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Yen H, Chen P, Huang RY, Jeng J, Lai I. Clinicopathological features and cancer transcriptomic profiling of poorly cohesive gastric carcinoma subtypes. J Pathol Clin Res 2024; 10:e12387. [PMID: 38860888 PMCID: PMC11165978 DOI: 10.1002/2056-4538.12387] [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: 03/18/2024] [Revised: 05/16/2024] [Accepted: 05/20/2024] [Indexed: 06/12/2024]
Abstract
Gastric poorly cohesive carcinoma (PCC) manifests with a diffuse pattern and diverse tumor cell morphologies, often indicating a more unfavorable prognosis. Recent consensus has reclassified PCC based on the proportion of signet-ring cells (SRCs) in tumors for research purposes. The two most distinct subtypes, poorly cohesive carcinoma not otherwise specified (PCC-NOS) and signet-ring cell carcinoma (SRCC), are characterized by less than 10% and more than 90% SRCs, respectively. However, research comparing the clinicopathological and transcriptomic differences between these subtypes remains limited. In this study, we conducted a comparative analysis of clinicopathological features in 55 advanced-stage PCCs, consisting of 43 PCC-NOS and 12 SRCC cases. Subsequently, 12 PCC-NOS and 5 SRCC cases were randomly selected for initial cancer-related gene expression profiling and pathway enrichment analysis using the GeoMx digital spatial profiler, followed by validation in a separate validation group comprising 16 PCC-NOS and 6 SRCC cases. These transcriptomic findings were then correlated with tumor morphology and clinicopathological data. PCC-NOS cases exhibited larger tumor size, a higher prevalence of pathological N3 disease, and a worse 1-year progression-free survival rate compared to SRCC cases. Clustering of PCC-NOS and SRCC was successfully achieved using the GeoMx Cancer Transcriptome Atlas. Among all studied genes, only MMP7 showed differential expression, with its overexpression significantly associated with the PCC-NOS subtype, increased perineural invasion, and earlier disease progression. Pathway analysis revealed significantly enriched pathways in PCC-NOS related to vesicle-mediated transport, adaptive immune systems, oncogenic signaling, and extracellular matrix organization, while SRCC displayed significant enrichment in pathways associated with respiratory electron transport and the cell cycle. In conclusion, this study compares and correlates clinicopathological features and transcriptomic data between PCC-NOS and SRCC at advanced stages, employing the latest consensus classification and a novel platform for analysis.
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Affiliation(s)
- Hung‐Hsuan Yen
- Department of SurgeryNational Taiwan University Hospital Hsin‐Chu BranchHsinchuTaiwan
- Department of SurgeryNational Taiwan University HospitalTaipeiTaiwan
| | - Pin‐Yu Chen
- Graduate Institute of Anatomy and Cell Biology, College of MedicineNational Taiwan UniversityTaipeiTaiwan
| | - Ruby Yun‐Ju Huang
- School of Medicine, College of MedicineNational Taiwan UniversityTaipeiTaiwan
| | - Jung‐Ming Jeng
- Department of PathologyNational Taiwan University HospitalTaipeiTaiwan
| | - I‐Rue Lai
- Department of SurgeryNational Taiwan University HospitalTaipeiTaiwan
- Graduate Institute of Anatomy and Cell Biology, College of MedicineNational Taiwan UniversityTaipeiTaiwan
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Doddawad V, Shivananda S, Kalabharathi HL, Shetty A, Sowmya S, Sowmya HK. Matrix metalloproteinases in oral cancer: A catabolic activity on extracellular matrix components. BIOMEDICAL AND BIOTECHNOLOGY RESEARCH JOURNAL (BBRJ) 2023. [DOI: 10.4103/bbrj.bbrj_10_23] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/16/2023]
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Alqahtani SS, Koltai T, Ibrahim ME, Bashir AHH, Alhoufie STS, Ahmed SBM, Molfetta DD, Carvalho TMA, Cardone RA, Reshkin SJ, Hifny A, Ahmed ME, Alfarouk KO. Role of pH in Regulating Cancer Pyrimidine Synthesis. J Xenobiot 2022; 12:158-180. [PMID: 35893264 PMCID: PMC9326563 DOI: 10.3390/jox12030014] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2022] [Revised: 06/17/2022] [Accepted: 06/28/2022] [Indexed: 11/18/2022] Open
Abstract
Replication is a fundamental aspect of cancer, and replication is about reproducing all the elements and structures that form a cell. Among them are DNA, RNA, enzymes, and coenzymes. All the DNA is doubled during each S (synthesis) cell cycle phase. This means that six billion nucleic acids must be synthesized in each cycle. Tumor growth, proliferation, and mutations all depend on this synthesis. Cancer cells require a constant supply of nucleotides and other macromolecules. For this reason, they must stimulate de novo nucleotide synthesis to support nucleic acid provision. When deregulated, de novo nucleic acid synthesis is controlled by oncogenes and tumor suppressor genes that enable increased synthesis and cell proliferation. Furthermore, cell duplication must be achieved swiftly (in a few hours) and in the midst of a nutrient-depleted and hypoxic environment. This also means that the enzymes participating in nucleic acid synthesis must work efficiently. pH is a critical factor in enzymatic efficiency and speed. This review will show that the enzymatic machinery working in nucleic acid synthesis requires a pH on the alkaline side in most cases. This coincides with many other pro-tumoral factors, such as the glycolytic phenotype, benefiting from an increased intracellular pH. An increased intracellular pH is a perfect milieu for high de novo nucleic acid production through optimal enzymatic performance.
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Affiliation(s)
- Saad Saeed Alqahtani
- Department of Pharmacy Practice, College of Pharmacy, Jazan University, Jazan 45142, Saudi Arabia;
- Pharmacy Practice Research Unit, College of Pharmacy, Jazan University, Jazan 45142, Saudi Arabia
| | | | - Muntaser E. Ibrahim
- Department of Molecular Biology, Institute of Endemic Diseases, University of Khartoum, Khartoum 11111, Sudan; (M.E.I.); (A.H.H.B.)
| | - Adil H. H. Bashir
- Department of Molecular Biology, Institute of Endemic Diseases, University of Khartoum, Khartoum 11111, Sudan; (M.E.I.); (A.H.H.B.)
| | - Sari T. S. Alhoufie
- Medical Laboratories Technology Department, College of Applied Medical Sciences, Taibah University, Medina 42353, Saudi Arabia;
| | - Samrein B. M. Ahmed
- Department of Biosciences and Chemistry, College of Health, Wellbeing and Life Sciences, Sheffield Hallam University, Sheffield S1 1WB, UK;
| | - Daria Di Molfetta
- Department of Biosciences, Biotechnologies, and Biopharmaceutics, University of Bari, 70126 Bari, Italy; (D.D.M.); (T.M.A.C.); (R.A.C.); (S.J.R.)
| | - Tiago M. A. Carvalho
- Department of Biosciences, Biotechnologies, and Biopharmaceutics, University of Bari, 70126 Bari, Italy; (D.D.M.); (T.M.A.C.); (R.A.C.); (S.J.R.)
