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Manjunatha BS, Handge KT, Shah VS, Al-Thobaiti YE, Pateel DGS. Immunohistochemical expression of matrix metalloproteinase-9 and 13 in oral squamous cell carcinoma and their role in predicting lymph node metastasis. World J Methodol 2025; 15:94514. [DOI: 10.5662/wjm.v15.i2.94514] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/19/2024] [Revised: 09/23/2024] [Accepted: 10/20/2024] [Indexed: 11/27/2024] Open
Abstract
BACKGROUND One of the main characteristics of oral squamous cell carcinoma (OSCC) is that it metastasizes to cervical lymph nodes frequently with a high degree of local invasiveness. A primary feature of malignant tumors is their penetration of neighboring tissues, such as lymphatic and blood arteries, due to the tumor cells' capacity to break down the extracellular matrix (ECM). Matrix metalloproteinases (MMPs) constitute a family of proteolytic enzymes that facilitate tissue remodeling and the degradation of the ECM. MMP-9 and MMP-13 belong to the group of extracellular matrix degrading enzymes and their expression has been studied in OSCC because of their specific functions. MMP-13, a collagenase family member, is thought to play an essential role in the MMP activation cascade by breaking down the fibrillar collagens, whereas MMP-9 is thought to accelerate the growth of tumors. Elevated MMP-13 expression has been associated with tumor behavior and patient prognosis in a number of malignant cases.
AIM To assess the immunohistochemical expression of MMP-9 and MMP-13 in OSCC.
METHODS A total of 40 cases with histologically confirmed OSCC by incisional biopsy were included in this cross-sectional retrospective study. The protocols for both MMP-9 and MMP-13 immunohistochemical staining were performed according to the manufacturer’s recommendations along with the normal gingival epithelium as a positive control. All the observations were recorded and Pearson’s χ² test with Fisher exact test was used for statistical analysis.
RESULTS Our study showed no significant correlation between MMP-9 and MMP-13 staining intensity and tumor size. The majority of the patients were in advanced TNM stages (III and IV), and showed intense expression of MMP-9 and MMP-13.
CONCLUSION The present study suggests that both MMP-9 and MMP-13 play an important and independent role in OSCC progression and invasiveness. Intense expression of MMP-9 and MMP-13, irrespective of histological grade of OSCC, correlates well with TNM stage. Consequently, it is evident that MMP-9 and MMP-13 are important for the invasiveness and progression of tumors. The findings may facilitate the development of new approaches for evaluating lymph node metastases and interventional therapy techniques, hence enhancing the prognosis of patients diagnosed with OSCC.
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Affiliation(s)
- Bhari Sharanesha Manjunatha
- Department of Basic Oral Medicine and Allied Dental Sciences, Taif University, At`Taif 26571, Makkah, Saudi Arabia
| | - Keshav T Handge
- Department of Oral and Maxillofacial Pathology, Dr. Vasantrao Pawar Medical College, Hospital and Research Centre, Nashik 423101, Maharashtra, India
| | - Vandana Sandeep Shah
- Department of Oral Pathology and Microbiology, KM Shah Dental College and Hospital, Sumandeep Vidyapeeth, Vadodara 391760, Gujarat, India
| | - Yasser Eid Al-Thobaiti
- Department of Oral and Maxillofacial Surgery and Diagnostic Sciences, Faculty of Dentistry, Taif University, Al-Haweiah 26571 Makkah, Saudi Arabia
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Oliveira SG, Jardim R, Kotowski N, Dávila AMR, Sampaio-Filho HR, Ruiz KGS, Aguiar FHB. Differential expression reveals inflammatory response and oxidative stress genes in dentin caries. Arch Oral Biol 2025; 175:106274. [PMID: 40305968 DOI: 10.1016/j.archoralbio.2025.106274] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2025] [Revised: 04/14/2025] [Accepted: 04/17/2025] [Indexed: 05/02/2025]
Abstract
OBJECTIVE This study employs RNA-Seq to investigate differentially expressed genes involved in extracellular matrix (ECM) degradation, focusing on collagenases (MMP-2 and MMP-9) and their inhibitors (TIMP-1 and TIMP-2). DESIGN Total RNA from caries and caries-free teeth was extracted from pulp, predentin, and dentin. Samples were sequenced using Illumina® technology. Quality validation was done with FASTQC, and low-quality bases were removed using TRIMMOMATIC. Reads were aligned using SALMON against the human transcriptome (CHR38), followed by quantification using Transcripts Per Million. Differential gene expression analysis was conducted using DESeq2 (FDR < 0.05, |log2FC| ≥ 1). Functional enrichment analyses employed Gene Ontology and KEGG databases. RESULTS Sequencing produced 16-37 million reads per sample, with an average alignment rate of 88.08 %. A total of 334 differentially expressed genes (DEGs) were identified: 195 upregulated and 139 downregulated. Upregulated genes included SAA1 (log2FC = 2.3, p-adj = 0.001) and ORM1 (log2FC = 2.0, p-adj = 0.002), associated with inflammation. MMP-9 was significantly downregulated (log2FC = -1.8, p-adj = 0.003), while MMP-2 showed higher expression in decayed tissues. TIMP-1 expression increased in decayed dentin; TIMP-2 was upregulated in both decayed and caries-free dentin. Protein interaction analysis identified EGFR and metallothioneins as key acute-phase proteins. CONCLUSIONS This study reveals the role of inflammatory and oxidative stress-related genes in dentin caries and shows disruption in the ECM degradation-repair balance. Increased MMP-2 and TIMP-1 expression suggests a compensatory response. MMP activity may serve as a therapeutic target to enhance tissue resilience and slow caries progression.
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Affiliation(s)
- Simone G Oliveira
- Department of Restorative Dentistry, Division of Operative Dentistry, Piracicaba Dental School, University of Campinas (UNICAMP), Av. Limeira, 901 - Areião, Piracicaba, SP 13414-903, Brazil; School of Dentistry, State University of Rio de Janeiro, Blvd. 28 de Setembro, 157 - Vila Isabel, Rio de Janeiro, RJ 20551-030, Brazil.
| | - Rodrigo Jardim
- Computational Biology and Systems Laboratory, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Av. Brasil, 4365 - Manguinhos, Rio de Janeiro, 21040-900, RJ, Brazil.
| | - Nelson Kotowski
- Computational Biology and Systems Laboratory, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Av. Brasil, 4365 - Manguinhos, Rio de Janeiro, 21040-900, RJ, Brazil
| | - Alberto M R Dávila
- Computational Biology and Systems Laboratory, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Av. Brasil, 4365 - Manguinhos, Rio de Janeiro, 21040-900, RJ, Brazil
| | - Hélio R Sampaio-Filho
- School of Dentistry, State University of Rio de Janeiro, Blvd. 28 de Setembro, 157 - Vila Isabel, Rio de Janeiro, RJ 20551-030, Brazil
| | - Karina G S Ruiz
- Department of Restorative Dentistry, Division of Operative Dentistry, Piracicaba Dental School, University of Campinas (UNICAMP), Av. Limeira, 901 - Areião, Piracicaba, SP 13414-903, Brazil
| | - Flávio H B Aguiar
- Department of Restorative Dentistry, Division of Operative Dentistry, Piracicaba Dental School, University of Campinas (UNICAMP), Av. Limeira, 901 - Areião, Piracicaba, SP 13414-903, Brazil
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Saini J, Bakshi J, Panda NK, Sharma M, Yadav AK, Narayansami S, Goyal AK. Diagnostic and Prognostic Accuracy of MMPs and TIMPs in Oral Cancer Patients on Enzyme-Linked Immunosorbent Assay (ELISA) as Compared to Immunohistochemistry (IHC). Indian J Surg Oncol 2025; 16:601-610. [PMID: 40337044 PMCID: PMC12052617 DOI: 10.1007/s13193-024-02113-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2024] [Accepted: 10/08/2024] [Indexed: 05/09/2025] Open
Abstract
Oral cancer is one of most common noncommunicable diseases that imposed significant burden on healthcare around the globe including India. Several molecular markers have been extensively researched for their potential as diagnostic and prognostic biomarkers for oral cancer. Matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) found to play a crucial role in cytoskeleton dynamics and thus tumor growth and metastasis. The present study aims to analyze the MMP (MMP-1, MMP-3, MMP-9, and MMP-13) and TIMP (TIMP-1 and TIMP-3) expression in the oral cancer patients as compared to healthy controls. We also aim to compare the diagnostic accuracy of MMPs and TIMPs on enzyme-linked immunosorbent assay (ELISA) with respect to the immunohistochemistry (IHC). A total of 15 oral cancer patients and 14 healthy controls were enrolled in this study. Blood sample from oral cancer patients and healthy controls was obtained to analyze the MMP and TIMP expression levels in serum sample using ELISA. Tumor tissue sample from patients for IHC analysis was obtained by biopsy under local anesthesia. Data were compared between ELISA and IHC for sensitivity and specificity analysis. The mean age of the patients was 47.07 ± 15.74 years with the highest incidence of disease found in male gender (86.7%). MMPs and TIMPs exhibited higher expression in oral cancer patients as compared to healthy controls and the difference was statistically significant in case of MMP-13. MMPs and TIMPs showed stronger expression at advanced stages of cancer on IHC with MMP-9 exhibiting the highest expression level. The highest sensitivity and specificity on ELISA with respect to IHC were exhibited by the MMP-3 followed by MMP-13, TIMP-1, TIMP-3, and MMP-1. MMP-3 and MMP-13 were found to be reliable in terms of diagnostic marker for oral cancer as they found to have the highest sensitivity and specificity on ELISA with respect to IHC. MMP-9 was found to be reliable as a prognostic marker as it expresses highest on IHC at advanced stages of oral cancer.
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Affiliation(s)
- Jyoti Saini
- Department of Otolaryngology and Head & Neck Surgery, Post Graduate Institute of Medical Education and Research, Chandigarh, India
| | - Jaimanti Bakshi
- Department of Otolaryngology and Head & Neck Surgery, Post Graduate Institute of Medical Education and Research, Chandigarh, India
| | - Naresh Kumar Panda
- Department of Otolaryngology and Head & Neck Surgery, Post Graduate Institute of Medical Education and Research, Chandigarh, India
| | - Maryada Sharma
- Department of Otolaryngology and Head & Neck Surgery, Post Graduate Institute of Medical Education and Research, Chandigarh, India
| | - Ashok Kumar Yadav
- Department of Experimental Medicine and Biotechnology, Post Graduate Institute of Medical Education and Research, Chandigarh, India
| | - Suruthy Narayansami
- Department of Histopathology, Post Graduate Institute of Medical Education and Research, Chandigarh, India
| | - Atul Kumar Goyal
- Department of Otolaryngology and Head & Neck Surgery, Post Graduate Institute of Medical Education and Research, Chandigarh, India
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Shoari A, Ashja Ardalan A, Dimesa AM, Coban MA. Targeting Invasion: The Role of MMP-2 and MMP-9 Inhibition in Colorectal Cancer Therapy. Biomolecules 2024; 15:35. [PMID: 39858430 PMCID: PMC11762759 DOI: 10.3390/biom15010035] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2024] [Revised: 12/27/2024] [Accepted: 12/29/2024] [Indexed: 01/27/2025] Open
Abstract
Colorectal cancer (CRC) remains one of the most prevalent and lethal cancers worldwide, prompting ongoing research into innovative therapeutic strategies. This review aims to systematically evaluate the role of gelatinases, specifically MMP-2 and MMP-9, as therapeutic targets in CRC, providing a critical analysis of their potential to improve patient outcomes. Gelatinases, specifically MMP-2 and MMP-9, play critical roles in the processes of tumor growth, invasion, and metastasis. Their expression and activity are significantly elevated in CRC, correlating with poor prognosis and lower survival rates. This review provides a comprehensive overview of the pathophysiological roles of gelatinases in CRC, highlighting their contribution to tumor microenvironment modulation, angiogenesis, and the metastatic cascade. We also critically evaluate recent advancements in the development of gelatinase inhibitors, including small molecule inhibitors, natural compounds, and novel therapeutic approaches like gene silencing techniques. Challenges such as nonspecificity, adverse side effects, and resistance mechanisms are discussed. We explore the potential of gelatinase inhibition in combination therapies, particularly with conventional chemotherapy and emerging targeted treatments, to enhance therapeutic efficacy and overcome resistance. The novelty of this review lies in its integration of recent findings on diverse inhibition strategies with insights into their clinical relevance, offering a roadmap for future research. By addressing the limitations of current approaches and proposing novel strategies, this review underscores the potential of gelatinase inhibitors in CRC prevention and therapy, inspiring further exploration in this promising area of oncological treatment.
