavbeta6 and ERK was barely detectable. However, the expression of other integrins and the levels of mitogen-activated protein kinase hardly changed. On these grounds, we presumed that norcantharidin induced HT-29 colon cancer cell apoptosis through the alphavbeta6-ERK signaling pathway. This finding elicited a novel strategy for targeting the whole alphavbeta6-ERK signal pathway, rather than simply blocking the combining site of alphavbeta6-ERK in colon cancer treatment.
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Affiliation(s)
- Cheng Peng
- Department of General Surgery, QiLu Hospital, Shandong University, Jinan, Shandong, China
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Kim YH, Kim MH, Kim BJ, Kim JJ, Chang DK, Son HJ, Rhee PL, Rhee JC. Inhibition of cell proliferation and invasion in a human colon cancer cell line by 5-aminosalicylic acid. Dig Liver Dis 2009; 41:328-37. [PMID: 18976971 DOI: 10.1016/j.dld.2008.09.003] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/12/2008] [Revised: 07/22/2008] [Accepted: 09/02/2008] [Indexed: 12/11/2022]
Abstract
BACKGROUND 5-Aminosalicylic acid lacks the well-known side effects associated with the long-term use of non-steroidal anti-inflammatory drugs. We investigated anti-carcinogenic mechanisms of 5-aminosalicylic acid on a colon cancer cell line. METHODS MTT analysis was performed for various colon cancer cell lines. The expression of NF-kappaB and metalloproteinases was examined in either HT-29 cells treated with IL-1beta and/or 5-aminosalicylic acid. Matrigel assay was used to evaluate invasive potential of HT-29 cells. Analysis of a cDNA microarray containing 8700 genes was performed to identify the alteration of gene expression in response to treatment to 5-aminosalicylic acid. RESULTS The use of MTT analysis showed that 5-aminosalicylic acid suppressed the growth of HT-29 cells. The activity of NF-kappaB was also decreased by combined-treatment with IL-1beta and 5-aminosalicylic acid. The use of an ELISA and zymography demonstrated that MMP-2 and MMP-9 enzyme activity were decreased in HT-29 cells by treatment with various concentration of 5-aminosalicylic acid. A matrigel analysis demonstrated that 5-aminosalicylic acid treatment on HT-29 significantly inhibited the invasiveness of the cells. In cDNA microarray, 163 genes following 5-aminosalicylic acid exposure showed altered expression. CONCLUSIONS This study indicated that 5-aminosalicylic acid suppresses the growth of human colon cancer cells and is able to inhibit MMPs expression via NF-kappaB mediated cell signals and invasiveness.
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Affiliation(s)
- Y-H Kim
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
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35
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Yang GY, Xu KS, Pan ZQ, Zhang ZY, Mi YT, Wang JS, Chen R, Niu J. Integrin alpha v beta 6 mediates the potential for colon cancer cells to colonize in and metastasize to the liver. Cancer Sci 2008; 99:879-87. [PMID: 18294287 PMCID: PMC11158270 DOI: 10.1111/j.1349-7006.2008.00762.x] [Citation(s) in RCA: 89] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Integrin alpha v beta 6 (alpha v beta 6) is correlated with colon cancer progression. To detect the effects of alpha v beta 6 on liver metastasis, the specificity of alpha v beta 6 against the monoclonal antibody (mAb) 2G2 was examined by immunoprecipitation. Integrin alpha v beta 6-immunoreactivity (IR) in liver metastasis tissues (63 cases) and colon carcinoma (358 cases) were examined. These results showed that alpha v beta 6 was specifically recognized by the mAb 2G2, and that rates of alpha v beta 6 positivity in liver metastatic tissues (71.4%, 45/63) were higher than that for primary colon cancer (34.0%, 122/358) (P < 0.01). Patients who were alpha v beta 6-positive had higher liver metastasis rates (17%, 21/122) than those who were alpha v beta 6-negative (only 3%, 7/236) (P < 0.01). To examine the underlying mechanisms associated with alpha v beta 6 regulating colonic metastasis in the liver, experimental liver metastasis (intrasplenic injection of HT29 transfectants) and liver colonization assays (direct injection of WiDr transfectants into the liver) in nude mice were performed; these demonstrated that alpha v beta 6 contributed to the promotion of the metastatic potential and the survival of cancer cells in the liver. Matrix metalloproteinase-9 (MMP-9) levels in the cultures of both HT29 and WiDr cells were detected by the Biotrak MMP-9 activity assay system and gelatin zymography assay, and showed that suppression of alpha v beta 6-IR inhibited MMP-9 activity and secretion. Transwell migration assay in vitro also showed that alpha v beta 6 promoted migration on fibronectin for HT29/WiDr mock compared with HT29/WiDr antisense beta 6 transfects (P < 0.01). We concluded that alpha v beta 6 may mediate the potential for colon cancer cells to colonize in and metastasize to the liver. The mechanisms that alpha v beta 6 may be involved in include the promotion of MMP-9 secretion, the enhancement of migration on fibronectin, and the survival of cancer cells in the liver.