| | - Rosa Angela Cardone
- Department of Biosciences, Biotechnologies, and Biopharmaceutics, University of Bari, 70126 Bari, Italy; (D.D.M.); (T.M.A.C.); (R.A.C.); (S.J.R.)
| | - Stephan Joel Reshkin
- Department of Biosciences, Biotechnologies, and Biopharmaceutics, University of Bari, 70126 Bari, Italy; (D.D.M.); (T.M.A.C.); (R.A.C.); (S.J.R.)
| | | | - Mohamed E. Ahmed
- Research Center, Zamzam University College, Khartoum 11123, Sudan;
| | - Khalid Omer Alfarouk
- Research Center, Zamzam University College, Khartoum 11123, Sudan;
- Alfarouk Biomedical Research LLC, Temple Terrace, FL 33617, USA
- Hala Alfarouk Cancer Center, Khartoum 11123, Sudan
- Correspondence:
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Sokolova O, Naumann M. Matrix Metalloproteinases in Helicobacter pylori-Associated Gastritis and Gastric Cancer. Int J Mol Sci 2022; 23:1883. [PMID: 35163805 PMCID: PMC8836485 DOI: 10.3390/ijms23031883] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2021] [Revised: 02/02/2022] [Accepted: 02/04/2022] [Indexed: 02/05/2023] Open
Abstract
Gastric cancer is one of the leading causes of the cancer-related mortality worldwide. The etiology of this disease is complex and involves genetic predisposition and environmental factors, including Helicobacter pylori. Infection of the stomach with H. pylori leads to gastritis and gastric atrophy, which can progress stepwise to gastric cancer. Matrix metalloproteinases (MMPs) actively participate in the pathology development. The further progression of gastric cancer seems to be less dependent on bacteria but of intra-tumor cell dynamics. Bioinformatics data confirmed an important role of the extracellular matrix constituents and specific MMPs in stomach carcinoma invasion and metastasis, and revised their potential as predictors of the disease outcome. In this review, we describe, in detail, the impact of MMPs in H. pylori-associated gastritis and gastric cancer.
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Affiliation(s)
- Olga Sokolova
- Institute of Experimental Internal Medicine, Medical Faculty, Otto von Guericke University, Leipziger Str. 44, 39120 Magdeburg, Germany
| | - Michael Naumann
- Institute of Experimental Internal Medicine, Medical Faculty, Otto von Guericke University, Leipziger Str. 44, 39120 Magdeburg, Germany
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Ito K, Kitajima Y, Kai K, Matsufuji S, Yamada K, Egawa N, Kitagawa H, Okuyama K, Tanaka T, Noshiro H. Matrix metalloproteinase‑1 expression is regulated by HIF‑1‑dependent and epigenetic mechanisms and serves a tumor‑suppressive role in gastric cancer progression. Int J Oncol 2021; 59:102. [PMID: 34738626 PMCID: PMC8577796 DOI: 10.3892/ijo.2021.5282] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2021] [Accepted: 10/11/2021] [Indexed: 02/05/2023] Open
Abstract
The matrix metalloproteinase (MMP) family is associated with degradation of the extracellular matrix and is known to promote cancer invasion. The present study aimed to investigate the biological role of MMP‑1 in gastric cancer cells and analyze the association between MMP‑1 expression and the clinical outcomes of gastric cancer patients. In the present study, hypoxia accelerated invasion, accompanied by elevated MMP‑1 expression in the gastric cancer cell line 58As9. Additionally, hypoxia‑inducible factor‑1α (HIF‑1α) knockdown in 58As9 cells reduced MMP‑1 expression under hypoxic conditions. Treatment with 5‑aza‑2‑deoxycytidine and trichostatin A restored MMP‑1 expression in the MMP‑1‑deficient cell lines MKN45 and MKN74. These results indicated that MMP‑1 expression was controlled by both HIF‑1α‑dependent and epigenetic mechanisms in gastric cancer cell lines. In addition, MMP‑1 knockdown impaired the hypoxia‑induced invasiveness of 58As9 cells, implicating MMP‑1 in the elevated invasion. By contrast, knockdown enhanced the proliferative ability of 58As9 cells, whereby expression of cell cycle‑related genes was subsequently altered. In nude mouse models, the knockdown accelerated the growth of xenograft tumor and the development of peritoneal dissemination. In an immunohistochemical study using 161 surgically resected cancer tissues, the Ki67 score was significantly higher in the group with low MMP‑1 expression (P<0.001). Disease‑free survival (DFS) and disease‑specific survival (DSS) were both significantly reduced in patients with low MMP‑1 expression (log‑rank test; DFS: P=0.005; DSS: P=0.022). Multivariate analysis demonstrated that MMP‑1 expression was an independent prognostic factor for DFS and DSS [DFS: HR=2.11 (1.22‑3.92) P=0.005, DSS: HR=2.90 (1.23‑8.50) P=0.012]. In conclusion, the present study indicated that MMP‑1 may serve as a tumor‑suppressive factor that inhibits gastric cancer progression, although it promoted invasion in vitro.