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Affiliation(s)
- Alireza Shoari
- Department of Cancer Biology, Mayo Clinic, Jacksonville, FL 32224, USA;
| | - Arghavan Ashja Ardalan
- Department of Pharmacy and Biotechnology, Alma Mater Studiorum, University of Bologna, 40126 Bologna, Italy;
| | | | - Mathew A. Coban
- Department of Cancer Biology, Mayo Clinic, Jacksonville, FL 32224, USA;
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Saini J, Bakshi J, Panda NK, Sharma M, Yadav AK, Kamboj K, Goyal AK. Serum Concentration of MMP-9 as a Predictive Biomarker for the Progression of Oral Cancer. J Maxillofac Oral Surg 2024; 23:1079-1088. [PMID: 39376770 PMCID: PMC11455997 DOI: 10.1007/s12663-023-01932-5] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2021] [Accepted: 04/29/2023] [Indexed: 10/09/2024] Open
Abstract
Background Oral cancer is the most prominent cancer subtype among all head and neck cancers, the incidence and prevalence of which has been consistently increasing in past years around the globe. At advanced stages, oral cancer imparts significant mortality, morbidity, and mutilation among the patients, and therefore, diagnosis and treatment of the disease at early stages are considered the optimum strategy for the management of the disease. Since molecular changes appear earlier than physical symptoms, several molecular biomarkers are currently being investigated for their role in diagnosing and treating disease. MMP-9 belongs to the family of proteinases that are involved in cytoskeletal degradation, which is a crucial phase of cancer progression. Objective In the present study, we analyzed the serum concentration of MMP-9 in oral cancer patients and tried to establish MMP-9 as a predictive biomarker for the progression of oral cancer. We also correlated the clinical, sociodemographic and biochemical parameters with the serum concentration of MMP-9 in oral cancer patients. Methods Serum was extracted from the blood sample of 38 oral cancer patients and was analyzed for the concentration of MMP-9 using sandwiched ELISA. Predesigned proforma was used to capture the clinical, sociodemographic and biochemical parameters. Unpaired t-test was used to compare two means, one way ANOVA was used to compare more than two means and Pearson's correlation was used to correlate the variables. Results The mean concentration of MMP-9 in patients of oral cancer was 816.9 ± 236.1 ng/mL. The MMP-9 expression level was higher at advanced oral cancer stages than in the early stages. No significant difference in the MMP expression was found in terms of sociodemographic risk factor and tumor site. MMP-9 exhibit significant negative correlation with the HDL and significantly positive correlation with the PTI. Rest of the biochemical parameters does not exhibit significant correlation. Conclusion The present study suggests that serum concentration of MMP-9 can be a predictive biomarker for the progression of oral cancer, which needs to be validated by performing further longitudinal cross-sectional studies by taking ample sample size.
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Affiliation(s)
- Jyoti Saini
- Department of Otolaryngology and Head Neck Surgery, Post Graduate Institute of Medical Education and Research, Chandigarh, India
| | - Jaimanti Bakshi
- Department of Otolaryngology and Head Neck Surgery, Post Graduate Institute of Medical Education and Research, Chandigarh, India
| | - Naresh K. Panda
- Department of Otolaryngology and Head Neck Surgery, Post Graduate Institute of Medical Education and Research, Chandigarh, India
| | - Maryada Sharma
- Department of Otolaryngology and Head Neck Surgery, Post Graduate Institute of Medical Education and Research, Chandigarh, India
| | - Ashok K. Yadav
- Department of Experimental Medicine and Biotechnology, Post Graduate Institute of Medical Education and Research, Chandigarh, India
| | - Kajal Kamboj
- Department of Nephrology, Post Graduate Institute of Medical Education and Research, Chandigarh, India
| | - Atul Kumar Goyal
- Department of Otolaryngology and Head Neck Surgery, Post Graduate Institute of Medical Education and Research, Chandigarh, India
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Balapure A, Dubey SK, Javed A, Chattopadhyay S, Goel S. A review: early detection of oral cancer biomarkers using microfluidic colorimetric point-of-care devices. ANALYTICAL METHODS : ADVANCING METHODS AND APPLICATIONS 2024; 16:6098-6118. [PMID: 39206589 DOI: 10.1039/d4ay01030b] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/04/2024]
Abstract
Oral squamous cell carcinoma (OSCC) is the most common type of head and neck cancers. OSCC constitutes 90% of the head and neck malignancies. The delayed identification of oral cancer is the primary cause of ineffective medical treatment. To address this issue, low-cost, reliable point-of-care devices that can be utilized for large-scale screening, even in low-resource settings, including rural areas and primary healthcare centers, are of great interest. Herein, a comprehensive analysis of numerous salivary biomarkers that exhibit significant variations in concentration between individuals with oral cancer and those without is given. Furthermore, the article explores several point-of-care devices that exhibit potential in the realm of oral cancer detection. The biomarkers are discussed with a focus on their structural characteristics and role in oral cancer progression. The devices based on colorimetry and microfluidics are discussed in detail, considering their compliance with the 'REASSURED' criteria given by the World Health Organization (WHO) and suitability for mass screening in low-resource settings. Finally, the discourse revolves around the fundamental aspects pertaining to the advancement of multiplex, cost-effective point-of-care devices designed for widespread screening purposes.
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Affiliation(s)
- Aniket Balapure
- MEMS, Microfluidics and Nanoelectronics (MMNE) Lab, Birla Institute of Technology and Science (BITS) Pilani, Hyderabad Campus, Jawahar Nagar, Kapra Mandal, Medchal District, 500 078, Telangana, India.
- Department of Electrical and Electronics Engineering, Birla Institute of Technology and Science (BITS) Pilani, Hyderabad Campus, Jawahar Nagar, Kapra Mandal, Medchal District, 500 078, Telangana, India
| | - Satish Kumar Dubey
- MEMS, Microfluidics and Nanoelectronics (MMNE) Lab, Birla Institute of Technology and Science (BITS) Pilani, Hyderabad Campus, Jawahar Nagar, Kapra Mandal, Medchal District, 500 078, Telangana, India.
- Department of Mechanical Engineering, Birla Institute of Technology and Science (BITS) Pilani, Hyderabad Campus, Jawahar Nagar, Kapra Mandal, Medchal District, 500 078, Telangana, India
| | - Arshad Javed
- MEMS, Microfluidics and Nanoelectronics (MMNE) Lab, Birla Institute of Technology and Science (BITS) Pilani, Hyderabad Campus, Jawahar Nagar, Kapra Mandal, Medchal District, 500 078, Telangana, India.
- Department of Mechanical Engineering, Birla Institute of Technology and Science (BITS) Pilani, Hyderabad Campus, Jawahar Nagar, Kapra Mandal, Medchal District, 500 078, Telangana, India
| | - Samit Chattopadhyay
- Department of Biological Sciences, Birla Institute of Technology and Science (BITS) Pilani, K K Birla Goa Campus, NH-17B, Zuarinagar, Goa 403726, India
| | - Sanket Goel
- MEMS, Microfluidics and Nanoelectronics (MMNE) Lab, Birla Institute of Technology and Science (BITS) Pilani, Hyderabad Campus, Jawahar Nagar, Kapra Mandal, Medchal District, 500 078, Telangana, India.
- Department of Electrical and Electronics Engineering, Birla Institute of Technology and Science (BITS) Pilani, Hyderabad Campus, Jawahar Nagar, Kapra Mandal, Medchal District, 500 078, Telangana, India
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Mastronikolis NS, Kyrodimos E, Piperigkou Z, Spyropoulou D, Delides A, Giotakis E, Alexopoulou M, Bakalis NA, Karamanos NK. Matrix-based molecular mechanisms, targeting and diagnostics in oral squamous cell carcinoma. IUBMB Life 2024; 76:368-382. [PMID: 38168122 DOI: 10.1002/iub.2803] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2023] [Accepted: 11/22/2023] [Indexed: 01/05/2024]
Abstract
Oral squamous cell carcinoma (OSCC) is a head and neck cancer (HNC) with a high mortality rate. OSCC is developed in the oral cavity and it is triggered by many etiologic factors and can metastasize both regionally and distantly. Recent research advances in OSCC improved our understanding on the molecular mechanisms involved in and the initiation of OSCC metastasis. The key roles of the extracellular matrix (ECM) in OSCC are an emerging area of intensive research as the ECM macromolecular network is actively involved in events that regulate cellular morphological and functional properties, transcription and cell signaling mechanisms in invasion and metastasis. The provisional matrix that is formed by cancer cells is profoundly different in composition and functions as compared with the matrix of normal tissue. Fibroblasts are mainly responsible for matrix production and remodeling, but in cancer, the tumor matrix in the tumor microenvironment (TME) also originates from cancer cells. Even though extensive research has been conducted on the role of ECM in regulating cancer pathogenesis, its role in modulating OSCC is less elucidated since there are several issues yet to be fully understood. This critical review is focused on recent research as to present and discuss on the involvement of ECM macromolecular effectors (i.e., proteoglycans, integrins, matrix metalloproteinases) in OSCC development and progression.
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Affiliation(s)
- Nicholas S Mastronikolis
- Department of Otorhinolaryngology - Head and Neck Surgery, School of Medicine, University of Patras, Patras, Greece
| | - Efthymios Kyrodimos
- 1st Otolaryngology Department, School of Medicine, National & Kapodistrian University of Athens, 'Ippokrateion' General Hospital, Athens, Greece
| | - Zoi Piperigkou
- Biochemistry, Biochemical Analysis & Matrix Pathobiology Research Group, Laboratory of Biochemistry, Department of Chemistry, University of Patras, Patras, Greece
- Foundation for Research and Technology - Hellas (FORTH)/Institute of Chemical Engineering Sciences (ICE-HT), Patras, Greece
| | - Despoina Spyropoulou
- Department of Radiation Oncology, School of Medicine, University of Patras, Patras, Greece
| | - Alexander Delides
- 2nd Otolaryngology Department, School of Medicine, National & Kapodistrian University of Athens, 'Attikon' University Hospital, Athens, Greece
| | - Evangelos Giotakis
- 1st Otolaryngology Department, School of Medicine, National & Kapodistrian University of Athens, 'Ippokrateion' General Hospital, Athens, Greece
- Department of Radiation Oncology, School of Medicine, University of Patras, Patras, Greece
- 2nd Otolaryngology Department, School of Medicine, National & Kapodistrian University of Athens, 'Attikon' University Hospital, Athens, Greece
| | - Miranda Alexopoulou
- Department of Maxillofacial Surgery, University Hospital of Patras, Patras, Greece
| | - Nick A Bakalis
- Department of Nursing, University of Patras, Patras, Greece
| | - Nikos K Karamanos
- Biochemistry, Biochemical Analysis & Matrix Pathobiology Research Group, Laboratory of Biochemistry, Department of Chemistry, University of Patras, Patras, Greece
- Foundation for Research and Technology - Hellas (FORTH)/Institute of Chemical Engineering Sciences (ICE-HT), Patras, Greece
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Fornieles G, Núñez MI, Expósito J. Matrix Metalloproteinases and Their Inhibitors as Potential Prognostic Biomarkers in Head and Neck Cancer after Radiotherapy. Int J Mol Sci 2023; 25:527. [PMID: 38203696 PMCID: PMC10778974 DOI: 10.3390/ijms25010527] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2023] [Revised: 12/18/2023] [Accepted: 12/27/2023] [Indexed: 01/12/2024] Open
Abstract
Head and neck cancer (HNC) is among the ten most frequent tumours, with 5-year survival rates varying from 30% to 70% depending on the stage and location of the tumour. HNC is traditionally known as head and neck squamous cell carcinoma (HNSCC), since 90% arises from epithelial cells. Metastasis remains a major cause of mortality in patients with HNSCC. HNSCC patients with metastatic disease have an extremely poor prognosis with a survival rate of less than a year. Matrix metalloproteinases (MMPs) have been described as biomarkers that promote cell migration and invasion. Radiotherapy is widely used to treat HNSCC, being a determining factor in the alteration of the tumour's biology and microenvironment. This review focuses on analysing the current state of the scientific literature on this topic. Although few studies have focused on the role of these proteinases in HNC, some authors have concluded that radiotherapy alters the behaviour of MMPs and tissue inhibitors of metalloproteinases (TIMPs). Therefore, more research is needed to understand the roles played by MMPs and their inhibitors (TIMPs) as prognostic biomarkers in patients with HNC and their involvement in the response to radiotherapy.