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Affiliation(s)
- Guang-Yun Yang
- General Surgical Department of Qilu Hospital and Institute of Hepatobiliary and Vascular Surgery, Shandong University, Jinan, China
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Zhao-Yang Z, Ke-Sen X, Qing-Si H, Wei-Bo N, Jia-Yong W, Yue-Tang M, Jin-Shen W, Guo-Qiang W, Guang-Yun Y, Jun N. Signaling and regulatory mechanisms of integrin alphavbeta6 on the apoptosis of colon cancer cells. Cancer Lett 2008; 266:209-15. [PMID: 18381232 DOI: 10.1016/j.canlet.2008.02.054] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2007] [Revised: 02/21/2008] [Accepted: 02/22/2008] [Indexed: 11/29/2022]
Abstract
Considerable researches have been done about integrin alphanubeta6 and carcinomas, but little information has been shown about the relationship between integrin alphanubeta6 and apoptosis. In this study, we investigated the apoptosis and its related signal pathways to integrin alphavbeta6 in colon cancer cells. After we blocked the function of integrin alphavbeta6 in HT29 cells used the monoclonal antibody, the apoptotic cells increased markedly. Meanwhile, cytochrome C released from mitochondria into cytosol, Bcl-2 decreased while Bax increased significantly, and Fas and Fas-ligand had no change. The activities of caspase-3 and caspase-9 increased, while caspase-8 remained no change. Moreover, the expression of phosphorylated extracellular signal-related kinase (P-ERK) decreased. We confirmed that integrin alphavbeta6 acted as an important role in inhibiting apoptosis in colon cancer cells, and the signaling involved the mitochondrial pathway.
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Affiliation(s)
- Zhang Zhao-Yang
- Department of General Surgery, QiLu Hospital of Shandong University, Jinan 250012, Shandong, China
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Zhang ZY, Xu KS, Wang JS, Yang GY, Wang W, Wang JY, Niu WB, Liu EY, Mi YT, Niu J. Integrin alphanvbeta6 acts as a prognostic indicator in gastric carcinoma. Clin Oncol (R Coll Radiol) 2007; 20:61-6. [PMID: 17981018 DOI: 10.1016/j.clon.2007.09.008] [Citation(s) in RCA: 78] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2007] [Revised: 07/07/2007] [Accepted: 09/24/2007] [Indexed: 12/13/2022]
Abstract
AIMS To investigate the relationships between integrin alphanubeta6 expression and the clinical-pathological features of gastric carcinoma and whether integrin alphanubeta6 can act as a prognostic indicator in gastric carcinoma. MATERIALS AND METHODS We generated the microarray of 300 human gastric carcinoma specimens, and used the method of immunohistochemistry to investigate the expression of alphanubeta6 in them and the relationships between the expression of alphanubeta6 and the clinical-pathological features of the tumours. Meanwhile, we retrospectively analysed the relationship between alphanubeta6 expression and the survival times of the patients. RESULTS The expression of alphanubeta6 was detected in 36.7% of gastric carcinomas, and the expression was associated with Lauren type, differentiation, N stage and TNM stage of the tumours (the P values were 0.004, 0.035, 0.024 and 0.001, respectively). The Kaplan-Meier plot showed that patients who were alphanubeta6 negative had much longer survival times than those who were alphanubeta6 positive (P<0.0001). The survival estimates showed a striking difference in median survival between the negative and positive alphanubeta6 expression patients, especially in early stage tumours. Univariate analysis indicated that significant factors for prognosis included alphanubeta6 expression, differentiation, TNM stage, T stage, N stage, M stage and R classification (R0: potentially curative resection; R1: had residual microscopic disease after resection; R2: had residual macroscopic disease after resection), whereas in multivariate analysis using the Cox regression model, only alphanubeta6 expression, M stage, TNM stage and R classification retained significance for prognosis. CONCLUSIONS Positive alphanubeta6 expression in gastric carcinoma is linked to significantly reduced survival times and, even more important, is that its value as a prognostic marker is significant for early stage tumours.