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MESH Headings
- Adult
- Aged
- Aged, 80 and over
- Animals
- Apoptosis
- Biomarkers, Tumor/genetics
- Biomarkers, Tumor/metabolism
- Cell Proliferation
- Epigenesis, Genetic
- Female
- Gene Expression Regulation, Neoplastic
- Genes, Tumor Suppressor
- Humans
- Hypoxia/physiopathology
- Hypoxia-Inducible Factor 1, alpha Subunit/genetics
- Hypoxia-Inducible Factor 1, alpha Subunit/metabolism
- Male
- Matrix Metalloproteinase 1/genetics
- Matrix Metalloproteinase 1/metabolism
- Mice
- Mice, Inbred BALB C
- Mice, Nude
- Middle Aged
- Neoplasm Invasiveness
- Prognosis
- Stomach Neoplasms/genetics
- Stomach Neoplasms/pathology
- Survival Rate
- Tumor Cells, Cultured
- Xenograft Model Antitumor Assays
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Affiliation(s)
- Kotaro Ito
- Department of Surgery, Saga University Faculty of Medicine, Saga 849-8501, Japan
| | - Yoshihiko Kitajima
- Department of Surgery, National Hospital Organization Higashisaga Hospital, Miyaki, Saga 849-0101, Japan
| | - Keita Kai
- Department of Pathology, Saga University Hospital, Saga 849-8501, Japan
| | - Shohei Matsufuji
- Department of Surgery, Saga University Faculty of Medicine, Saga 849-8501, Japan
| | - Kohei Yamada
- Department of Surgery, Saga University Faculty of Medicine, Saga 849-8501, Japan
| | - Noriyuki Egawa
- Department of Surgery, Saga University Faculty of Medicine, Saga 849-8501, Japan
| | - Hiroshi Kitagawa
- Department of Surgery, Saga University Faculty of Medicine, Saga 849-8501, Japan
| | - Keiichiro Okuyama
- Department of Surgery, Saga University Faculty of Medicine, Saga 849-8501, Japan
| | - Tomokazu Tanaka
- Department of Surgery, Saga University Faculty of Medicine, Saga 849-8501, Japan
| | - Hirokazu Noshiro
- Department of Surgery, Saga University Faculty of Medicine, Saga 849-8501, Japan
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Rhode P, Mehdorn M, Lyros O, Kahlert C, Kurth T, Venus T, Schierle K, Estrela-Lopis I, Jansen-Winkeln B, Lordick F, Gockel I, Thieme R. Characterization of Total RNA, CD44, FASN, and PTEN mRNAs from Extracellular Vesicles as Biomarkers in Gastric Cancer Patients. Cancers (Basel) 2021; 13:cancers13235975. [PMID: 34885085 PMCID: PMC8656496 DOI: 10.3390/cancers13235975] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2021] [Revised: 11/24/2021] [Accepted: 11/25/2021] [Indexed: 12/11/2022] Open
Abstract
Simple Summary Liquid biopsy is an easily accessible and non-invasive method to gain information about tumor diseases. The purpose of our study was to determine the value of extracellular vesicle-derived mRNAs as biomarkers for the diagnosis of gastric cancer and the response to its treatment. In a cohort of 87 gastric cancer patients and a control group of 14 individuals, we analyzed the absolute RNA concentration from extracellular vesicles (EV) and the relative levels of FASN, PTEN, and CD44 mRNA, and their correlation with clinico-pathological features. These correlated with treatment, tumor grading, and the pathological subtype according to Laurén’s classification. This might reflect their potential as both diagnostic and therapeutic predictors. Abstract In-depth characterization has introduced new molecular subtypes of gastric cancer (GC). To identify these, new approaches and techniques are required. Liquid biopsies are trendsetting and provide an easy and feasible method to identify and to monitor GC patients. In a prospective cohort of 87 GC patients, extracellular vesicles (EVs) were isolated from 250 µL of plasma. The total RNA was isolated with TRIZOL. The total RNA amount and the relative mRNA levels of CD44, PTEN, and FASN were measured by qRT-PCR. The isolation of EVs and their contained mRNA was possible in all 87 samples investigated. The relative mRNA levels of PTEN were higher in patients already treated by chemotherapy than in chemo-naïve patients. In patients who had undergone neoadjuvant chemotherapy followed by gastrectomy, a decrease in the total RNA amount was observed after neoadjuvant chemotherapy and gastrectomy, while FASN and CD44 mRNA levels decreased only after gastrectomy. The amount of RNA and the relative mRNA levels of FASN and CD44 in EVs were affected more significantly by chemotherapy and gastrectomy than by chemotherapy alone. Therefore, they are a potential biomarker for monitoring treatment response. Future analyses are needed to identify GC-specific key RNAs in EVs, which could be used for the diagnosis of gastric cancer patients in order to determine their molecular subtype and to accompany the therapeutic response.
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Affiliation(s)
- Philipp Rhode
- Department of Visceral, Transplant, Thoracic and Vascular Surgery, University Hospital Leipzig, D-04103 Leipzig, Germany; (P.R.); (M.M.); (O.L.); (B.J.-W.); (I.G.)
| | - Matthias Mehdorn
- Department of Visceral, Transplant, Thoracic and Vascular Surgery, University Hospital Leipzig, D-04103 Leipzig, Germany; (P.R.); (M.M.); (O.L.); (B.J.-W.); (I.G.)
| | - Orestis Lyros
- Department of Visceral, Transplant, Thoracic and Vascular Surgery, University Hospital Leipzig, D-04103 Leipzig, Germany; (P.R.); (M.M.); (O.L.); (B.J.-W.); (I.G.)
| | - Christoph Kahlert
- Department for Visceral, Thoracic and Vascular Surgery, University Hospital Carl Gustav Carus, D-01307 Dresden, Germany;
| | - Thomas Kurth
- Center for Molecular and Cellular Bioengineering (CMCB), Technology Platform, Technische Universität Dresden, D-01307 Dresden, Germany;
| | - Tom Venus
- Institute of Medical Physics and Biophysics, University of Leipzig, D-0407 Leipzig, Germany; (T.V.); (I.E.-L.)
| | - Katrin Schierle
- Institute of Pathology, University Hospital Leipzig, D-04103 Leipzig, Germany;
| | - Irina Estrela-Lopis
- Institute of Medical Physics and Biophysics, University of Leipzig, D-0407 Leipzig, Germany; (T.V.); (I.E.-L.)
| | - Boris Jansen-Winkeln
- Department of Visceral, Transplant, Thoracic and Vascular Surgery, University Hospital Leipzig, D-04103 Leipzig, Germany; (P.R.); (M.M.); (O.L.); (B.J.-W.); (I.G.)
| | - Florian Lordick
- Department of Oncology, Gastroenterology, Hepatology, Pulmonology and Infectious Diseases, University Hospital Leipzig, D-04103 Leipzig, Germany;
- University Cancer Center Leipzig (UCCL), University Hospital Leipzig, D-04103 Leipzig, Germany
| | - Ines Gockel
- Department of Visceral, Transplant, Thoracic and Vascular Surgery, University Hospital Leipzig, D-04103 Leipzig, Germany; (P.R.); (M.M.); (O.L.); (B.J.-W.); (I.G.)
| | - René Thieme
- Department of Visceral, Transplant, Thoracic and Vascular Surgery, University Hospital Leipzig, D-04103 Leipzig, Germany; (P.R.); (M.M.); (O.L.); (B.J.-W.); (I.G.)
- Correspondence:
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Abstract
Methylxanthine derivatives, such as caffeine and theophylline, enhance cell apoptosis and autophagy and reportedly induce the activity of phosphatase and tensin homologue (PTEN) and inhibit the mammalian target of rapamycin (mTOR). This study investigated the impacts of caffeine and theophylline on gastric cancer cell apoptosis and autophagy using a gastric cancer cell line (MGC-803) and a nude mouse model. Peritumoural and tumour tissues were collected from five patients diagnosed with gastric carcinoma who underwent laparoscopic radical gastrectomy at our hospital. Autophagy was suppressed in gastric cancer tumour tissue compared with peritumoural tissue. In vitro, both caffeine and theophylline effectively suppressed MGC-803 cell proliferation and migration and induced autophagy. To assess the involvement of PTEN in caffeine-mediated and theophylline-mediated gastric cancer cell death, we transiently transfected MGC-803 cells with an siRNA targeting PTEN. PTEN knockdown impaired the methylxanthine derivative-mediated inhibition of PI3K/Akt/mTOR signalling. In nude mice treated with caffeine or theophylline, MGC-803 cell tumours injected with siPTEN were larger than those injected with negative control siRNA. These results show that the methylxanthine derivatives (caffeine and theophylline) effectively induce gastric cancer cell apoptosis and autophagy by PTEN activation and PI3K/Akt/mTOR pathway suppression and strongly support the use of methylxanthine derivatives as potential anticancer therapeutics.