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Affiliation(s)
- Gabriel Fornieles
- Doctoral Programme in Clinical Medicine and Public Health, University of Granada, 18012 Granada, Spain;
| | - María Isabel Núñez
- Department of Radiology and Physical Medicine, School of Medicine, University of Granada, 18016 Granada, Spain;
- Biopathology and Regenerative Medicine Institute (IBIMER), Centre for Biomedical Research, University of Granada, 18016 Granada, Spain
- Biosanitary Institute of Granada (ibs.GRANADA), 18012 Granada, Spain
| | - José Expósito
- Department of Radiology and Physical Medicine, School of Medicine, University of Granada, 18016 Granada, Spain;
- Biosanitary Institute of Granada (ibs.GRANADA), 18012 Granada, Spain
- Radiation Oncology Department, Virgen de las Nieves University Hospital, 18014 Granada, Spain
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Dalir Abdolahinia E, Han X. The Three-Dimensional In Vitro Cell Culture Models in the Study of Oral Cancer Immune Microenvironment. Cancers (Basel) 2023; 15:4266. [PMID: 37686542 PMCID: PMC10487272 DOI: 10.3390/cancers15174266] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2023] [Revised: 08/22/2023] [Accepted: 08/22/2023] [Indexed: 09/10/2023] Open
Abstract
The onset and progression of oral cancer are accompanied by a dynamic interaction with the host immune system, and the immune cells within the tumor microenvironment play a pivotal role in the development of the tumor. By exploring the cellular immunity of oral cancer, we can gain insight into the contribution of both tumor cells and immune cells to tumorigenesis. This understanding is crucial for developing effective immunotherapeutic strategies to combat oral cancer. Studies of cancer immunology present unique challenges in terms of modeling due to the extraordinary complexity of the immune system. With its multitude of cellular components, each with distinct subtypes and various activation states, the immune system interacts with cancer cells and other components of the tumor, ultimately shaping the course of the disease. Conventional two-dimensional (2D) culture methods fall short of capturing these intricate cellular interactions. Mouse models enable us to learn about tumor biology in complicated and dynamic physiological systems but have limitations as the murine immune system differs significantly from that of humans. In light of these challenges, three-dimensional (3D) culture systems offer an alternative approach to studying cancer immunology and filling the existing gaps in available models. These 3D culture models provide a means to investigate complex cellular interactions that are difficult to replicate in 2D cultures. The direct study of the interaction between immune cells and cancer cells of human origin offers a more relevant and representative platform compared to mouse models, enabling advancements in our understanding of cancer immunology. This review explores commonly used 3D culture models and highlights their significant contributions to expanding our knowledge of cancer immunology. By harnessing the power of 3D culture systems, we can unlock new insights that pave the way for improved strategies in the battle against oral cancer.
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Affiliation(s)
| | - Xiaozhe Han
- Department of Oral Science and Translation Research, College of Dental Medicine, Nova Southeastern University, Fort Lauderdale, FL 33314, USA
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10
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Alaouna M, Penny C, Hull R, Molefi T, Chauke-Malinga N, Khanyile R, Makgoka M, Bida M, Dlamini Z. Overcoming the Challenges of Phytochemicals in Triple Negative Breast Cancer Therapy: The Path Forward. PLANTS (BASEL, SWITZERLAND) 2023; 12:2350. [PMID: 37375975 DOI: 10.3390/plants12122350] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/18/2023] [Revised: 06/02/2023] [Accepted: 06/13/2023] [Indexed: 06/29/2023]
Abstract
Triple negative breast cancer (TNBC) is a very aggressive subtype of breast cancer that lacks estrogen, progesterone, and HER2 receptor expression. TNBC is thought to be produced by Wnt, Notch, TGF-beta, and VEGF pathway activation, which leads to cell invasion and metastasis. To address this, the use of phytochemicals as a therapeutic option for TNBC has been researched. Plants contain natural compounds known as phytochemicals. Curcumin, resveratrol, and EGCG are phytochemicals that have been found to inhibit the pathways that cause TNBC, but their limited bioavailability and lack of clinical evidence for their use as single therapies pose challenges to the use of these phytochemical therapies. More research is required to better understand the role of phytochemicals in TNBC therapy, or to advance the development of more effective delivery mechanisms for these phytochemicals to the site where they are required. This review will discuss the promise shown by phytochemicals as a treatment option for TNBC.
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Affiliation(s)
- Mohammed Alaouna
- SAMRC Precision Oncology Research Unit (PORU), DSI/NRF SARChI Chair in Precision Oncology and Cancer Prevention (POCP), Pan African Cancer Research Institute (PACRI), University of Pretoria, Pretoria 0001, South Africa
- Department of Internal Medicine, School of Clinical Medicine, Faculty of Health Sciences, University of the Witwatersrand, Parktown 2193, South Africa
| | - Clement Penny
- Department of Internal Medicine, School of Clinical Medicine, Faculty of Health Sciences, University of the Witwatersrand, Parktown 2193, South Africa
| | - Rodney Hull
- SAMRC Precision Oncology Research Unit (PORU), DSI/NRF SARChI Chair in Precision Oncology and Cancer Prevention (POCP), Pan African Cancer Research Institute (PACRI), University of Pretoria, Pretoria 0001, South Africa
| | - Thulo Molefi
- SAMRC Precision Oncology Research Unit (PORU), DSI/NRF SARChI Chair in Precision Oncology and Cancer Prevention (POCP), Pan African Cancer Research Institute (PACRI), University of Pretoria, Pretoria 0001, South Africa
- Department of Medical Oncology, Steve Biko Academic Hospital and University of Pretoria, Pretoria 0001, South Africa
| | - Nkhensani Chauke-Malinga
- SAMRC Precision Oncology Research Unit (PORU), DSI/NRF SARChI Chair in Precision Oncology and Cancer Prevention (POCP), Pan African Cancer Research Institute (PACRI), University of Pretoria, Pretoria 0001, South Africa
- Department of Plastic and Reconstructive Surgery, Faculty of Health Sciences, Steve Biko Academic Hospital, University of Pretoria, Pretoria 0001, South Africa
| | - Richard Khanyile
- SAMRC Precision Oncology Research Unit (PORU), DSI/NRF SARChI Chair in Precision Oncology and Cancer Prevention (POCP), Pan African Cancer Research Institute (PACRI), University of Pretoria, Pretoria 0001, South Africa
- Department of Medical Oncology, Steve Biko Academic Hospital and University of Pretoria, Pretoria 0001, South Africa
| | - Malose Makgoka
- SAMRC Precision Oncology Research Unit (PORU), DSI/NRF SARChI Chair in Precision Oncology and Cancer Prevention (POCP), Pan African Cancer Research Institute (PACRI), University of Pretoria, Pretoria 0001, South Africa
- Department of Surgery, Faculty of Health Sciences, Steve Biko Academic Hospital, University of Pretoria, Pretoria 0001, South Africa
| | - Meshack Bida
- SAMRC Precision Oncology Research Unit (PORU), DSI/NRF SARChI Chair in Precision Oncology and Cancer Prevention (POCP), Pan African Cancer Research Institute (PACRI), University of Pretoria, Pretoria 0001, South Africa
- Department of Anatomical Pathology, National Health Laboratory Service (NHLS), University of Pretoria, Pretoria 0001, South Africa
| | - Zodwa Dlamini
- SAMRC Precision Oncology Research Unit (PORU), DSI/NRF SARChI Chair in Precision Oncology and Cancer Prevention (POCP), Pan African Cancer Research Institute (PACRI), University of Pretoria, Pretoria 0001, South Africa
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11
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Liu JF, Wee Y, Luo SD, Chang SF, Jia S, Feng SW, Huang HM, Lin JH, Wang CS. Proanthocyanidins-loaded complex coacervates-based drug delivery attenuates oral squamous cell carcinoma cells metastatic potential through down-regulating the Akt signaling pathway. Front Oncol 2022; 12:1001126. [PMID: 36330492 PMCID: PMC9623311 DOI: 10.3389/fonc.2022.1001126] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2022] [Accepted: 10/03/2022] [Indexed: 11/16/2022] Open
Abstract
Oral cancer, constituted up to 90% by squamous cell carcinomas, is a significant health burden globally. Grape seed proanthocyanidins (PA) have been suggested as a potential chemopreventive agent for oral cancer. However, their efficacy can be restricted due to the low bioavailability and bioaccessibility. Inspired by sandcastle worm adhesive, we adapted the concept of complex coacervation to generate a new type of drug delivery platform. Complex coacervates are a dense liquid phase formed by the associative separation of a mixture of oppositely charged polyelectrolytes, can serve as a drug delivery platform to protect labile cargo. In this study, we developed a complex coacervates-based delivery of PA. The release kinetics was measured, and anticancer effects were determined in two human tongue squamous cell carcinoma cell lines. The results showed that complex coacervate successfully formed and able to encapsulate PA. Additionally, PA were steadily released from the system in a pH-dependent manner. The drug delivery system could significantly inhibit the cell proliferation, migration, and invasion of cancer cells. Moreover, it could markedly reduce the expression of certain matrix metalloproteinases (MMP-2, 9, and 13) crucial to metastatic processes. We also found that suppression of protein kinase B (Akt) pathway might be the underlying mechanism for these anticancer activities. Taken together, complex coacervates-based delivery of PA can act as an effective anticancer approach for oral cancer therapy.
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Affiliation(s)
- Ju-Fang Liu
- School of Oral Hygiene, College of Oral Medicine, Taipei Medical University, Taipei, Taiwan
| | - Yinshen Wee
- Department of Pathology, University of Utah, Salt Lake City, UT, United States
| | - Shen-Dean Luo
- Department of Otolaryngology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Shwu-Fen Chang
- Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Shihai Jia
- Department of Neurobiology, University of Utah, Salt Lake City, UT, United States
| | - Sheng-Wei Feng
- School of Dentistry, College of Oral Medicine, Taipei Medical University, Taipei, Taiwan
| | - Huei-Mei Huang
- Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Jiann-Her Lin
- Department of Neurosurgery, Taipei Medical University Hospital, Taipei, Taiwan
| | - Ching-Shuen Wang
- School of Dentistry, College of Oral Medicine, Taipei Medical University, Taipei, Taiwan
- *Correspondence: Ching-Shuen Wang,
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12
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Xue Y, Song X, Fan S, Deng R. The role of tumor-associated macrophages in oral squamous cell carcinoma. Front Physiol 2022; 13:959747. [PMID: 36105288 PMCID: PMC9464857 DOI: 10.3389/fphys.2022.959747] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2022] [Accepted: 08/04/2022] [Indexed: 11/25/2022] Open
Abstract
Oral squamous cell carcinoma (OSCC) is a common head and neck cancer with a high recurrence rate and a low 5-year survival rate. Tumor-associated macrophages (TAMs) are important immune cells in the tumor microenvironment, which play an important role in the progression of many tumors. This article reviews the origin, and the role of TAMs in the invasion, metastasis, angiogenesis and immunosuppression of OSCC. Therapeutic strategies targeting TAMs are also discussed in hopes of providing new ideas for the treatment of OSCC.