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Affiliation(s)
- Z-Y Zhang
- Department of General Surgery of QiLu Hospital Affiliated Shandong University, Jinan 250012, Shandong, China
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Lubbe WJ, Zhou ZY, Fu W, Zuzga D, Schulz S, Fridman R, Muschel RJ, Waldman SA, Pitari GM. Tumor epithelial cell matrix metalloproteinase 9 is a target for antimetastatic therapy in colorectal cancer. Clin Cancer Res 2006; 12:1876-82. [PMID: 16551873 DOI: 10.1158/1078-0432.ccr-05-2686] [Citation(s) in RCA: 49] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
BACKGROUND The current paradigm suggests that matrix metalloproteinase 9 (MMP-9) expressed by stromal cells is a therapeutic target in human colorectal tumors which presumably regulates metastatic disease progression. Conversely, whereas cancer cells within those tumors may induce stromal cells to produce MMP-9 and may be targets for MMP-9 activity, they are not the source of MMP-9 underlying metastasis. METHODS MMP-9 expression in matched colorectal tumors and normal adjacent mucosa from patients and human colon cancer cell lines was examined by real-time reverse transcription-PCR, laser capture microdissection, immunoelectron microscopy, and immunoblot analysis. The role of colon cancer cell MMP-9 in processes underlying metastasis was explored in vitro by examining degradation of extracellular matrix components by gelatin zymography and formation of locomotory organelles by cell spreading analysis and in vivo by quantifying hematogenous tumor cell seeding of mouse lungs. RESULTS Primary colorectal tumors overexpress MMP-9 compared with matched normal adjacent mucosa. In contrast to the current paradigm, MMP-9 is expressed equally by cancer and stromal cells within human colon tumors. Cancer cell MMP-9 regulates metastatic behavior in vitro, including degradation of extracellular matrix components and formation of locomotory organelles. Moreover, this MMP-9 critically regulates hematogenous seeding of mouse lungs by human colon cancer cells in vivo. CONCLUSIONS These observations reveal that MMP-9 produced by human colon cancer, rather than stromal, cells is central to processes underlying metastasis. They underscore the previously unrecognized potential of specifically targeting tumor cell MMP-9 in interventional strategies to reduce mortality from metastatic colorectal cancer.