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Yadav PK, Gupta SK, Kumar S, Ghosh M, Yadav BS, Kumar D, Kumar A, Saini M, Kataria M. IL-18 immunoadjuvanted xenogeneic canine MMP-7 DNA vaccine overcomes immune tolerance and supresses the growth of murine mammary tumor. Int Immunopharmacol 2020; 82:106370. [PMID: 32155464 DOI: 10.1016/j.intimp.2020.106370] [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] [Received: 01/13/2020] [Revised: 02/27/2020] [Accepted: 03/02/2020] [Indexed: 12/22/2022]
Abstract
The development of the tumorigenesis and angiogenesis through proteolytic cleavage of extracellular matrix protein and basement membranes is promoted by Matrix metelloproteinases-7 (MMP-7). Consequently, MMP-7 is presumed as potential target for mammary cancer immunotherapy. However, MMP-7 is an endogenous tumor associated antigen (TAA); therefore, immunization is challenging. In current study, a potent anti-tumor immune response has been elicited through recombinant bivalent plasmid pVIVO2.IL18.cMMP7 which subside the highly metastatic 4 T1 cell line induced mammary tumors and efficiently negate the existing challenge of using MMP-7 as immunotherapeutic target. Balb/c mice were immunized with canine MMP-7 (cMMP-7) using interleukine-18 (IL-18), as an immunoadjuvant, to explore the potential of the combination regarding elicitation of a potent anti-tumor immune response. Mice vaccinated with pVIVO2.IL18.cMMP7 DNA plasmid reduced the tumor growth significantly along with augmentation of the immune response to fight against tumor antigen as depicted by substantial enrichment of CD4+ and CD8+ population in splenocytes, infiltration of immune system cells in tumor tissue and enhanced survival time of mice. Further, splenocyte supernatant examination of the cytokines revealed that Th1 cytokines (IFN-γ and IL-2) were remarkably up-regulated demonstrating the stimulation of cell-mediated immune response. Thus the current observations vividly portray that administration of xenogeneic MMP-7 DNA vaccine bypasses the tolerance barrier.
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Affiliation(s)
- Pavan Kumar Yadav
- ICAR-Indian Veterinary Research Institute, Izatnagar, Bareilly 243122, Uttar Pradesh, India; Faculty of Veterinary and Animal Sciences, Rajiv Gandhi South Campus, Banaras Hindu University, Mirzapur 231001, Uttar Pradesh, India.
| | - Shishir Kumar Gupta
- ICAR-Indian Veterinary Research Institute, Izatnagar, Bareilly 243122, Uttar Pradesh, India; Laboratory Animal Facility, CSIR-CDRI, Lucknow 226031, Uttar Pradesh, India
| | - Saroj Kumar
- ICAR-Indian Veterinary Research Institute, Izatnagar, Bareilly 243122, Uttar Pradesh, India; Faculty of Veterinary and Animal Sciences, Rajiv Gandhi South Campus, Banaras Hindu University, Mirzapur 231001, Uttar Pradesh, India
| | - Mayukh Ghosh
- Faculty of Veterinary and Animal Sciences, Rajiv Gandhi South Campus, Banaras Hindu University, Mirzapur 231001, Uttar Pradesh, India
| | - Brijesh Singh Yadav
- ICAR-Indian Veterinary Research Institute, Izatnagar, Bareilly 243122, Uttar Pradesh, India; University of Information Science & Technology St. Paul the apostle Partizanska bb., 6000 Ohrid, The Former Yugolav Republic of Macedonia
| | - Dinesh Kumar
- ICAR-Indian Veterinary Research Institute, Izatnagar, Bareilly 243122, Uttar Pradesh, India; College of Agriculture, Tikamgarh, Jawaharlal Nehru Krishi Vishwa Vidylaya, Jabalpur 482004, Madhya Pradesh, India
| | - Ajay Kumar
- ICAR-Indian Veterinary Research Institute, Izatnagar, Bareilly 243122, Uttar Pradesh, India
| | - Mohini Saini
- ICAR-Indian Veterinary Research Institute, Izatnagar, Bareilly 243122, Uttar Pradesh, India
| | - Meena Kataria
- ICAR-Indian Veterinary Research Institute, Izatnagar, Bareilly 243122, Uttar Pradesh, India
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Hong WG, Ko YS, Pyo JS. Clinicopathological significance and prognostic role of microvessel density in gastric cancer: A meta-analysis. Pathol Res Pract 2017; 213:1459-1463. [PMID: 29129495 DOI: 10.1016/j.prp.2017.11.001] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/14/2017] [Revised: 10/21/2017] [Accepted: 11/03/2017] [Indexed: 01/04/2023]
Abstract
OBJECTIVE The aim of this study was to elucidate the clinicopathological significance and prognostic role of microvessel density (MVD) in gastric cancer (GC) through a meta-analysis. METHODS This meta-analysis included 4094 patients from 26 eligible studies. We investigated the correlation between MVD and clinicopathological characteristics, including survival rate. In addition, subgroup analysis based on microscopic magnification among evaluation criteria of MVD was performed. RESULTS High MVD was significantly correlated with worse overall and disease-free survival rates [hazard ratio (HR), 3.028, 95% confidence interval (CI) 2.105-4.357 and HR 2.045, 95% CI 1.530-2.732, respectively]. MVD was significantly increased in GC with diffuse type of Lauren's classification [mean difference (MD) 3.091, 95% CI 0.615-5.567], lymphatic invasion (MD 8.262, 95% CI 3.310-13.214), lymph node metastasis (MD 5.730, 95% CI 2.444-9.016), higher pT stage (pT3-4) (MD 7.093, 95% CI 0.060-14.126) and higher pTNM stage (III-IV) (MD 3.023, 95% CI 0.181-5.865). However, MD of MVD was not significantly different in regard to vascular invasion (MD 7.430, 95% CI 1.015-15.875), tumor differentiation (MD 5.501, 95% CI 1.353-12.355) and tumor size (MD 4.731, 95% CI 2.003-11.465). CONCLUSION Taken together, higher MVD was significantly correlated with worse prognosis. In addition, MVD was significantly higher in GC with aggressive tumor behavior than in GC without aggressive features.
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Affiliation(s)
- Won Gi Hong
- Eulji University School of Medicine, Daejeon 34824, Republic of Korea
| | - Young San Ko
- Department of Forensic Medicine, National Forensic Service Busan Institute, Yangsan 50612, Republic of Korea
| | - Jung-Soo Pyo
- Department of Pathology, Eulji University Hospital, Eulji University School of Medicine, 95 Dunsanseo-ro, Seo-gu, Daejeon 35233, Republic of Korea.