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Affiliation(s)
- Yiwen Xue
- Department of Oral and Maxillofacial Surgery, Nanjing Stomatological Hospital, Medical School of Nanjing University, Nanjing, Jiangsu, China
- Central Laboratory of Stomatology, Nanjing Stomatological Hospital, Medical School of Nanjing University, Nanjing, Jiangsu, China
| | - Xiao Song
- Department of Oral and Maxillofacial Surgery, Nanjing Stomatological Hospital, Medical School of Nanjing University, Nanjing, Jiangsu, China
- Central Laboratory of Stomatology, Nanjing Stomatological Hospital, Medical School of Nanjing University, Nanjing, Jiangsu, China
| | - Siyu Fan
- Department of Oral and Maxillofacial Surgery, Nanjing Stomatological Hospital, Medical School of Nanjing University, Nanjing, Jiangsu, China
- Central Laboratory of Stomatology, Nanjing Stomatological Hospital, Medical School of Nanjing University, Nanjing, Jiangsu, China
| | - Runzhi Deng
- Department of Oral and Maxillofacial Surgery, Nanjing Stomatological Hospital, Medical School of Nanjing University, Nanjing, Jiangsu, China
- *Correspondence: Runzhi Deng,
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13
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Imani A, Maleki N, Bohlouli S, Kouhsoltani M, Sharifi S, Maleki Dizaj S. Molecular mechanisms of anticancer effect of rutin. Phytother Res 2021; 35:2500-2513. [PMID: 33295678 DOI: 10.1002/ptr.6977] [Citation(s) in RCA: 88] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2020] [Revised: 10/13/2020] [Accepted: 11/24/2020] [Indexed: 12/16/2022]
Abstract
Because of the extensive biological functions of natural substances such as bioflavonoids, and their high safety and low costs, they could have high priority application in the health care system. The antioxidant properties of rutin, a polyphenolic bioflavonoid, have been well documented and demonstrated a wide range of pharmacological applications in cancer research. Since chemotherapeutic drugs have a wide range of side effects and rutin is a safe anticancer agent with minor side effects so recent investigations are performed for study of mechanisms of its anticancer effect. Both in-vivo and in-vitro examinations on anticancer mechanisms of this natural agent have been widely carried out. Regulation of different cellular signaling pathways such as Wnt/β-catenin, p53-independent pathway, PI3K/Akt, JAK/STAT, MAPK, p53, apoptosis as well as NF-ĸB signaling pathways helps to mediate the anticancer impacts of this agent. This study tried to review the molecular mechanisms of rutin anticancer effect on various types of cancer. Deep exploration of these anticancer mechanisms can facilitate the development of this beneficial compound for its application in the treatment of different cancers.
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Affiliation(s)
- Amir Imani
- Department of Oral Medicine, Faculty of Dentistry, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Nasim Maleki
- Department of Prosthodontics, Faculty of Dentistry, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Sepideh Bohlouli
- Department of Oral Medicine, Faculty of Dentistry, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Maryam Kouhsoltani
- Oral and Maxillofacial Department of Pathology, Faculty of Dentistry, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Simin Sharifi
- Dental and Periodontal Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Solmaz Maleki Dizaj
- Dental and Periodontal Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
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14
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Wang X, Jin J, Li W, Wang Q, Han Y, Liu H. Differential in vitro sensitivity of oral precancerous and squamous cell carcinoma cell lines to 5-aminolevulinic acid-mediated photodynamic therapy. Photodiagnosis Photodyn Ther 2020; 29:101554. [PMID: 31479802 DOI: 10.1016/j.pdpdt.2019.08.036] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2019] [Revised: 08/16/2019] [Accepted: 08/30/2019] [Indexed: 12/22/2022]
Abstract
OBJECTIVES The clinical effect of 5-aminolevulinic acid-mediated photodynamic therapy (ALA-PDT) may be correlated with the degree of dysplasia of cancer tissues, but much is still unknown regarding the differences in its effectiveness, especially in oral cancer and precancerous lesions. The aim of this study is to compare the effects of ALA-PDT on a human oral precancerous cell line (DOK) and an oral squamous cell carcinoma cell line (CAL-27). METHODS First, we explored the dose- and time-dependent responses of DOK and CAL-27 cells to ALA-PDT. DOK and CAL-27 cells were incubated with various concentrations of ALA (from 0.25 to 2 mM), followed by PDT using laser irradiation at 635 nm. The resulting photocytotoxicity was assessed in both cell lines using MTT assays. Further, apoptosis was assessed using flow cytometry, reactive oxygen species (ROS) generation was evaluated with 2,7-dichlorofluorescein diacetate (DCFH2-DA), and the response to treatment was examined via RT-qPCR and Western blotting to measure the mRNA and protein expression levels of matrix metallopeptidase 2 (MMP-2) and MMP-9. RESULTS ALA-PDT inhibited the proliferation of DOK and CAL-27 cells in a dose- and time-dependent manner. Dose-effect and inhibition-time relationships were also found. The rates of DOK and CAL-27 cell apoptosis when the ALA dose was 1 mM were 30.66 ± 3.10% and 75.40 ± 1.29%, respectively (P < 0.01). Following PDT, compared with DOK cells, the ROS level in CAL-27 cells was significantly increased and was correlated with an increase in the ALA concentration. Mechanistically, both the mRNA and protein expression levels of MMP-2 and MMP-9 were found to be regulated in both cell types after ALA-PDT. CONCLUSION ALA-PDT effectively killed DOK and CAL-27 cells in a dose- and time-dependent manner in vitro. However, under the same conditions, the susceptibilities of these cell lines to ALA-PDT were different. Further studies are necessary to confirm whether this difference is present in clinical oral cancer and precancerous lesions.
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Affiliation(s)
- Xing Wang
- Department of Oral Medicine, Peking University School and Hospital of Stomatology, Beijing 100081, PR China
| | - Jianqiu Jin
- Department of Oral Medicine, Peking University School and Hospital of Stomatology, Beijing 100081, PR China
| | - Wenwen Li
- Department of Oral Medicine, Peking University School and Hospital of Stomatology, Beijing 100081, PR China
| | - Qian Wang
- Department of Oral Medicine, Peking University School and Hospital of Stomatology, Beijing 100081, PR China
| | - Ying Han
- Department of Oral Medicine, Peking University School and Hospital of Stomatology, Beijing 100081, PR China.
| | - Hongwei Liu
- Department of Oral Medicine, Peking University School and Hospital of Stomatology, Beijing 100081, PR China.
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15
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Agarwal A, Garg C, Ganesh MS, Reddy S. Molecular mechanisms of tobacco induced oral and oropharyngeal cancer: Results of a tissue microarray and immunohistochemistry-based study from a tertiary cancer center in India. INDIAN J PATHOL MICR 2020; 63:7-12. [PMID: 32031115 DOI: 10.4103/ijpm.ijpm_783_18] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND It is well established that chronic exposure to tobacco induces head and neck cancers but the exact etiopathogenesis is not known. Though studies have shown expression of TIMP1, EPS8 and AXL in cancers, their role in tobacco-induced cancers is not known. We aimed this study to evaluate the role of these molecules in oral and oropharyngeal squamous cell cancers (SCC). MATERIALS AND METHODS In this single institutional study, 31 patients of oral and oropharyngeal SCC with history of chewing tobacco were included. Smokers were excluded from the study. After informed consent biopsies were taken from affected and contralateral normal mucosa. Paraffin blocks were made and tissue microarray (TMA) were constructed using these blocks. Immunohistochemistry (IHC) for TIMP1, EPS8, AXL kinase was carried out on these tissue microarrays. The intensity of staining was scored from 0 to 3+, related to expression of each of the three molecules. RESULTS The expression of TIMP1, EPS8 and AXL kinase was significantly more in the cancerous mucosa versus non-cancerous mucosa (P = 0.000 in all three) in oral and oropharyngeal SCC exposed to chewing tobacco. CONCLUSION Immunohistochemical expression of these molecular markers in oral and oropharyngeal SCC correlated with their molecular based studies. Significant IHC expression of TIMP1, EPS8 and AXL establishes their role in the pathogenesis of oral and oropharyngeal squamous cell carcinomas. Novel targeted therapies may be researched that can detect and target these molecules at an earlier stage of pathogenesis of these tumors.
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Affiliation(s)
- Arjun Agarwal
- Department of Surgical Oncology, Vydehi Institute of Oncology, Bengaluru, Karnataka, India
| | - Cheena Garg
- Department of Pathology, Rohilkhand Medical College and Hospital, Bareilly, Uttar Pradesh, India
| | - M S Ganesh
- Department of Surgical Oncology, Vydehi Institute of Oncology, Bengaluru, Karnataka, India
| | - Sreekanth Reddy
- Department of Surgical Oncology, Vydehi Institute of Oncology, Bengaluru, Karnataka, India
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16
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Zhu M, Zhang W, Ma J, Dai Y, Zhang Q, Liu Q, Yang B, Li G. MicroRNA-139-5p regulates chronic inflammation by suppressing nuclear factor-κB activity to inhibit cell proliferation and invasion in colorectal cancer. Exp Ther Med 2019; 18:4049-4057. [PMID: 31616518 PMCID: PMC6781828 DOI: 10.3892/etm.2019.8032] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2018] [Accepted: 08/22/2019] [Indexed: 12/12/2022] Open
Abstract
The inflammatory microenvironment, which mediates the initiation and malignant development of tumors, has been reported to be associated with microRNA (miRNA) dysregulation. In the present study, the expression of miR-139-5p was analyzed in colorectal cancer (CRC) cell lines SW480, HT29, HCT-8, LoVo and HCT116, aiming to investigate the function and mechanism of miR-139-5p in the regulation of the malignant phenotypes of CRC. miR-139-5p expression was found to be considerably downregulated in CRC cell lines compared with the human normal colon mucosal epithelial cell line NCM460. Subsequently, it was demonstrated that overexpression of miR-139-5p in colon cancer cell lines significantly suppressed the cell proliferation in vitro and in vivo. In addition, overexpression of miR-139-5p further inhibited the invasion ability of colon cancer cells in vitro, concomitantly with downregulation of key invasion-associated proteins, including matrix metalloproteinase 9 (MMP9) and MMP7. Furthermore, it was demonstrated that overexpression of miR-139-5p decreased the expression levels of inflammatory cytokines, including interleukin-1β (IL-1β), IL-6 and tumor necrosis factor-α (TNF-α), by suppressing nuclear factor (NF)-κB activity. Therefore, these findings collectively indicated that miR-139-5p regulated chronic inflammation by suppressing NF-κB activity in order to inhibit cell proliferation and invasion in CRC, thereby indicating a novel molecular mechanism in CRC therapy.
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Affiliation(s)
- Mingming Zhu
- Department of Abdominal Tumor Surgery, Third Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650118, P.R. China
| | - Wen Zhang
- Department of Abdominal Tumor Surgery, Third Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650118, P.R. China
| | - Jun Ma
- Department of Abdominal Tumor Surgery, Third Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650118, P.R. China
| | - Youguo Dai
- Department of Abdominal Tumor Surgery, Third Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650118, P.R. China
| | - Qi Zhang
- Department of Abdominal Tumor Surgery, Third Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650118, P.R. China
| | - Qin Liu
- Department of Abdominal Tumor Surgery, Third Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650118, P.R. China
| | - Burong Yang
- Department of Abdominal Tumor Surgery, Third Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650118, P.R. China
| | - Gang Li
- Department of Abdominal Tumor Surgery, Third Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650118, P.R. China
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17
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Rodrigues-Junior DM, Tan SS, de Souza Viana L, Carvalho AL, Lim SK, Iyer NG, Vettore AL. A preliminary investigation of circulating extracellular vesicles and biomarker discovery associated with treatment response in head and neck squamous cell carcinoma. BMC Cancer 2019; 19:373. [PMID: 31014274 PMCID: PMC6480898 DOI: 10.1186/s12885-019-5565-9] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2019] [Accepted: 03/31/2019] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND There is a paucity of plasma-based biomarkers that prospectively segregate the outcome of patients with head and neck squamous-cell carcinoma (HNSCC) treated with chemoradiation therapy (CRT). Plasma extracellular vesicles (EVs) might be an alternative source for discovery of new specific markers present in patients with HNSCC, which could help to re-direct patients to appropriate curative therapies without delay. METHODS In order to identify new markers in plasma compartments, Cholerae toxin B chain (CTB) and Annexin V (AV) were used to isolate EVs from pooled plasma samples from patients with locally advanced HNSCC who responded (CR, n = 6) or presented incomplete response (NR, n = 6) to CRT. The crude plasma and EVs cargo were screened by antibody array. RESULTS Of the 370 polypeptides detected, 119 proteins were specific to NR patients while 38 were exclusive of the CR subjects. The Gene Set Enrichment Analysis (GSEA) and Search Tool for the Retrieval of Interacting Genes (STRING) database analysis indicated that the content of circulating plasma EVs might have a relevant function for the tumor intercellular communication in the HNSCC patients. CONCLUSION This study provides a list of potential markers present in plasma compartments that might contribute to the development of tools for prediction and assessment of CRT response and potentially guide therapeutic decisions in this context.