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Affiliation(s)
- Wilhelm J Lubbe
- Division of Clinical Pharmacology, Department of Pharmacology and Experimental Therapeutics, Thomas Jefferson University, Philadelphia, PA 19107, USA
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Alonso-Escolano D, Medina C, Cieslik K, Radomski A, Jurasz P, Santos-Martínez MJ, Jiffar T, Ruvolo P, Radomski MW. Protein kinase C delta mediates platelet-induced breast cancer cell invasion. J Pharmacol Exp Ther 2006; 318:373-80. [PMID: 16617167 DOI: 10.1124/jpet.106.103358] [Citation(s) in RCA: 44] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
Platelets play an important role in carcinogenesis, but the underlying molecular mechanisms remain poorly understood. To investigate the effects of platelets on in vitro invasion of MCF7 human breast cancer cells, human MCF7 cells were used to study their interactions with platelets using aggregometry and cell invasion chambers. Zymography and quantitative polymerase chain reaction (PCR) were used to study matrix metalloproteinases (MMPs), whereas Western blot was used to study protein kinase C (PKC) delta in MCF7 cells. We observed that platelets promoted invasion of MCF7 cells (3-fold increase, p<0.05, n=3) and that this process correlated with a dramatic increase in MMP-9 (8 fold-increase, p<0.001, n=3), which is known to facilitate cancer cell invasion. Because both platelets and MCF7 cells have been shown to release MMP-9, we investigated the cellular source that accounted for this increase. The time course and the use of specific protein synthesis inhibitors demonstrated that most of the increase in MMP-9 levels derived from de novo synthesis of this protease by cancer cells. Furthermore, platelets activated PKCdelta in MCF7 cells after 1 h of incubation (18.45+/-4.75% increase, p<0.05, n=4-7), which, in turn, led to an up-regulation of MMP-9 mRNA (from 60+/-20 to 1040+/-100 pg, p<0.001, n=3) and protein levels (18-fold increase, p<0.001, n=3), with the subsequent cell invasion-promoting effects. PKCdelta plays a crucial role in transducing the invasion-promoting effects of platelets in breast cancer cells, and the specific inhibition of PKCdelta may be a strategy to decrease platelet-mediated cancer cell invasion.
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Affiliation(s)
- David Alonso-Escolano
- Department of Integrative Biology and Pharmacology, Institute of Molecular Medicine for the Prevention of Human Diseases, University of Texas, Houston, USA
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Abstract
Members of the integrin family recognize a variety of spatially-restricted extracellular ligands. Classically, ligation of integrins activates cytoplasmic signals in the integrin-expressing cell and contributes to cell adhesion, migration, proliferation and survival. At least two members of this family, alphavbeta6 and alphavbeta8 perform an additional function, activation of latent complexes of transforming growth factor beta. In effect, this process allows integrins on one cell to activate signals on adjacent (in the case of alphavbeta6) or nearby cells (in the case of alphavbeta8). Integrin-mediated TGFbeta activation has been shown to play important roles in modulating tissue fibrosis, acute lung injury and pulmonary emphysema. Given the important roles that TGFbeta plays in modulating epithelial cell growth, epithelial-to-mesenchymal transformation and tumor invasion and metastasis, integrin-mediated TGFbeta activation is likely to play important roles in tumor growth and metastasis.
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Affiliation(s)
- Dean Sheppard
- Lung Biology Center, University of California San Francisco, 2922, San Francisco, CA, 94143-2922, USA.
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Björklund M, Koivunen E. Gelatinase-mediated migration and invasion of cancer cells. Biochim Biophys Acta Rev Cancer 2005; 1755:37-69. [PMID: 15907591 DOI: 10.1016/j.bbcan.2005.03.001] [Citation(s) in RCA: 264] [Impact Index Per Article: 13.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2004] [Revised: 03/23/2005] [Accepted: 03/24/2005] [Indexed: 01/13/2023]
Abstract
The matrix metalloproteinases(MMP)-2 and -9, also known as the gelatinases have been long recognized as major contributors to the proteolytic degradation of extracellular matrix during tumor invasion. In the recent years, a plethora of non-matrix proteins have also been identified as gelatinase substrates thus significantly broadening our understanding of these enzymes as proteolytic executors and regulators in various physiological and pathological states including embryonic growth and development, angiogenesis and tumor progression, inflammation, infective diseases, degenerative diseases of the brain and vascular diseases. Although the effect of broad-spectrum inhibitors of MMPs in the treatment of cancer has been disappointing in clinical trials, novel mechanisms of gelatinase inhibition have been now identified. Inhibition of the association of the gelatinases with cell-surface integrins appears to offer highly specific means to target these enzymes without inhibiting their catalytic activity in multiple cell types including endothelial cells, tumor cells and leukocytes. Here, we review the multiple functions of the gelatinases in cancer, and especially their role in the tumor cell migration and invasion.