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Shen J, Niu W, Zhang H, Jun M, Zhang H. Downregulation of MicroRNA-147 Inhibits Cell Proliferation and Increases the Chemosensitivity of Gastric Cancer Cells to 5-Fluorouracil by Directly Targeting PTEN. Oncol Res 2017; 26:901-911. [PMID: 28950928 PMCID: PMC7844761 DOI: 10.3727/096504017x15061902533715] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Gastric cancer is the fourth most common malignancy and the third leading cause of cancer-related deaths worldwide. This study aimed to investigate the expression patterns, biological roles, and underlying mechanisms of microRNA-147 (miR-147) in gastric cancer. The present study demonstrated that miR-147 was significantly upregulated in gastric cancer tissues and cell lines. Downregulation of miR-147 decreased cell proliferation and enhanced the chemosensitivity of gastric cancer cells to 5-fluorouracil (5-FU) through the cell apoptosis pathway. In addition, phosphatase and tensin homolog (PTEN) was mechanically identified as the direct target of miR-147 in gastric cancer. PTEN knockdown reversed the effects of miR-147 downregulation on the proliferation, chemosensitivity, and 5-FU-induced apoptosis of gastric cancer cells. Moreover, miR-147 regulated the PI3K/AKT signaling pathway in gastric cancer by targeting PTEN. In conclusion, miR-147 suppressed the proliferation and enhanced the chemosensitivity of gastric cancer cells to 5-FU by promoting cell apoptosis through directly targeting PTEN and regulating the PI3K/AKT signaling pathway. This study provides important insight into the molecular mechanism that underlies the chemoresistance of gastric cancer cells. The results of this study could aid the development of a novel therapeutic strategy for gastric cancer.
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Affiliation(s)
- Jianjun Shen
- Department of Radiation Oncology, Anhui Provincial Hospital, Hefei, Anhui, P.R. China
| | - Weina Niu
- Department of Oncology, Anhui Cancer Hospital, Hefei, Anhui, P.R. China
| | - Hongbo Zhang
- Department of Radiation Oncology, Anhui Provincial Hospital, Hefei, Anhui, P.R. China
| | - Ma Jun
- Department of Radiation Oncology, Anhui Provincial Hospital, Hefei, Anhui, P.R. China
| | - Hongyan Zhang
- Department of Radiation Oncology, Anhui Provincial Hospital, Hefei, Anhui, P.R. China
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Nemtsova MV, Strelnikov VV, Tanas AS, Bykov II, Zaletaev DV, Rudenko VV, Glukhov AI, Kchorobrich TV, Li Y, Tarasov VV, Barreto GE, Aliev G. Implication of Gastric Cancer Molecular Genetic Markers in Surgical Practice. Curr Genomics 2017; 18:408-415. [PMID: 29081696 PMCID: PMC5635646 DOI: 10.2174/1389202918666170329110021] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2015] [Revised: 01/17/2016] [Accepted: 03/20/2016] [Indexed: 12/12/2022] Open
Abstract
INTRODUCTION We have investigated aberrant methylation of genes CDH1, RASSF1A, MLH1, N33, DAPK, expression of genes hTERT, MMP7, MMP9, BIRC5 (survivin), PTGS2, and activity of telomerase of 106 gastric tumor samples obtained intra-operatively and 53 gastric tumor samples from the same group of patients obtained endoscopically before surgery. Biopsy specimens obtained from 50 patients with chronic calculous cholecystitis were used as a control group. Together with tissue samples obtained from different sites remote to tumors, a total of 727 samples have been studied. The selected parameters comprise a system of molecular markers that can be used in both diagnostics of gastric cancer and in dynamic monitoring of patients after surgery. Special attention was paid to the use of molecular markers for the diagnostics of malignant process in the material obtained endoscopically since the efficacy of morphological diagnostics in biopsies is compromised by intratumoral heterogeneity, which may prevent reliable identification of tumor cells in the sampling. Our data indicated that certain molecular genetic events provided more sensitive yet specific markers of the tumor. CONCLUSION We demonstrated that molecular profiles detected in preoperative biopsies were confirmed by the material obtained intra-operatively. The use of endoscopic material facilitates gastric tumors pre-operative diagnostics, improving early detection of gastric cancer and potential effective treatment strategies.
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Affiliation(s)
- Marina V Nemtsova
- Institute of Molecular Medicine, Sechenov First Moscow State Medical University, Russian Ministry of Health, Trubetskaya St. 8/2, Moscow, 119991, Russian Federation.,Department of Medical Genetics, Russian Medical Academy of Postgraduate Education, Ministry of Health of the Russian Federation, Moscow, 119991, Russian Federation
| | | | - Alexander S Tanas
- Research Centre for Medical Genetics, Moskvorechie St. 1, 115472, Moscow, Russia
| | - Igor I Bykov
- Department No 1, Medical Faculty, Faculty Surgery, Sechenov First Moscow State Medical University, Russian Ministry of Health, Trubetskaya St. 8/2, Moscow, 119991, Russian Federation
| | - Dmitry V Zaletaev
- Institute of Molecular Medicine, Sechenov First Moscow State Medical University, Russian Ministry of Health, Trubetskaya St. 8/2, Moscow, 119991, Russian Federation.,Research Centre for Medical Genetics, Moskvorechie St. 1, 115472, Moscow, Russia
| | - Viktoria V Rudenko
- Research Centre for Medical Genetics, Moskvorechie St. 1, 115472, Moscow, Russia
| | - Alexander I Glukhov
- Department of Biochemistry, Sechenov First Moscow State Medical University, Russian Ministry of Health, Trubetskaya, 8/2, Moscow, 119991, Russian Federation.,National Research Centre "Kurchatov Institute", Moscow, 123182, Russia
| | - Tatiana V Kchorobrich
- Department No 1, Medical Faculty, Faculty Surgery, Sechenov First Moscow State Medical University, Russian Ministry of Health, Trubetskaya St. 8/2, Moscow, 119991, Russian Federation
| | - Yi Li
- Department of Human Sciences, Texas A&M University-Kingsville, TX 78363, USA
| | - Vadim V Tarasov
- Institute of Pharmacy and Translational Medicine, Sechenov First Moscow State Medical University, 119991Moscow, Russia
| | - George E Barreto
- Departamento de Nutrición y Bioquímica, Facultad de Ciencias, Pontificia Universidad Javeriana, BogotáD.C., Colombia
| | - Gjumrakch Aliev
- "GALLY" International Biomedical Research Consulting LLC, San Antonio, TX78229, USA.,School of Health Sciences, University of Atlanta, Johns Creek, GA 30097, USA.,Institute of Physiologically Active Compounds, Russian Academy of Sciences, Chernogolovka, 142432, Russia
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12
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Banskota S, Regmi SC, Kim JA. NOX1 to NOX2 switch deactivates AMPK and induces invasive phenotype in colon cancer cells through overexpression of MMP-7. Mol Cancer 2015; 14:123. [PMID: 26116564 PMCID: PMC4482031 DOI: 10.1186/s12943-015-0379-0] [Citation(s) in RCA: 65] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2014] [Accepted: 05/06/2015] [Indexed: 01/01/2023] Open
Abstract
Background Although matrix metalloproteinase (MMP)-7 expression is correlated with increased metastatic potential in human colon cancer cells, the underlying molecular mechanism of invasive phenotype remains unknown. In the current study, we investigated the regulatory effects of membrane NADPH oxidase (NOX) and AMP activated protein kinase (AMPK) on MMP-7 expression and invasive phenotype change in colon cancer cells. Methods Production of superoxide anion was measured by lucigenin chemiluminescence assay using whole cells and protein extracts (NADPH oxidase activity), and intracellular reactive oxygen species (ROS) by fluorescence microscopy using 2’,7’-dichlorofluorescein diacetate (DCF-DA). Quantitative real-time polymerase chain reaction (qRT-PCR) and Western blotting were used to measure mRNA and protein levels, respectively. siRNA transfection was used to assess involvement of genes in cancer invasion, which were identified by Matrigel transwell invasion assay. Luciferase reporter assay was performed to identify transcription factors linked to gene expression. Results Under basal conditions, less invasive human colon cancer cells (HT29 and Caco-2) showed low MMP-7 expression but high NOX1 expression and AMPK phosphorylation. Treatment of HT29 and Caco-2 cells with 12-O-tetradecanoylphorbol-13-acetate (TPA) induced an invasive phenotype response along with corresponding increases in ROS production and NOX2 and MMP-7 expression as well as reduced AMPK phosphorylation, which resemble basal conditions of highly invasive human colon cancer cells (SW620 and HCT116). In addition, inverse regulation between AMPK phosphorylation and NOX2 and MMP-7 expression was observed in HT29 cells treated with different concentrations of exogenous hydrogen peroxide. TPA-induced invasive phenotype in HT29 cells was abolished by treatment with Vit. E, DPI, apocynin, and NOX2 siRNA but not NOX1 siRNA, indicating NOX2-derived ROS production induced an invasive phenotype. TPA-induced induction of MMP-7 expression was suppressed by AP-1, NF-κB, and MAPK (ERK, p38, and JNK) inhibitors, whereas TPA-induced expression of NOX2 and its regulators, p47phox and p67phox, was blocked by p38 and NF-κB inhibitors. Conclusions Molecular switch from NOX1 to NOX2 in colon cancer cells induces ROS production and subsequently enhances MMP-7 expression by deactivating AMPK, which otherwise inhibits stimulus-induced autoregulation of ROS and NOX2 gene expression. Electronic supplementary material The online version of this article (doi:10.1186/s12943-015-0379-0) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Suhrid Banskota
- College of Pharmacy, Yeungnam University, Gyeongsan, 712-749, South Korea.