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Affiliation(s)
- Dorival Mendes Rodrigues-Junior
- Department of Biological Science, Laboratório de Biologia Molecular do Câncer, UNIFESP, Universidade Federal de São Paulo, Rua Pedro de Toledo, 669 - 11° andar, São Paulo, SP, 04039-032, Brazil.,Cancer Therapeutics Research Laboratory, National Cancer Centre of Singapore, 11 Hospital Drive, Singapore, 169610, Singapore
| | - Soon Sim Tan
- Institute of Medical Biology, A*-STAR, Singapore, Singapore
| | | | - Andre Lopes Carvalho
- Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos, SP, Brazil
| | - Sai Kiang Lim
- Institute of Medical Biology, A*-STAR, Singapore, Singapore
| | - N Gopalakrishna Iyer
- Cancer Therapeutics Research Laboratory, National Cancer Centre of Singapore, 11 Hospital Drive, Singapore, 169610, Singapore. .,Division of Surgical Oncology, National Cancer Centre of Singapore, Singapore, Singapore.
| | - Andre Luiz Vettore
- Department of Biological Science, Laboratório de Biologia Molecular do Câncer, UNIFESP, Universidade Federal de São Paulo, Rua Pedro de Toledo, 669 - 11° andar, São Paulo, SP, 04039-032, Brazil.
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18
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Rodrigues-Junior DM, Tan SS, Lim SK, de Souza Viana L, Carvalho AL, Vettore AL, Iyer NG. High expression of MLANA in the plasma of patients with head and neck squamous cell carcinoma as a predictor of tumor progression. Head Neck 2019; 41:1199-1205. [PMID: 30803092 DOI: 10.1002/hed.25510] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2017] [Revised: 05/04/2018] [Accepted: 08/15/2018] [Indexed: 11/11/2022] Open
Abstract
BACKGROUND There is a paucity of plasma-based biomarkers that predict outcome in patients with head and neck squamous cell carcinoma (HNSCC) treated with chemoradiation therapy (CRT). Here, we evaluate the prognostic potential of plasma Melanoma-Antigen Recognized by T-cells 1 (MLANA) in this setting. METHODS MLANA expression in HNSCC lines were evaluated by reverse transcription polymerase chain reaction, whereas plasma levels were quantified using ELISA in 48 patients with locally advanced HNSCC undergoing a phase 2 trial with CRT. RESULTS MLANA is expressed at variable levels in a panel of HNSCC lines. In plasma, levels were elevated in patients with tumor relapse compared to those without (P < .004); 73.9% of the patients expressing high plasma MLANA levels progressed with recurrent disease (P = .020). Multivariate analysis showed that plasma MLANA levels and tumor resectability were independent prognostic factors for progression free survival. CONCLUSION Plasma MLANA expression appears to be an effective noninvasive biomarker for outcomes in patients treated with CRT, and could potentially guide therapeutic decisions in this context.
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Affiliation(s)
- Dorival Mendes Rodrigues-Junior
- Biological Science Department, Campus Diadema, Universidade Federal de São Paulo, Diadema, São Paulo, Brazil.,Cancer Therapeutics Research Laboratory, National Cancer Centre, Singapore
| | | | | | - Luciano de Souza Viana
- Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos, São Paulo, Brazil
| | - Andre Lopes Carvalho
- Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos, São Paulo, Brazil
| | - Andre Luiz Vettore
- Biological Science Department, Campus Diadema, Universidade Federal de São Paulo, Diadema, São Paulo, Brazil
| | - N Gopalakrishna Iyer
- Cancer Therapeutics Research Laboratory, National Cancer Centre, Singapore.,Division of Surgical Oncology, National Cancer Centre, Singapore
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19
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Hung YW, Tsai CW, Wu CN, Shih LC, Chen YY, Liu YF, Hung HS, Shen MY, Chang WS, Bau DAT. The Contribution of Matrix Metalloproteinase-8 Promoter Polymorphism to Oral Cancer Susceptibility. ACTA ACUST UNITED AC 2018; 31:585-590. [PMID: 28652424 DOI: 10.21873/invivo.11098] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2017] [Revised: 05/22/2017] [Accepted: 05/23/2017] [Indexed: 12/21/2022]
Abstract
BACKGROUND/AIM Metalloproteinases (MMPs) are a family of multifunctional proteins reported to be overexpressed in several types of cancers. However, the contribution of MMP8 genotype to oral cancer has not been elucidated. In this study, we focused on the contribution of polymorphisms in the promoter region of MMP-8 (C-799T) and two non-synonymous polymorphisms (Val436Ala and Lys460Thr) to Taiwanese oral cancer. MATERIALS AND METHODS In this case-control study, MMP-8 genotype, was examined among 788 patients with oral cancer and 956 gender- and age-matched healthy controls regarding its potential to determine oral cancer risk. RESULTS The distributions of MMP-8 C-799T, Val436Ala and Lys460Thr genotypes were not different between the oral cancer and non-cancer control groups. We also analyzed the allelic frequency distributions and no significant difference was found. As for gene-environment interaction analysis, there was an increased risk for smokers, alcohol drinkers or betel quid chewers with variant MMP-8 C-799T or Val436Ala genotypes. CONCLUSION Our findings suggest that the polymorphisms at MMP-8 C-799T or Val436Ala may not play a major role in mediating personal risk of oral cancer; however, the detailed mechanisms require further investigation.
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Affiliation(s)
- Yi-Wen Hung
- Department of Medicine Research, Taichung Veterans General Hospital, Taichung, Taiwan, R.O.C
| | - Chia-Wen Tsai
- Department of Medical Laboratory Science and Biotechnology, Central Taiwan University of Science and Technology, Taichung, Taiwan, R.O.C.,Terry Fox Cancer Research Laboratory, China Medical University Hospital, Taichung, Taiwan, R.O.C
| | - Cheng-Nan Wu
- Department of Medical Laboratory Science and Biotechnology, Central Taiwan University of Science and Technology, Taichung, Taiwan, R.O.C
| | - Liang-Chun Shih
- Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan, R.O.C.,Department of Otolaryngology, China Medical University Hospital, Taichung, Taiwan, R.O.C
| | - Yen-Yu Chen
- Terry Fox Cancer Research Laboratory, China Medical University Hospital, Taichung, Taiwan, R.O.C
| | - Yen-Fang Liu
- Terry Fox Cancer Research Laboratory, China Medical University Hospital, Taichung, Taiwan, R.O.C
| | - Huey-Shan Hung
- Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan, R.O.C
| | - Ming-Yi Shen
- Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan, R.O.C
| | - Wen-Shin Chang
- Terry Fox Cancer Research Laboratory, China Medical University Hospital, Taichung, Taiwan, R.O.C
| | - DA-Tian Bau
- Terry Fox Cancer Research Laboratory, China Medical University Hospital, Taichung, Taiwan, R.O.C. .,Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan, R.O.C.,Department of Bioinformatics and Medical Engineering, Asia University, Taichung, Taiwan, R.O.C
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20
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Jia Y, Yue Y, Hu DN, Chen JL, Zhou JB. Human aqueous humor levels of transforming growth factor-β2: Association with matrix metalloproteinases/tissue inhibitors of matrix metalloproteinases. Biomed Rep 2017; 7:573-578. [PMID: 29188062 DOI: 10.3892/br.2017.1004] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2017] [Accepted: 09/29/2017] [Indexed: 01/04/2023] Open
Abstract
The present study aims to investigate the association of transforming growth factor-β2 (TGF-β2) and matrix metalloproteinases (MMPs), MMP-2 and MMP-3, and tissue inhibitors of matrix metalloproteinases (TIMPs), TIMP-1, TIMP-2 and TIMP-3 in the aqueous humor of patients with high myopia or cataracts. The levels of TGF-β2 and MMPs/TIMPs were measured with the Luminex xMAP Technology using commercially available Milliplex xMAP kits. The association between TGF-β2 and MMPs/TIMPs levels was analyzed using the Spearmans correlation test. The levels of TGF-β2 were identified to be positively correlated with the levels of TIMP-1 and TIMP-3 (TIMP-1: r=0.334; P=0.007; TIMP-3: r=0.309; P=0.012). The levels of MMP-2, MMP-3 and TIMP-2 did not significantly correlate with TGF-β2 levels (P>0.05). A positive correlation was identified between TGF-β2 and TIMPs in the aqueous humor of human eyes with elongated axial length. It appears that TGF-β2 stimulates the expression of TIMPs as a compensatory reaction to the development of high myopia.
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Affiliation(s)
- Yan Jia
- Department of Ophthalmology, Shanghai Ninth People's Hospital, Shanghai Jiaotong University, School of Medicine, Shanghai 200011, P.R. China.,Department of Ophthalmology, Children's Hospital of Fudan University, Shanghai Fudan University, School of Medicine, Shanghai 201102, P.R. China
| | - Yu Yue
- Department of Ophthalmology, Shanghai Ninth People's Hospital, Shanghai Jiaotong University, School of Medicine, Shanghai 200011, P.R. China
| | - Dan-Ning Hu
- Departments of Ophthalmology and Pathology, New York Eye and Ear Infirmary of Mount Sinai, New York, NY 10003, USA
| | - Ji-Li Chen
- Department of Ophthalmology, Shibei Hospital, Shanghai 200435, P.R. China
| | - Ji-Bo Zhou
- Department of Ophthalmology, Shanghai Ninth People's Hospital, Shanghai Jiaotong University, School of Medicine, Shanghai 200011, P.R. China
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Isaacson KJ, Martin Jensen M, Subrahmanyam NB, Ghandehari H. Matrix-metalloproteinases as targets for controlled delivery in cancer: An analysis of upregulation and expression. J Control Release 2017; 259:62-75. [PMID: 28153760 DOI: 10.1016/j.jconrel.2017.01.034] [Citation(s) in RCA: 98] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2016] [Revised: 01/18/2017] [Accepted: 01/26/2017] [Indexed: 02/07/2023]
Abstract
While commonly known for degradation of the extracellular matrix, matrix metalloproteinases (MMPs) exhibit broad potential for use in targeting of bioactive and imaging agents in cancer treatment. MMPs are upregulated at all stages of expression in cancers. A comprehensive analysis of published literature on expression of all MMP subtypes at the genetic, protein, and activity levels in normal and diseased tissues indicate targeting applicability in a variety of cancers. This expression significantly increases at advanced cancer stages, providing an improved opportunity for controlled release in higher-stage patients. Since MMPs are integral at every stage of metastasis, MMP roles in cancer are discussed with a focus on MMP distribution and mobility within cells and tumors for cancer targeting applications. Several strategies for MMP utilization in targeting - such as matrix degradation, MMP cleavage, MMP binding, and MMP-induced environmental changes - are addressed.
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Affiliation(s)
- Kyle J Isaacson
- Department of Bioengineering, University of Utah, Salt Lake City, UT, USA; Utah Center for Nanomedicine, Nano Institute of Utah, University of Utah, Salt Lake City, UT, USA
| | - M Martin Jensen
- Department of Bioengineering, University of Utah, Salt Lake City, UT, USA; Utah Center for Nanomedicine, Nano Institute of Utah, University of Utah, Salt Lake City, UT, USA
| | - Nithya B Subrahmanyam
- Department of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, Salt Lake City, UT, USA; Utah Center for Nanomedicine, Nano Institute of Utah, University of Utah, Salt Lake City, UT, USA
| | - Hamidreza Ghandehari
- Department of Bioengineering, University of Utah, Salt Lake City, UT, USA; Department of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, Salt Lake City, UT, USA; Utah Center for Nanomedicine, Nano Institute of Utah, University of Utah, Salt Lake City, UT, USA.