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Affiliation(s)
- Mikael Björklund
- Department of Biological and Environmental Sciences, P.O. B 56 (Viikinkaari 5D), University of Helsinki, Finland
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Ridgway PF, Ziprin P, Peck DH, Darzi AW. Hypoxia increases reepithelialization via an alphavbeta6-dependent pathway. Wound Repair Regen 2005; 13:158-64. [PMID: 15828940 DOI: 10.1111/j.1067-1927.2005.130206.x] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
Reepithelialization is an essential step in successful cutaneous wound healing. Human keratinocytes, integral in this process, have been shown to have increased motility in the hypoxic healing edge of wounds correlating with the clinical success of semiocclusive hypoxic dressings, although the underlying mechanisms remain poorly understood. Subconfluent human keratinocyte cell monolayers were exposed to 1% hypoxia for up to 24 hours or control conditions. Re-oxygenation studies were performed up to 72 hours. Cellular alphav subunit and alphavbeta6 integrin expression was measured by flow cytometry. Migration scratch assays on fibronectin following hypoxic exposure were performed over 24 hours. Relative matrix metallo-proteinase (MMP)-2, 9 activity was determined by gelatin zymography with TIMP-1 levels assayed by enzyme-linked immunoassay. Sustained increases in alphav and alphavbeta6 expression were shown up to 48 hours in re-oxygenation studies (P < 0.001). Standardized scratch assays confirmed increased migration in the hypoxic group (P < 0.05). This effect was attenuated by the addition of a specific inhibitor of the alphavbeta6 integrin. MMP-2 and -9 activity was up-regulated following hypoxic exposure (P < 0.001; P < 0.05, respectively), whereas increased MMP expression was significantly retarded by addition of an alphavbeta6 inhibitor (P < 0.05). Migration on fibronectin was attenuated by a specific gelatinase inhibitor. We conclude that integrin alphavbeta6-dependent MMP-2 and -9 up-regulation is an important feature of increased migration in hypoxic human keratinocytes.
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Affiliation(s)
- Paul F Ridgway
- Department of Surgical Oncology and Technology, Division of Surgery, Anesthetics and Intensive Care, Imperial College Faculty of Medicine, St. Mary's Hospital, London, United Kingdom.
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Lygoe KA, Norman JT, Marshall JF, Lewis MP. AlphaV integrins play an important role in myofibroblast differentiation. Wound Repair Regen 2004; 12:461-70. [PMID: 15260812 DOI: 10.1111/j.1067-1927.2004.12402.x] [Citation(s) in RCA: 53] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Transforming growth factor-beta1 is a potent mediator of the differentiation of fibroblasts into myofibroblasts, which is characterized by the appearance of the cytoskeletal protein alpha-smooth muscle actin. The aim of this study was to investigate the role of integrin extracellular matrix receptors in transforming growth factor-beta1-induced myofibroblast differentiation. We show that blockade of the alphav and/or beta1 integrins prevents the transforming growth factor-beta1-induced myofibroblast differentiation, seen by the increased expression of alpha-smooth muscle actin and enhanced collagen gel contraction in three human fibroblast cell lines (from the mouth, skin, and kidney). Further, blockade of alphav specific integrins alphavbeta5 and alphavbeta3 suppressed myofibroblast differentiation in fibroblasts from the mouth and skin; however, in the kidney cells, the prevention of differentiation was seen only with blockade of alphavbeta5 integrin but not alphavbeta3. A possible reason for this result may be different degrees of responsiveness to transforming growth factor-beta1 treatment seen from different anatomical origins of the cell lines. These data indicate a novel role for alphav integrins in the differentiation of human fibroblasts from the mouth, skin, and kidney into myofibroblasts and suggest that there is a common differentiation pathway.