| | - Sushil C Regmi
- College of Pharmacy, Yeungnam University, Gyeongsan, 712-749, South Korea.
| | - Jung-Ae Kim
- College of Pharmacy, Yeungnam University, Gyeongsan, 712-749, South Korea.
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13
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Xu WT, Yang Z, Lu NH. Roles of PTEN (Phosphatase and Tensin Homolog) in gastric cancer development and progression. Asian Pac J Cancer Prev 2014; 15:17-24. [PMID: 24528021 DOI: 10.7314/apjcp.2014.15.1.17] [Citation(s) in RCA: 56] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Gastric cancer is highly invasive, aggressively malignant, and amongst the most prevalent of all forms of cancer. Despite improved management strategies, early stage diagnosis of gastric cancer and accurate prognostic assessment is still lacking. Several recent reports have indicated that the pathogenesis of gastric cancer involves complex molecular mechanisms and multiple genetic and epigenetic alterations in oncogenes and tumor suppressor genes. Functional inactivation of the tumor suppressor protein PTEN (Phosphatase and Tensin Homolog) has been detected in multiple cases of gastric cancer, and already shown to be closely linked to the development, progression and prognosis of the disease. Inactivation of PTEN can be attributed to gene mutation, loss of heterozygosity, promoter hypermethylation, microRNA- mediated regulation of gene expression, and post-translational phosphorylation. PTEN is also involved in mechanisms regulating tumor resistance to chemotherapy. This review provides a comprehensive analysis of PTEN and its roles in gastric cancer, and emphasizes its potential benefits in early diagnosis and gene therapy-based treatment strategies.
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Affiliation(s)
- Wen-Ting Xu
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang, China E-mail :
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14
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Zhang X, Park JS, Park KH, Kim KH, Jung M, Chung HC, Rha SY, Kim HS. PTEN deficiency as a predictive biomarker of resistance to HER2-targeted therapy in advanced gastric cancer. Oncology 2014; 88:76-85. [PMID: 25300346 DOI: 10.1159/000366426] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2014] [Accepted: 08/03/2014] [Indexed: 12/16/2022]
Abstract
BACKGROUND To investigate the role of the phosphoinositide 3-kinase (PI3K) pathway activation in human epidermal growth factor receptor 2 (HER2)-targeted therapy. METHODS We evaluated the predictive roles of PI3K, catalytic alpha (PIK3CA), and phosphatase and tensin homolog (PTEN) in HER2-based therapy (either trastuzumab or lapatinib). PTEN expression and PIK3CA mutation were analyzed using immunohistochemistry and pyrosequencing. RESULTS Forty-eight patients received trastuzumab (n = 39) or lapatinib (n = 9) combination chemotherapy. PTEN loss was found in 47.9% (n = 23), but no PIK3CA mutations were identified. Twenty-six (54.1%) patients responded to HER2-based therapy, without a significant difference between patients with PTEN loss and those without (52.2 vs. 56.0%). Among the patients with responsive disease, time to best response did not differ by PTEN status, but the duration of response was significantly shorter for patients with PTEN loss (median 4.2 vs. 6.1 months, p = 0.04). In addition, patients with PTEN loss had a significantly shorter progression-free survival time (median 4.9 vs. 7.3 months, p = 0.047). CONCLUSIONS PTEN deficiency is an important predictive marker for early resistance to HER2 inhibitor treatment in gastric cancer patients. This finding may be useful for the development of drug combinations and identification of patients who need a modified treatment strategy.
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Affiliation(s)
- Xianglan Zhang
- Oral Cancer Research Institute, Yonsei University College of Medicine, Seoul, Korea
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15
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Long ZW, Wang JL, Wang YN. Matrix metalloproteinase-7 mRNA and protein expression in gastric carcinoma: a meta-analysis. Tumour Biol 2014; 35:11415-26. [PMID: 25123263 DOI: 10.1007/s13277-014-2441-8] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2014] [Accepted: 08/04/2014] [Indexed: 12/30/2022] Open
Abstract
Messenger RNA (mRNA) acts as template for protein synthesis. The matrix metalloproteinase-7 (MMP-7) protein and its mRNA expression have been suggested to be involved in the development of various diseases and cancers. We aimed to study associations between the MMP-7 protein and mRNA expression in gastric carcinoma (GC) patients. We searched in the Science Citation Index, the Cochrane Library, PubMed, Embase, CINAHL, Current Contents Index, and several Chinese databases. Studies were pooled and odds ratios and their corresponding 95 % confidence intervals were calculated. Subgroup analyses and publication bias detection were also conducted. Statistical analysis was performed via Version 12.0 STATA software. An updated meta-analysis based on 16 independent cohort studies was performed to investigate this association. The study suggests that significant differences in MMP-7 protein levels were observed in tumor-node-metastasis (TNM) I-II vs. III-IV (odds radio (OR) =3.19, 95 % confidence interval (95%CI) =1.59 ∼ 6.41, P=0.001), in T1-2 vs. T3-4 invasive grade (OR=1.82, 95%CI=1.07 ∼ 3.12, P=0.028), and in distant metastasis-positive vs. metastasis-negative samples (OR=3.14, 95%CI=1.05 ∼ 9.35, P=0.040). Increased MMP-7 mRNA levels were found to be significantly correlated with invasive grade (T3-4 vs. T1-2: OR=5.61, 95%CI=2.64 ∼ 11.95, P<0.001) and in the lymph node (LN) metastasis (positive vs. negative: OR=7.08, 95%CI=4.20 ∼ 11.93, P<0.001) group. Country subgroup analysis yielded significantly different estimates in the protein expression of MMP-7 of all experimental groups. MMP-7 mRNA levels were increased in LN metastasis-positive GC in contrast to metastasis-negative in China and Korea (all P<0.05); this was not shown in Japan (P>0.05). Higher protein and mRNA levels of MMP-7 were statistically associated with aggressive LN metastasis, advanced TNM stage, and invasion in GC patients; MMP-7 can thus potentially serve as a useful biomarker in determining GC progression and prognosis.