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Su CW, Su BF, Chiang WL, Yang SF, Chen MK, Lin CW. Plasma levels of the tissue inhibitor matrix metalloproteinase-3 as a potential biomarker in oral cancer progression. Int J Med Sci 2017; 14:37-44. [PMID: 28138307 PMCID: PMC5278657 DOI: 10.7150/ijms.17024] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2016] [Accepted: 11/01/2016] [Indexed: 01/21/2023] Open
Abstract
Oral cancer is the most common malignancy with poor prognosis and is the fourth most common cancer in men in Taiwan. The tissue inhibitor of metalloproteinase-3 (TIMP3) acts as a tumor suppressor gene by inhibiting the growth, angiogenesis, migration, and invasion of cancer cells. However, few studies have examined the association of plasma TIMP3 levels with oral squamous cell carcinoma (OSCC), and the role of plasma TIMP3 levels in OSCC progression is still unclear. We measured the plasma TIMP3 levels of 450 OSCC patients and 64 healthy controls by using a commercial enzyme-linked immunosorbent assay. We also analyzed TIMP3 mRNA levels of 328 OSCC patients and 32 normal tissues from The Cancer Genome Atlas (TCGA) dataset. Our results revealed that plasma TIMP3 levels were significantly lower in patients with OSCC than in healthy controls (p < 0.001). Moreover, plasma TIMP3 levels in patients with OSCC were significantly associated with the tumor stage and tumor status but not with the lymph node status, metastasis, and cell differentiation. To verify our findings, we also examined TCGA bioinformatics database and discovered similar results for the association with the pathological stage of OSCC. In conclusion, our results suggest that plasma TIMP3 is a potential biomarker for predicting the tumor stage and T status in patients with OSCC.
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Affiliation(s)
- Chun-Wen Su
- Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan
| | - Bo-Feng Su
- Department of Orthopedics, Changhua Christian Hospital, Changhua, Taiwan
| | - Whei-Ling Chiang
- School of Medical Laboratory and Biotechnology, Chung Shan Medical University, Taichung, Taiwan
| | - Shun-Fa Yang
- Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan.; Department of Medical Research, Chung Shan Medical University Hospital, Taichung, Taiwan
| | - Mu-Kuan Chen
- Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan.; Department of Otorhinolaryngology-Head and Neck Surgery, Changhua Christian Hospital, Changhua, Taiwan
| | - Chiao-Wen Lin
- Institute of Oral Sciences, Chung Shan Medical University, Taichung, Taiwan.; Department of Dentistry, Chung Shan Medical University Hospital, Taichung, Taiwan
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23
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Glycosylation: a hallmark of cancer? Glycoconj J 2016; 34:147-156. [DOI: 10.1007/s10719-016-9755-2] [Citation(s) in RCA: 165] [Impact Index Per Article: 18.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2016] [Revised: 11/11/2016] [Accepted: 11/28/2016] [Indexed: 12/18/2022]
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Jia Y, Hu DN, Sun J, Zhou J. Correlations Between MMPs and TIMPs Levels in Aqueous Humor from High Myopia and Cataract Patients. Curr Eye Res 2016; 42:600-603. [PMID: 28402202 DOI: 10.1080/02713683.2016.1223317] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
PURPOSE To study the relationships between matrix metalloproteinases (MMP)-2, MMP-3, and tissue inhibitors of matrix metalloproteinases (TIMP)-1, TIMP-2, and TIMP-3 aqueous humor levels in patients with high myopia or cataract. MATERIALS AND METHODS MMPs and TIMPs protein levels in 65 aqueous humor samples collected from patients with high myopia or cataract during cataract or clear lens extraction surgery were measured with the Luminex xMAP Technology. The relationship between MMPs and TIMPs levels was analyzed with Spearman's correlation test. RESULTS MMP-2 levels, but not MMP-3 levels, were increased in the aqueous humor from high-myopia patients. Levels of TIMP-1, -2, and -3 were positively and very significantly correlated with the MMP-2 levels (TIMP-1: r=0.626, p < 0.001; TIMP-2: r = 0.545, p < 0.001; TIMP-3: r = 0.439, p < 0.001). TIMP-2 and-3 levels did not significantly correlate with MMP-3 levels (TIMP-2: r = 0.175, p > 0.05; TIMP-3: r = 0.127, p > 0.05) and TIMP-1 levels only marginally correlated with MMP-3 levels (r = 0.278, 0.01< P < 0.05). CONCLUSIONS Compared to the present findings with the relationship of MMPs and TIMPs in other fields of medicine, our results are consistent with the homeostasis hypothesis that the increase of TIMPs serves as a compensation reaction to inhibit the excessive degradation caused by the increase of MMPs and limits the development of myopia.
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Affiliation(s)
- Yan Jia
- a Department of Ophthalmology , Shanghai Ninth People's Hospital, Shanghai Jiaotong University, School of Medicine , Shanghai , P. R. China
| | - Dan-Ning Hu
- b Departments of Ophthalmology and Pathology , New York Eye and Ear Infirmary of Mount Sinai , New York , NY USA
| | - Jing Sun
- a Department of Ophthalmology , Shanghai Ninth People's Hospital, Shanghai Jiaotong University, School of Medicine , Shanghai , P. R. China
| | - Jibo Zhou
- a Department of Ophthalmology , Shanghai Ninth People's Hospital, Shanghai Jiaotong University, School of Medicine , Shanghai , P. R. China
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25
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Osteopontin expression in co-cultures of human squamous cell carcinoma-derived cells and osteoblastic cells and its effects on the neoplastic cell phenotype and osteoclastic activation. Tumour Biol 2016; 37:12371-12385. [DOI: 10.1007/s13277-016-5104-0] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2016] [Accepted: 04/09/2016] [Indexed: 11/26/2022] Open
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26
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Oral squamous cell carcinoma: Key clinical questions, biomarker discovery, and the role of proteomics. Arch Oral Biol 2016; 63:53-65. [PMID: 26691574 DOI: 10.1016/j.archoralbio.2015.11.017] [Citation(s) in RCA: 55] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2014] [Revised: 09/08/2015] [Accepted: 11/20/2015] [Indexed: 12/19/2022]
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27
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Santos BL, Oliveira MN, Coelho PLC, Pitanga BPS, da Silva AB, Adelita T, Silva VDA, Costa MDFD, El-Bachá RS, Tardy M, Chneiweiss H, Junier MP, Moura-Neto V, Costa SL. Flavonoids suppress human glioblastoma cell growth by inhibiting cell metabolism, migration, and by regulating extracellular matrix proteins and metalloproteinases expression. Chem Biol Interact 2015; 242:123-38. [PMID: 26408079 DOI: 10.1016/j.cbi.2015.07.014] [Citation(s) in RCA: 62] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2013] [Revised: 06/05/2015] [Accepted: 07/24/2015] [Indexed: 02/02/2023]
Abstract
The malignant gliomas are very common primary brain tumors with poor prognosis, which require more effective therapies than the current used, such as with chemotherapy drugs. In this work, we investigated the effects of several polyhydroxylated flavonoids namely, rutin, quercetin (F7), apigenin (F32), chrysin (F11), kaempferol (F12), and 3',4'-dihydroxyflavone (F2) in human GL-15 glioblastoma cells. We observed that all flavonoids decreased the number of viable cells and the mitochondrial metabolism. Furthermore, they damaged mitochondria and rough endoplasmic reticulum, inducing apoptosis. Flavonoids also induced a delay in cell migration, related to a reduction in filopodia-like structures on the cell surface, reduction on metalloproteinase (MMP-2) expression and activity, as well as an increase in intra- and extracellular expression of fibronectin, and intracellular expression of laminin. Morphological changes were also evident in adherent cells characterized by the presence of a condensed cell body with thin and long cellular processes, expressing glial fibrillary acidic protein (GFAP). Therefore, these flavonoids should be tested as potential antitumor agents in vitro and in vivo in other malignant glioma models.
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Affiliation(s)
- Balbino L Santos
- Laboratório de Neuroquímica e Biologia Celular, Instituto de Ciências da Saúde, Universidade Federal da Bahia (UFBA), Av. Reitor Miguel Calmon s/n, Vale do Canela, 40110-902, Salvador, BA, Brazil
| | - Mona N Oliveira
- Laboratório de Neuroquímica e Biologia Celular, Instituto de Ciências da Saúde, Universidade Federal da Bahia (UFBA), Av. Reitor Miguel Calmon s/n, Vale do Canela, 40110-902, Salvador, BA, Brazil
| | - Paulo L C Coelho
- Laboratório de Neuroquímica e Biologia Celular, Instituto de Ciências da Saúde, Universidade Federal da Bahia (UFBA), Av. Reitor Miguel Calmon s/n, Vale do Canela, 40110-902, Salvador, BA, Brazil
| | - Bruno P S Pitanga
- Laboratório de Neuroquímica e Biologia Celular, Instituto de Ciências da Saúde, Universidade Federal da Bahia (UFBA), Av. Reitor Miguel Calmon s/n, Vale do Canela, 40110-902, Salvador, BA, Brazil
| | - Alessandra B da Silva
- Laboratório de Neuroquímica e Biologia Celular, Instituto de Ciências da Saúde, Universidade Federal da Bahia (UFBA), Av. Reitor Miguel Calmon s/n, Vale do Canela, 40110-902, Salvador, BA, Brazil
| | - Taís Adelita
- Laboratório de Neuroquímica e Biologia Celular, Instituto de Ciências da Saúde, Universidade Federal da Bahia (UFBA), Av. Reitor Miguel Calmon s/n, Vale do Canela, 40110-902, Salvador, BA, Brazil
| | - Victor Diógenes A Silva
- Laboratório de Neuroquímica e Biologia Celular, Instituto de Ciências da Saúde, Universidade Federal da Bahia (UFBA), Av. Reitor Miguel Calmon s/n, Vale do Canela, 40110-902, Salvador, BA, Brazil
| | - Maria de F D Costa
- Laboratório de Neuroquímica e Biologia Celular, Instituto de Ciências da Saúde, Universidade Federal da Bahia (UFBA), Av. Reitor Miguel Calmon s/n, Vale do Canela, 40110-902, Salvador, BA, Brazil
| | - Ramon S El-Bachá
- Laboratório de Neuroquímica e Biologia Celular, Instituto de Ciências da Saúde, Universidade Federal da Bahia (UFBA), Av. Reitor Miguel Calmon s/n, Vale do Canela, 40110-902, Salvador, BA, Brazil
| | - Marcienne Tardy
- Laboratório de Neuroquímica e Biologia Celular, Instituto de Ciências da Saúde, Universidade Federal da Bahia (UFBA), Av. Reitor Miguel Calmon s/n, Vale do Canela, 40110-902, Salvador, BA, Brazil
| | - Hervé Chneiweiss
- Neuroscience Paris Seine INSERM U 1130, CNRS UMR 8246, UPMC UM CR18, Université Pierre et Marie Curie, Campus Jussieu, 9 Quai Saint-Bernard, Batiments A-B, 75005, Paris
| | - Marie-Pierre Junier
- Neuroscience Paris Seine INSERM U 1130, CNRS UMR 8246, UPMC UM CR18, Université Pierre et Marie Curie, Campus Jussieu, 9 Quai Saint-Bernard, Batiments A-B, 75005, Paris
| | - Vivaldo Moura-Neto
- Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, CCS - Bloco F, 21949-590, Rio de Janeiro, Brazil
| | - Silvia L Costa
- Laboratório de Neuroquímica e Biologia Celular, Instituto de Ciências da Saúde, Universidade Federal da Bahia (UFBA), Av. Reitor Miguel Calmon s/n, Vale do Canela, 40110-902, Salvador, BA, Brazil.