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Affiliation(s)
- Kate A Lygoe
- Eastman Dental Institute, University College London, 256 Grays Inn Road, London WC1 X8LD, United Kingdom
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Morgan MR, Thomas GJ, Russell A, Hart IR, Marshall JF. The Integrin Cytoplasmic-tail Motif EKQKVDLSTDC Is Sufficient to Promote Tumor Cell Invasion Mediated by Matrix Metalloproteinase (MMP)-2 or MMP-9. J Biol Chem 2004; 279:26533-9. [PMID: 15067014 DOI: 10.1074/jbc.m401736200] [Citation(s) in RCA: 40] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
Integrins promote cellular invasion through a combination of activities, including adhesion to an extracellular matrix ligand, which result in the generation of intracellular signals that lead to changes in cell behavior. Until now, there have been no data that identify a particular region of the cytoplasmic tail of integrin subunits as being responsible specifically for promoting the invasive activity of tumor cells. In this report, we show that amino acids with the sequence EKQKVDLSTDC, which are the C-terminal residues of the integrin beta6 subunit, promote alphavbeta6-dependent invasion in a matrix metalloproteinase (MMP)-9-dependent fashion. This same peptide sequence, when expressed at the cytoplasmic end of the beta3 integrin subunit, was able to enhance alphavbeta3-mediated invasive and enzymatic activity of tumor cells in an MMP-2-dependent fashion. Our results show that these 11 amino acids, when expressed at the C terminus of the beta subunit, are responsible for regulating the activity of invasion-promoting degradative enzymes, whereas the specific MMP involved in this cellular behavior is dependent on the context of the remainder of the beta integrin subunit.
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Affiliation(s)
- Mark R Morgan
- Tumour Biology Laboratory, Cancer Research UK Clinical Centre, Barts and The London School of Medicine and Dentistry, John Vane Science Centre, Charterhouse Sq., London EC1M 6BQ, United Kingdom
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Dalvi N, Thomas GJ, Marshall JF, Morgan M, Bass R, Ellis V, Speight PM, Whawell SA. Modulation of the urokinase-type plasminogen activator receptor by the β6 integrin subunit. Biochem Biophys Res Commun 2004; 317:92-9. [PMID: 15047152 DOI: 10.1016/j.bbrc.2004.02.178] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2004] [Indexed: 11/21/2022]
Abstract
Over-expression of components of the urokinase system is well documented in cancer and is thought to enable tumour cells to migrate and invade. Changes in integrin expression are also a common feature of tumours and have been linked to changes in protease activity. It has been shown that the alphavbeta6 integrin is neo-expressed in a number of epithelial carcinomas and in wound healing situations. We therefore investigated whether alphavbeta6 is able to modulate a key regulator of proteolysis, the urokinase receptor. We report that epithelial cells expressing full-length alphavbeta6 exhibit decreased urokinase receptor expression and function. Furthermore, this novel modulation requires the C-terminal 11 amino acids of the cytoplasmic tail of the beta6 integrin subunit. Cells expressing alphavbeta3, however, did not affect urokinase receptor expression. De novo expression of beta6 by melanoma cells and beta3 by epithelial cells did not influence urokinase receptor expression or function, suggesting that modulation of urokinase system is both integrin subunit and cell-specific.
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Affiliation(s)
- Nafisa Dalvi
- Department of Oral Pathology, Eastman Dental Institute for Oral Health Care Sciences, University College London, London WC1X 8LD, UK.
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Kawashima A, Tsugawa S, Boku A, Kobayashi M, Minamoto T, Nakanishi I, Oda Y. Expression of alphav integrin family in gastric carcinomas: increased alphavbeta6 is associated with lymph node metastasis. Pathol Res Pract 2003; 199:57-64. [PMID: 12747466 DOI: 10.1078/0344-0338-00355] [Citation(s) in RCA: 57] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
To investigate the alterations as to integrin expression in human gastric carcinomas, we analyzed the alphav subunit and 5 types of beta subunits using reverse transcription-polymerase chain reaction (RT-PCR) and competitive RT-PCR. The incidence of alphav, beta6 and beta8 expression was significantly higher in carcinoma tissues than in non-neoplastic gastric mucosal tissues (NGMTs). Out of 18 carcinoma cases with coexpression of alphav and beta6 subunits, which was demonstrated by RT-PCR, 17 cases (94%) showed lymph node metastasis (p = 0.0033). This tendency was confirmed by immunohistochemistry; most cases (23/28, 82%) in which alphavbeta6 integrin was immunohistochemically detected showed lymph node metastasis (p = 0.0193). RT-PCR and immunohistochemical studies showed that gastric carcinoma tissues expressed beta5 subunit in all cases. Furthermore, in a quantitative analysis using competitive RT-PCR, the mean level of beta5 expression was approximately 140 times higher in gastric carcinomas than in NGMTs. Most gastric carcinoma cases (27/38, 71%) were immunohistochemically positive for beta8 subunit. These findings suggest that some members of the alphav integrin family (alphavbeta5, alphavbeta6, alphavbeta8) are up-regulated, and that alphavbeta6 integrin may be involved in the lymphatic metastasis of gastric carcinomas.