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Affiliation(s)
- Zi-Wen Long
- Department of Gastric cancer and soft tissue sarcoma surgery, Fudan University, Shanghai Cancer Center, No. 270, Dongan Road, Shanghai, 200032, China
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16
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Dey N, Young B, Abramovitz M, Bouzyk M, Barwick B, De P, Leyland-Jones B. Differential activation of Wnt-β-catenin pathway in triple negative breast cancer increases MMP7 in a PTEN dependent manner. PLoS One 2013; 8:e77425. [PMID: 24143235 PMCID: PMC3797090 DOI: 10.1371/journal.pone.0077425] [Citation(s) in RCA: 52] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2013] [Accepted: 09/02/2013] [Indexed: 01/22/2023] Open
Abstract
Mutations of genes in tumor cells of Triple Negative subset of Breast Cancer (TNBC) deregulate pathways of signal transduction. The loss of tumor suppressor gene PTEN is the most common first event associated with basal-like subtype (Martins, De, Almendro, Gonen, and Park, 2012). Here we report for the first time that the functional upregulation of secreted-MMP7, a transcriptional target of Wnt-β-catenin signature pathway in TNBC is associated to the loss of PTEN. We identified differential expression of mRNAs in several key-components genes, and transcriptional target genes of the Wnt-β-catenin pathway (WP), including beta-catenin, FZD7, DVL1, MMP7, c-MYC, BIRC5, CD44, PPARD, c-MET, and NOTCH1 in FFPE tumors samples from TNBC patients of two independent cohorts. A similar differential upregulation of mRNA/protein for beta-catenin, the functional readout of WP, and for MMP7, a transcriptional target gene of beta-catenin was observed in TNBC cell line models. Genetic or pharmacological attenuation of beta-catenin by SiRNA or WP modulators (XAV939 and sulindac sulfide) and pharmacological mimicking of PTEN following LY294002 treatment downregulated MMP7 levels as well as enzymatic function of the secreted MMP7 in MMP7 positive PTEN-null TNBC cells. Patient data revealed that MMP7 mRNA was high in only a subpopulation of TNBC, and this subpopulation was characterized by a concurrent low expression of PTEN mRNA. In cell lines, a high expression of casein-zymograph-positive MMP7 was distinguished by an absence of functional PTEN. A similar inverse relationship between MMP7 and PTEN mRNA levels was observed in the PAM50 data set (a correlation coefficient of -0.54). The PAM50 subtype and outcome data revealed that the high MMP7 group had low pCR (25%) and High Rd (74%) in clinical stage T3 pathologic response in contrast to the high pCR (40%) and low residual disease (RD) (60%) of the low MMP7 group.
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Affiliation(s)
- Nandini Dey
- Edith Sanford Breast Cancer, Sanford Research, Sioux Falls, South Dakota, United States of America
- Internal Medicine, University of South Dakota, Sioux Falls, South Dakota, United States of America
| | - Brandon Young
- Edith Sanford Breast Cancer, Sanford Research, Sioux Falls, South Dakota, United States of America
- The Scripps Research Institute Jupiter, Florida, United States of America
| | | | - Mark Bouzyk
- Human Genetics, Emory University, Atlanta, Georgia, United States of America
| | - Benjamin Barwick
- Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia, United States of America
| | - Pradip De
- Edith Sanford Breast Cancer, Sanford Research, Sioux Falls, South Dakota, United States of America
- Internal Medicine, University of South Dakota, Sioux Falls, South Dakota, United States of America
| | - Brian Leyland-Jones
- Edith Sanford Breast Cancer, Sanford Research, Sioux Falls, South Dakota, United States of America
- Internal Medicine, University of South Dakota, Sioux Falls, South Dakota, United States of America
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17
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Lai CK, Lu YL, Hsieh JT, Tsai SC, Feng CL, Tsai YS, Tsai PC, Su HL, Lin YH, Lai CH. Development of chitosan/heparin nanoparticle-encapsulated cytolethal distending toxin for gastric cancer therapy. Nanomedicine (Lond) 2013; 9:803-17. [PMID: 24024568 DOI: 10.2217/nnm.13.54] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023] Open
Abstract
AIM The aim of this work was to develop pH-responsive nanoparticles encapsulating CdtB and to demonstrate that these particles represent a potential therapeutic agent for gastric cancer. MATERIALS & METHODS Chitosan/heparin nanoparticle-encapsulated CdtB was prepared and the delivery efficiency was monitored by confocal laser scanning microscopy. The molecular basis of the nanoparticle-encapsulated CdtB-mediated p53 activation pathway was explored by immunoblot analysis. Antitumoral activities were investigated by analyzing the cell cycle and apoptosis. RESULTS Chitosan/heparin nanoparticle-encapsulated CdtB preferentially inhibited the proliferation of cells derived from gastric cancer, but not in primary gastric epithelial cells. Treatment of cells with nanoparticle-encapsulated CdtB enhanced cell-cycle arrest at G2/M, followed by apoptosis. Moreover, our data showed that the mechanism for nanoparticle-encapsulated CdtB-induced cell death was mediated by ATM-dependent DNA damage checkpoint responses. CONCLUSION These findings indicate that chitosan/heparin nanoparticle-encapsulated CdtB could represent a new CdtB delivery strategy for the treatment of gastric cancer.