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Jimenez L, Jayakar SK, Ow TJ, Segall JE. Mechanisms of Invasion in Head and Neck Cancer. Arch Pathol Lab Med 2015; 139:1334-48. [PMID: 26046491 DOI: 10.5858/arpa.2014-0498-ra] [Citation(s) in RCA: 52] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023]
Abstract
CONTEXT The highly invasive properties demonstrated by head and neck squamous cell carcinoma (HNSCC) are often associated with locoregional recurrence and lymph node metastasis in patients and is a key factor leading to an expected 5-year survival rate of approximately 50% for patients with advanced disease. It is important to understand the features and mediators of HNSCC invasion so that new treatment approaches can be developed. OBJECTIVES To provide an overview of the characteristics, mediators, and mechanisms of HNSCC invasion. DATA SOURCES A literature review of peer-reviewed articles in PubMed on HNSCC invasion. CONCLUSIONS Histologic features of HNSCC tumors can help predict prognosis and influence clinical treatment decisions. Cell surface receptors, signaling pathways, proteases, invadopodia function, epithelial-mesenchymal transition, microRNAs, and tumor microenvironment are all involved in the regulation of the invasive behavior of HNSCC cells. Identifying effective HNSCC invasion inhibitors has the potential to improve outcomes for patients by reducing the rate of spread and increasing responsiveness to chemoradiation.
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Affiliation(s)
| | | | | | - Jeffrey E Segall
- From the Departments of Pathology (Mss Jimenez and Jayakar, and Drs Ow and Segall) and Anatomy and Structural Biology (Mss Jimenez and Jayakar, and Dr Segall), Albert Einstein College of Medicine, Bronx, New York
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29
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Lotfi A, Mohammadi G, Tavassoli A, mousaviagdas M, Chavoshi H, Saniee L. Serum Levels of MMP9 and MMP2 in Patients with Oral Squamous Cell Carcinoma. Asian Pac J Cancer Prev 2015; 16:1327-30. [DOI: 10.7314/apjcp.2015.16.4.1327] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
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30
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Matrix Metalloproteinase Family as Molecular Biomarkers in Oral Squamous Cell Carcinoma. BIOMARKERS IN CANCER 2015. [DOI: 10.1007/978-94-007-7681-4_10] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
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Sun Q, Zhao C, Xia L, He Z, Lu Z, Liu C, Jia M, Wang J, Niu J. High expression of matrix metalloproteinase-9 indicates poor prognosis in human hilar cholangiocarcinoma. INTERNATIONAL JOURNAL OF CLINICAL AND EXPERIMENTAL PATHOLOGY 2014; 7:6157-6164. [PMID: 25337264 PMCID: PMC4203235] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Subscribe] [Scholar Register] [Received: 07/29/2014] [Accepted: 08/23/2014] [Indexed: 06/04/2023]
Abstract
High expression of matrix metalloproteinase-9 (MMP-9) was found to be correlated with tumor progression and poor prognosis in a variety of carcinomas. However, few studies have investigated the role of MMP-9 in human hilar cholangiocarcinoma. In this study, a total of 58 patients with hilar cholangiocarcinoma who underwent curative resection were included in this study. The expression of MMP-9 was analyzed by immunohistochemistry using the streptavidin peroxidase complex method. The correlation of MMP-9 overexpression with clinicopathological features and survival time of patients was investigated. The results showed that MMP-9 overexpression was prominent in cancer cells and mainly localized in the cytoplasm. MMP-9 overexpression was observed in 46.5% tumors, which showed no correlation with clinicopathological parameters. Patients with high MMP-9 expression had a significantly poorer overall survival rate than those with negative or low MMP-9 expression (P = 0.038). Multivariate analysis confirmed that MMP-9 overexpression was an independent prognostic factor (P = 0.007). In conclusion, overexpression of MMP-9 is a valuable independent prognostic indicator in hilar cholangiocarcinoma.
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Affiliation(s)
- Qi Sun
- Department of Hepatobiliary Surgery, Qilu Hospital of Shandong UniversityJinan 250012, Shandong, China
| | - Chuanzong Zhao
- Department of Hepatobiliary Surgery, Qilu Hospital of Shandong UniversityJinan 250012, Shandong, China
| | - Leizhou Xia
- Department of General Surgery, Affiliated People’s Hospital of Jiangsu UniversityZhenjiang, Jiangsu, China
| | - Zhaobin He
- Department of Hepatobiliary Surgery, Qilu Hospital of Shandong UniversityJinan 250012, Shandong, China
| | - Zhihua Lu
- Department of Hepatobiliary Surgery, Qilu Hospital of Shandong UniversityJinan 250012, Shandong, China
| | - Chuan Liu
- Department of General Surgery, Qilu Hospital of Shandong UniversityJinan 250012, Shandong, China
| | - Ming Jia
- Department of Pathology, Qilu Hospital of Shandong UniversityJinan 250012, Shandong, China
| | - Jiayong Wang
- Department of Hepatobiliary Surgery, Qilu Hospital of Shandong UniversityJinan 250012, Shandong, China
| | - Jun Niu
- Department of Hepatobiliary Surgery, Qilu Hospital of Shandong UniversityJinan 250012, Shandong, China
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Ogawa T, Washio J, Takahashi T, Echigo S, Takahashi N. Glucose and glutamine metabolism in oral squamous cell carcinoma: insight from a quantitative metabolomic approach. Oral Surg Oral Med Oral Pathol Oral Radiol 2014; 118:218-25. [PMID: 24927638 DOI: 10.1016/j.oooo.2014.04.003] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2014] [Revised: 03/31/2014] [Accepted: 04/07/2014] [Indexed: 01/26/2023]
Abstract
OBJECTIVE To characterize the metabolic system of oral squamous cell carcinoma (OSCC) by metabolome analysis. STUDY DESIGN The metabolome profiles, including the Embden-Meyerhof-Parnas pathway (EMPP), the pentose phosphate pathway, the tricarboxylic acid cycle (TCAC), and amino acids, were obtained from OSCC and its surrounding normal tissues (32 patients) using capillary electrophoresis and a time-of-flight mass spectrometer. RESULTS Enhancement of glucose consumption and lactate production (Warburg effect) was observed in OSCC tissues. The decrease of glucose along with the decrease of the downstream intermediates in the EMPP suggests that incorporated glucose is mainly consumed for biosynthesis. Glutamine consumption with the increase of the intermediates in the last half of the TCAC suggests the involvement of glutaminolysis, in which glutamine is converted to lactate via the last half of the TCAC. CONCLUSIONS It is suggested that OSCC tissues show the Warburg effect, which stems from the combined enhancement of glucose consumption and glutaminolysis.
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Affiliation(s)
- Tamaki Ogawa
- Division of Oral Ecology and Biochemistry, Department of Oral Biology, Tohoku University Graduate School of Dentistry, Sendai, Japan; Division of Oral and Maxillofacial Surgery, Tohoku University Graduate School of Dentistry, Sendai, Japan
| | - Jumpei Washio
- Division of Oral Ecology and Biochemistry, Department of Oral Biology, Tohoku University Graduate School of Dentistry, Sendai, Japan
| | - Tetsu Takahashi
- Division of Oral and Maxillofacial Surgery, Tohoku University Graduate School of Dentistry, Sendai, Japan
| | - Seishi Echigo
- Division of Oral and Maxillofacial Surgery, Tohoku University Graduate School of Dentistry, Sendai, Japan
| | - Nobuhiro Takahashi
- Division of Oral and Maxillofacial Surgery, Tohoku University Graduate School of Dentistry, Sendai, Japan.
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Kavitha K, Kranthi Kiran Kishore T, Bhatnagar RS, Nagini S. Cytomodulin-1, a synthetic peptide abrogates oncogenic signaling pathways to impede invasion and angiogenesis in the hamster cheek pouch carcinogenesis model. Biochimie 2014; 102:56-67. [PMID: 24582832 DOI: 10.1016/j.biochi.2014.02.010] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2013] [Accepted: 02/14/2014] [Indexed: 01/21/2023]
Abstract
Constitutive activation of the various oncogenic signaling pathways plays a pivotal role in promoting malignant transformation. The aim of this study was to investigate the therapeutic potential of a synthetic bioactive heptapeptide cytomodulin-1 (CM-1) against hamster cheek pouch carcinomas based on its influence on the predominant carcinogenic signaling pathways - NF-κB, TGFβ, and Wnt/β-catenin and their downstream target events invasion and angiogenesis. Topical application of CM-1 to DMBA-painted hamsters significantly inhibited activation of the canonical NF-κB pathway by blocking kinase activity of IKKβ and increasing the cytosolic accumulation of the inhibitor IκB-α. In addition, CM-1 inactivated IKKβ by disrupting IKKβ/Nemo interactions. CM-1 also hampered the activation of TGFβ and Wnt/β-catenin signaling by averting the phosphorylation of the key upstream ser/thr kinases TGFβ RI and GSK-3β respectively. Attenuation of these oncogenic signaling pathways by CM-1 also mitigated invasion and angiogenesis by suppressing the expression of pro-invasive matrix metalloproteinases, pro-angiogenic VEGF and HIF-1α and upregulating the anti-angiogenic TIMP-2. Synthetic peptides such as CM-1 that target multiple key molecules in oncogenic signaling pathways and their downstream events are ideal candidate agents for cancer chemotherapy.
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Affiliation(s)
- K Kavitha
- Department of Biochemistry and Biotechnology, Faculty of Science, Annamalai University, Annamalainagar 608 002, Tamil Nadu, India
| | - T Kranthi Kiran Kishore
- Department of Biochemistry and Biotechnology, Faculty of Science, Annamalai University, Annamalainagar 608 002, Tamil Nadu, India
| | - R S Bhatnagar
- Bioengineering, University of California, San Francisco and Berkeley, USA
| | - S Nagini
- Department of Biochemistry and Biotechnology, Faculty of Science, Annamalai University, Annamalainagar 608 002, Tamil Nadu, India.
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LI HAIXIA, HUANG DAYONG, GAO ZHONGXIUZI, CHEN YAN, ZHANG LINA, ZHENG JINHUA. Scutellarin inhibits the growth and invasion of human tongue squamous carcinoma through the inhibition of matrix metalloproteinase-2 and -9 and αvβ6 integrin. Int J Oncol 2013; 42:1674-81. [DOI: 10.3892/ijo.2013.1873] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2013] [Accepted: 02/25/2013] [Indexed: 11/06/2022] Open
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Matrix metalloproteinase and its drug targets therapy in solid and hematological malignancies: an overview. Mutat Res 2013; 753:7-23. [PMID: 23370482 DOI: 10.1016/j.mrrev.2013.01.002] [Citation(s) in RCA: 77] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2012] [Revised: 01/21/2013] [Accepted: 01/21/2013] [Indexed: 12/16/2022]
Abstract
Matrix metalloproteinase (MMP) comprises a family of zinc-dependent endopeptidases that degrade various components of the extracellular matrix (ECM) and basement membrane. MMPs are involved in solid and hematological malignancy through modification of cell growth, activation of cancer cells and modulation of immune functions. Several polymorphisms of different MMPs such as MMP-1 (-1607 1G/2G), MMP-2 (-1306 C/T), MMP-3 (-1171 5A/6A) & MMP-9 (-1562 C/T) and their expression levels have been well documented in different types of solid cancer. These polymorphic variations were found to be associated with angiogenesis, cancer progression, invasion and metastasis. There is paucity of data available in the field of hematological malignancies. Hence the field of matrix biology of hematological malignancies is an area of active exploration. A number of MMP inhibitors (MMPIs) have been developed for the cancer treatment. The most extensively studied classes of MMP inhibitors include Batimastat, Marismastat, Salimatat, Prinomastat and Tanomastat. However, their efficacy and action have not been confirmed and more data is required. The application of one or more selective targeted MMPIs in combination with conventional anti-leukemic treatment may represent a positive approach in combat against hematopoietic malignancies. Balance of MMPs and TIMPs is altered in different malignancies and biochemical pathways. These alternations will add another dimension in the matrix biology of both solid tumor and leukemia. MMP and TIMP singly and in combination are increasingly being recognized as an important player in basic cellular biology. Exploration and exploitation of MMP and TIMP balance in various malignant and nonmalignant lesions is going to be one of the most interesting facets of future use of this system for human health care.