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Affiliation(s)
- Atsuhiro Kawashima
- Department of Molecular and Cellular Pathology, Graduate School of Medical Science, Kanazawa University, Kanazawa, Japan.
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Abstract
Signals from integrins are now known to play critical roles in virtually every aspect of the behavior of epithelial cells, including survival, proliferation, maintenance of polarity, secretory differentiation, and malignant transformation. The cells that line the conducting airways and alveoli of the lung, like most surface epithelia, simultaneously express multiple members of the integrin family, including several with broadly overlapping ligand binding specificities. Although multiple integrins on airway epithelial cells may support adhesion to the same ligands, the functional roles of each integrin that has been examined in detail are quite distinct. Findings from mice expressing null mutations of some of these integrins have identified roles for epithelial cells and epithelial integrins in lung development and in the regulation of lung inflammation, macrophage protease expression, pulmonary fibrosis, and the pulmonary edema that follows acute lung injury. Epithelial integrins are thus attractive targets for intervention in a number of common lung disorders.
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Affiliation(s)
- Dean Sheppard
- University of California, San Francisco, Box 0854, San Francisco, CA 94143-0854, USA.
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Ahmed N, Riley C, Rice GE, Quinn MA, Baker MS. Alpha(v)beta(6) integrin-A marker for the malignant potential of epithelial ovarian cancer. J Histochem Cytochem 2002; 50:1371-80. [PMID: 12364570 DOI: 10.1177/002215540205001010] [Citation(s) in RCA: 82] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
Abstract
The mechanism(s) responsible for the progression of non-metastatic or borderline ovarian cancer to invasive Grade I/III ovarian cancer is still unknown. An epithelium-restricted integrin, alpha(v)beta(6), is present in malignant epithelia but not in normal epithelia. We studied the relative expression and distribution of alpha(v)beta(6) integrin in early and late-stage invasive (Grade I and Grade III) and non-invasive (benign and borderline) ovarian tumors of serous, mucinous, endometrioid, and clear-cell carcinoma subtypes, to assess its potential as a marker for epithelial ovarian cancer progression. Sixty-six specimens, including eight normal, 13 benign, 14 borderline, 13 Grade I, and 18 Grade III tumors were evaluated by immunohistochemistry (IHC) using a monoclonal antibody (MAb) against alpha(v)beta(6) integrin. Normal ovarian surface epithelium was negative for alpha(v)beta(6) integrin expression. All 45 carcinomas studied were positive, and the staining intensity significantly correlated with the grade of the tumor. The Grade III carcinomas of all types showed strong staining intensity. Only mucinous benign tissues were positive, and no reactivity was observed in benign serous neoplasms. On the basis of these observations, we hypothesize that the expression of alpha(v)beta(6) integrin is associated with epithelial ovarian cancer and that a gradual increase in the expression of the molecule may be a correlative index of the progression of this disease.
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MESH Headings
- Antigens, Neoplasm
- Biomarkers, Tumor/metabolism
- Carcinoma, Endometrioid/diagnosis
- Carcinoma, Endometrioid/metabolism
- Carcinoma, Endometrioid/pathology
- Carcinoma, Transitional Cell/diagnosis
- Carcinoma, Transitional Cell/metabolism
- Carcinoma, Transitional Cell/pathology
- Cystadenoma, Mucinous/diagnosis
- Cystadenoma, Mucinous/metabolism
- Cystadenoma, Mucinous/pathology
- Cystadenoma, Serous/diagnosis
- Cystadenoma, Serous/metabolism
- Cystadenoma, Serous/pathology
- Epithelium/pathology
- Female
- Humans
- Immunohistochemistry
- Integrins/metabolism
- Neoplasm Invasiveness
- Neoplasm Staging
- Ovarian Neoplasms/diagnosis
- Ovarian Neoplasms/metabolism
- Ovarian Neoplasms/pathology
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Affiliation(s)
- Nuzhat Ahmed
- Gynaecological Cancer Research Centre, The University of Melbourne and Royal Women's Hospital, Carlton, Victoria, Australia.
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Hosotani R, Kawaguchi M, Masui T, Koshiba T, Ida J, Fujimoto K, Wada M, Doi R, Imamura M. Expression of integrin alphaVbeta3 in pancreatic carcinoma: relation to MMP-2 activation and lymph node metastasis. Pancreas 2002; 25:e30-5. [PMID: 12142752 DOI: 10.1097/00006676-200208000-00021] [Citation(s) in RCA: 108] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
INTRODUCTION Overexpression of integrin alphaVbeta3 had been demonstrated in various tumors. Studies have suggested that elevated levels of integrin alphaVbeta3 in melanoma cells are deeply involved in the mechanism of increased melanoma invasiveness. AIMS To examine the expression of integrin alphaVbeta3 in pancreatic carcinoma and to evaluate the correlation between integrin expression accompanied by MMP-2 activation and clinicopathologic factors. METHODOLOGY Integrin alphaVbeta3 specific antibody LM-609 was used for immunochemical analysis, and intracellular localization was determined in human pancreatic cancer cell lines cultured on vitronectin coating. Fifty pancreatic adenocarcinomas analyzed immunohistochemically and 26 frozen samples were analyzed gelatin-zymographically. RESULTS Two of three pancreatic cancer cell lines demonstrated integrin alphaVbeta3 immunofluorescence with a membranous pattern, and 29 of 50 pancreatic carcinomas showed positive immunostaining of tumor cells. There was no significant correlation between integrin alphaVbeta3 expression and tumor size, tumor grade, or peripancreatic invasion. However, primary tumors with lymph node metastasis featured significantly higher expression of integrin alphaVbeta3 than those without node metastasis. Tumors with high integrin alphaVbeta3 expression showed significantly higher MMP-2 activation ratios than did tumors with low expression. CONCLUSION Expression analysis in pancreatic cancer tissue demonstrated involvement of alphaVbeta3 integrin in lymph node metastasis rather than peripancreatic invasion. MMP-2 activation is linked, at least in part, to the expression of integrin alphaVbeta3 of pancreatic cancer cells.
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Affiliation(s)
- Ryo Hosotani
- Department of Surgery and Surgical Basic Science, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
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Gu X, Niu J, Dorahy DJ, Scott R, Agrez MV. Integrin alpha(v)beta6-associated ERK2 mediates MMP-9 secretion in colon cancer cells. Br J Cancer 2002; 87:348-51. [PMID: 12177807 PMCID: PMC2364215 DOI: 10.1038/sj.bjc.6600480] [Citation(s) in RCA: 37] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2002] [Revised: 05/25/2002] [Accepted: 05/27/2002] [Indexed: 12/31/2022] Open
Abstract
There is general consensus that matrix metalloproteinases are involved in tumour progression. We show herein that inhibition of integrin alpha(v)beta6 expression in colon cancer cells suppresses MMP-9 secretion. This integrin-mediated event is dependent upon direct binding between the beta6 integrin subunit and extracellular signal-regulated kinase 2. Targetting either beta6 or its interaction with extracellular signal-regulated kinase in order to inhibit matrix metalloproteinase activity may offer a useful therapeutic approach in preventing growth and spread of colon cancer.
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Affiliation(s)
- X Gu
- Newcastle Bowel Cancer Research Collaborative, Hunter Medical Research Institute, John Hunter Hospital and The University of Newcastle, NSW 2308, Australia
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