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Fluctuating roles of matrix metalloproteinase-9 in oral squamous cell carcinoma. ScientificWorldJournal 2013; 2013:920595. [PMID: 23365550 PMCID: PMC3556887 DOI: 10.1155/2013/920595] [Citation(s) in RCA: 64] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2012] [Accepted: 12/10/2012] [Indexed: 12/12/2022] Open
Abstract
One hallmark of cancer is the degradation of the extracellular matrix (ECM), which is caused by proteinases. In oral cancers, matrix metalloproteinases (MMPs), especially MMP-9, are associated with this degradation. MMPs break down the ECM allowing cancer to spread; they also release various factors from their cryptic sites, including cytokines. These factors modulate cell behavior and enhance cancer progression by regulating angiogenesis, migration, proliferation, and invasion. The development of early metastases is typical for oral cancer, and increased MMP-9 expression is associated with a poor disease prognosis. However, many studies fail to relate MMP-9 expression with metastasis formation. Contrary to earlier models, recent studies show that MMP-9 plays a protective role in oral cancers. Therefore, the role of MMP-9 is complicated and may fluctuate throughout the different types and stages of oral cancers.
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Yen CY, Huang CY, Hou MF, Yang YH, Chang CH, Huang HW, Chen CH, Chang HW. Evaluating the performance of fibronectin 1 (FN1), integrin α4β1 (ITGA4), syndecan-2 (SDC2), and glycoprotein CD44 as the potential biomarkers of oral squamous cell carcinoma (OSCC). Biomarkers 2012; 18:63-72. [DOI: 10.3109/1354750x.2012.737025] [Citation(s) in RCA: 49] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
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Deng S, Wang J, Hou L, Li J, Chen G, Jing B, Zhang X, Yang Z. Annexin A1, A2, A4 and A5 play important roles in breast cancer, pancreatic cancer and laryngeal carcinoma, alone and/or synergistically. Oncol Lett 2012; 5:107-112. [PMID: 23255903 DOI: 10.3892/ol.2012.959] [Citation(s) in RCA: 59] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2012] [Accepted: 08/22/2012] [Indexed: 01/10/2023] Open
Abstract
Annexins are associated with metastasis and infiltration of cancer cells. Proteomic analysis and immunohistochemical staining were used to understand whether several annexins play important roles in cancer alone and/or synergistically. Seven fresh breast cancer samples with 23 paraffin specimens, three fresh pancreatic samples and five fresh laryngeal carcinoma samples with 25 paraffin specimens were obtained from humans, as well as ten golden hamster pancreatic cancer tissue samples, and they were used to observe differential expression of annexins compared with normal tissues using proteomics and immunohistochemical staining. Annexin A2, A4 and A5 were overexpressed in human breast cancer and laryngeal carcinoma tissues and in golden hamster pancreatic cancer tissue samples, respectively, as shown by proteomics and immunohistochemical staining. In addition, annexin A4 and A5 were expressed in breast cancer tissues, while annexin A1 was not expressed. Annexin A1, A2 and A4 were expressed in human laryngeal carcinoma tissues as shown by immunohistochemical staining. Annexin A1, A2, A4 and A5 played important roles in breast cancer, pancreatic cancer and laryngeal carcinoma, alone and/or synergistically, and they may be targets of therapy for malignant tumors. The choice of which annexins to target should depend on their respective biological behaviors.
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Affiliation(s)
- Shishan Deng
- Department of Anatomy and ; Morphometric Research Laboratory, North Sichuan Medical College
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Li Y, Xu Q, Zhang Z, Liu S, Shi C, Tan Y. The impact of TGF-β1 on the mRNA expression of TβR I, TβR II, Smad4 and the invasiveness of the JEG-3 placental choriocarcinoma cell line. Oncol Lett 2012. [PMID: 23205135 DOI: 10.3892/ol.2012.906] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023] Open
Abstract
Human choriocarcinoma is one of the most aggressive malignant tumors characterized by early hematogenous spread to lung and brain tissues, and may be a cause of death in patients. Choriocarcinoma may occur following pregnancy and during implantation; however, trophoblastic invasion in human pregnancy is tightly regulated. The transforming growth factor-beta 1 (TGF-β1) has been suggested to play a role in controlling this process. In this study, we investigated the impact of TGF-β1 on invasion, as well as its sites of action in the TGF-β1/Smad pathway using a JEG-3 choriocarcinoma cell line. Following the treatment of cells with different doses of TGF-β1, cell invasion was observed. We also detected the expression of TGF-β receptor type I (TβR I) and TGF-β receptor type II (TβR II), Smad4, matrix metalloprotease (MMP)-9 and tissue inhibitor of metalloproteinase (TIMP)-1 in JEG-3 cells. Our data demonstrated that TGF-β1 promoted the invasive capability of JEG-3 cells depending on the downregulation of TβR I, TβR II, Smad4 and the upregulation of MMP-9 and TIMP-1. These observations suggest that TGF-β1 may play a critical role in the initiation of the trophoblastic invasion process.
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Affiliation(s)
- Yuhong Li
- Department of Basic Medicine, Chengde Medical College, Chengde, Hebei 067000, P.R. China
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Chen QJ, Lv ZL, Dang YW, Wei JJ. Correlation between MMP-9/TIMP-1 imbalance and ZHX2 expression in gastric carcinoma. Shijie Huaren Xiaohua Zazhi 2012; 20:1832-1837. [DOI: 10.11569/wcjd.v20.i20.1832] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
AIM: To detect the expression of matrix metalloproteinase 9 (MMP-9), tissue inhibitor of metalloproteinase-l (TIMP-1) and ZHX2 in gastric carcinoma and to analyze their association with pathological features.
METHODS: Immunohistochemistry was used to examine the expression of MMP-9, TIMP-1, and ZHX2 proteins in 62 cases of gastric carcinoma and matched tumor-adjacent tissue specimens. The correlation of MMP-9, TIMP-1 and ZHX2 protein expression with clinicopathological characteristics of gastric carcinoma was then analyzed.
RESULTS: The positive rate of MMP-9 expression was significantly higher (66.13% vs 29.03%, P < 0.01), and that of TIMP-1 was significantly lower (41.94% vs 74.19%, P < 0.01) in gastric carcinoma than in tumor-adjacent tissue. The positive rate of MMP-9 expression was significantly higher in the ZHX2-positive group than in the ZHX2-negative group (84.44% vs 17.65%, P < 0.05). MMP-9 expression was not associated with age, gender, tumor size, tumor location, general type, tumor differentiation, lymph node metastasis, distant metastasis, or TNM stage, but was significantly associated with depth of invasion (P < 0.05). The positive rate of TIMP-1 expression was significantly lower in the ZHX2-positive group than in the ZHX2-negative group (28.89% vs 76.49%, P < 0.05). TIMP-1 expression was not associated with age, gender, tumor size, tumor location, general type, tumor differentiation, depth of invasion, lymph node metastasis, distant metastasis, or TNM stage.
CONCLUSION: Detection of MMP-9 protein expression may be used to assess the malignant biological behavior and prognosis of gastric carcinoma. MMP-9/TIMP-1 imbalance may be related to the expression of ZHX2 in gastric carcinoma.
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Rubaci AH, Kazancioglu HO, Olgac V, Ak G. The roles of matrix metalloproteinases-2, -7, -10 and tissue inhibitor of metalloproteinase-1 in the pathogenesis of oral lichen planus. J Oral Pathol Med 2012; 41:689-96. [DOI: 10.1111/j.1600-0714.2012.01160.x] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
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Pérez-Sayáns M, Suárez-Peñaranda JM, Gayoso-Diz P, Barros-Angueira F, Gándara-Rey JM, García-García A. Tissue inhibitor of metalloproteinases in oral squamous cell carcinomas - a therapeutic target? Cancer Lett 2012; 323:11-19. [PMID: 22484495 DOI: 10.1016/j.canlet.2012.03.040] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2012] [Accepted: 03/30/2012] [Indexed: 11/30/2022]
Abstract
Matrix metalloproteinases (MMPs) are proteases responsible for remodeling the extracellular matrix (ECM) and enabling spreading and metastasis of tumor cells, a common phenomenon in oral squamous cell carcinomas (OSCC). They are strongly blocked by several inhibitors, among which we must highlight, for their specificity and potency, the endogenous tissue inhibitors of metalloproteinases (TIMP-1, -2, -3 and -4). The goal of this paper is to describe the expression of TIMPs in OSCC, determining their relation with clinical, histological and prognostic factors, delving into OSCC regulation mechanisms and discussing the use of exogenous TIMPs to treat this type of tumors. Expression of TIMPs in OSCC is higher in tumors than in normal tissue, which correlates with an increase of metastatic risk and regional lymph node affectation. Although some metalloproteinases inhibitors (MMIs) have shown promising results in the treatment of these tumors, their use in OSCC has not been widely tested; and although some indirect MMIs, like COX-2 inhibitors, flavonoids and endostatin seem to have beneficial effects on the invasive capacity of OSCC through regulation of MMPs and TIMP levels, routine clinical use has not been accepted yet.
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Affiliation(s)
- Mario Pérez-Sayáns
- Oral Medicine, Oral Surgery and Implantology Unit, Faculty of Medicine and Dentistry, Instituto de Investigación Sanitaria de Santiago (IDIS), Santiago de Compostela, Spain; Entrerríos s/n, Santiago de Compostela C.P. 15782, Spain.
| | - José Manuel Suárez-Peñaranda
- Servicio de Anatomia Patológica, Hospital Clinico Universitario de Santiago, Choupana s/n, Santiago de Compostela C.P. 15706, Spain.
| | - Pilar Gayoso-Diz
- Clinical Epidemiology and Biostatistics Unit, Hospital Clínico Universitario de Santiago de Compostela, Instituto de Investigación Sanitaria de Santiago (IDIS), A Choupana s/n, Santiago de Compostela 15706, Spain.
| | - Francisco Barros-Angueira
- Unidad de Medicina Molecular, Fundación Pública Galega de Medicina Xenómica, Edificio de Consultas planta-2, Hospital Clinico Universitario, Santiago de Compostela C.P. 15706, Spain.
| | | | - Abel García-García
- Oral Medicine, Oral Surgery and Implantology Unit, Faculty of Medicine and Dentistry, Instituto de Investigación Sanitaria de Santiago (IDIS), Santiago de Compostela, Spain; Entrerríos s/n, Santiago de Compostela C.P. 15782, Spain.
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Shah FD, Begum R, Vajaria BN, Patel KR, Patel JB, Shukla SN, Patel PS. A review on salivary genomics and proteomics biomarkers in oral cancer. Indian J Clin Biochem 2011; 26:326-34. [PMID: 23024467 DOI: 10.1007/s12291-011-0149-8] [Citation(s) in RCA: 71] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2011] [Accepted: 07/04/2011] [Indexed: 11/28/2022]
Abstract
Oral cancer has emerged as an alarming public health problem with increasing incidence and mortality rates all over the world. Therefore, the implementation of newer screening and early detection approaches are of utmost importance which could reduce the morbidity and mortality associated with this disease. Sensitive and specific biomarkers for oral cancer are likely to be most effective for screening, diagnosis, staging and follow-up for this dreaded malignancy. Unlike other deep cancers, oral cancer is located in oral cavity. Hence, the direct contact between saliva and oral cancer lesion makes the measurement of tumor markers in saliva an attractive alternative to serum and tissue testing. The DNA, RNA and protein molecules derived from the living cancer cells can be conveniently obtained from saliva. Thus, salivary biomarkers, a non-invasive alternative to serum and tissue-based biomarkers may be an effective modality for early diagnosis, prognostication and monitoring post therapy status. In the current post-genomic era, various technologies provide opportunities for high-throughput approaches to genomics and proteomics; which have been used to evaluate altered expressions of gene and protein targets in saliva of oral cancer patients. The emerging field of salivary biomarkers has great potentials to prove its clinical significance to combat oral cancer. Hence, we have reviewed importance of several salivary genomics and proteomics biomarkers for oral cancer.
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Affiliation(s)
- Franky D Shah
- Biochemistry Research Division, The Gujarat Cancer & Research Institute, Asarwa, Ahmedabad, 380 016 Gujarat India
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