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Affiliation(s)
- Cheng-Kuo Lai
- Department of Life Sciences, Agricultural Biotechnology Center, National Chung Hsing University, Taichung, Taiwan
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Ali A, Saluja SS, Hajela K, Mishra PK, Rizvi MA. Mutational and expressional analyses of PTEN
gene in colorectal cancer from Northern India. Mol Carcinog 2013; 53 Suppl 1:E45-52. [DOI: 10.1002/mc.22001] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2012] [Revised: 11/24/2012] [Accepted: 12/17/2012] [Indexed: 12/12/2022]
Affiliation(s)
- Asgar Ali
- Genome Biology Laboratory; Department of Biosciences; Jamia Millia Islamia New Delhi India
| | - Sundeep S. Saluja
- Department of Gastrointestinal Surgery; G. B. Pant Hospital; New Delhi India
| | - Krishnan Hajela
- School of Life Sciences; Devi Ahilya Vishwavidyalaya; Indore India
| | - Pramod K. Mishra
- Department of Gastrointestinal Surgery; G. B. Pant Hospital; New Delhi India
| | - Moshahid A. Rizvi
- Genome Biology Laboratory; Department of Biosciences; Jamia Millia Islamia New Delhi India
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Nishimura J, Handa R, Yamamoto H, Tanaka F, Shibata K, Mimori K, Takemasa I, Mizushima T, Ikeda M, Sekimoto M, Ishii H, Doki Y, Mori M. microRNA-181a is associated with poor prognosis of colorectal cancer. Oncol Rep 2012; 28:2221-6. [PMID: 23023298 DOI: 10.3892/or.2012.2059] [Citation(s) in RCA: 48] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2012] [Accepted: 08/03/2012] [Indexed: 01/12/2023] Open
Abstract
miRNAs regulate gene expression at the post-transcriptional level by degradation of mRNA and translational repression. Recent studies have shown that miR-181a is dysregulated in several types of cancer; however, the clinical significance of miR‑181a in colorectal cancer (CRC) remains unclear. We addressed this question by using quantitative real-time PCR (qRT-PCR) to analyze miR-181a expression in 162 CRC patients. There was no significant difference in miR-181a expression in normal colon vs. colorectal cancer tissue. The cancer tissue samples were categorized into a low and high expression group based on miR-181a expression. Comparison of the clinicopathological factors and prognosis in these two groups showed that the high expression group had a significantly poorer prognosis than the low expression group (P=0.011). Multivariate analysis indicated that high miR-181a expression was an independent significant prognostic factor for CRC. However, there no correlation was observed between miR-181a expression and clinicopathological parameters. In vitro analysis revealed that the overexpression of miR-181a repressed the expression of the tumor suppressor, phosphatase and tensin homolog (PTEN) located on chromosome 10, at the mRNA level. These data suggest that miR-181a may be a new independent prognostic factor for CRC patients.
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Affiliation(s)
- Junichi Nishimura
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan
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20
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Yang X, Takano Y, Zheng HC. The pathobiological features of gastrointestinal cancers (Review). Oncol Lett 2012; 3:961-969. [PMID: 22783373 DOI: 10.3892/ol.2012.628] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2011] [Accepted: 12/16/2011] [Indexed: 01/05/2023] Open
Abstract
Gastrointestinal adenocarcinoma (GIA) is a common malignant disease worldwide. Its tumorigenesis and progression is a multistage process with the involvement of a multifactorial etiology. Knowledge regarding altered expression of these genes during carcinogenesis may not only provide information about the molecular events during the initiation and progression of cancer, but may also result in the discovery of biological markers for the evaluation of cancer diagnosis and prognosis. In this review, we assessed molecular markers of pathogenesis, invasion, metastasis and prognosis, such as tumor suppressor and metastasis suppressor genes, and angiogenesis, cell adhesion, cell mobility, ER stress, mucin production, threonine protein kinase and REG family protein expression, by the establishment of tissue microarray (TMA) of GIA and immunohistochemistry (IHC) by intermittent microwave irradiation and in situ hybridization (ISH). Finally, we characterized the pathobiological features of Lauren's and WHO subtypes. It was found that the aberrant and cell-specific expression of these molecules is important in the malignant transformation of gastrointestinal epithelium and subsequent progression. These molecules also underlie the histogenic mechanisms of gastric carcinoma according to Lauren's and WHO classification. The combination of TMA, IHC and ISH may be widely applied to screen for molecular markers in GIA.
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Affiliation(s)
- Xue Yang
- Department of Biochemistry and Molecular Biology and Institute of Pathology and Pathophysiology, College of Basic Medicine, China Medical University, Shenyang, P.R. China
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Wang XR, Li XN, Bai GH, Guo YD. Significance of expression of nuclear PTEN and survivin in gastric cancer. Shijie Huaren Xiaohua Zazhi 2011; 19:2974-2978. [DOI: 10.11569/wcjd.v19.i28.2974] [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: 02/06/2023] Open
Abstract
AIM: To investigate the expression of nuclear PTEN and survivin in gastric cancer and to evaluate their clinicopathological significance.
METHODS: The expression of nuclear PTEN and survivin was measured in 116 cases of gastric cancer and 35 cases of normal gastric mucosa tissue on tissue array sections by EnVision immunohistochemical method. The relationship of their expression with lymph node metastasis and Lauren's classification, as well as the correlation between nuclear PTEN and survivin expression were evaluated.
RESULTS: The positive rates of nuclear PTEN and survivin in normal gastric mucosa were higher than those in gastric cancer (100% vs 57.1%; 100% vs 44.0%). The expression of nuclear PTEN and Survivin was significantly correlated with lymph node metastasis in gastric cancer (P < 0.05). Nuclear PTEN was significantly related to Lauren's classification and differentiation (both P < 0.05). The expression of nuclear PTEN had a significant correlation with that of survivin (r = 0.088, P = 0.001).
CONCLUSION: Nuclear PTEN and survivin are lowly expressed in gastric cancer. Nuclear PTEN and survivin may be good predictors of metastasis and prognosis of gastric cancer.
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22
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Yang Z, Lv NH. Role of PTEN in gastric carcinogenesis. Shijie Huaren Xiaohua Zazhi 2011; 19:608-613. [DOI: 10.11569/wcjd.v19.i6.608] [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: 02/06/2023] Open
Abstract
The PTEN (phosphatase and tensin homolog deleted on chromosome ten) gene is another important tumor suppressor gene found after p53 gene, and its encoded protein is involved in cellular differentiation, reproduction and apoptosis, as well as cellular adhesion and mobility, and genetic stability that is often lost in various human cancers. Recently, some studies have indicated that down-regulation of PTEN protein expression due to genetic or epigenetic changes, like mutation, loss of heterozygosity (LOH) and promoter hypermethylation, participates in gastric carcinogenesis. These studies could help us understand the pathogenesis of gastric cancer (GC), and show us a new molecular marker that could be used to evaluate TNM stage, histological type, or differentiation grade of GC biopsies, and GC treatment. In this article, we will focus on the functions of PTEN, the mechanisms of its inactivation in GC, and the important role of its inactivation in the development and prognosis of GC.
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Sakai H, Ohuchida K, Mizumoto K, Cui L, Nakata K, Toma H, Nagai E, Tanaka M. Inhibition of p600 expression suppresses both invasiveness and anoikis resistance of gastric cancer. Ann Surg Oncol 2011; 18:2057-65. [PMID: 21347795 PMCID: PMC3115059 DOI: 10.1245/s10434-010-1523-0] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2010] [Indexed: 12/22/2022]
Abstract
BACKGROUND Advanced gastric cancers often metastasize to distant organs and the peritoneum, leading to a poor prognosis. Both invasiveness and resistance to anchorage-independent cell death (anoikis) are important factors in the process of metastasis. p600 (600-kDa protein), recently identified from a cervical cancer cell line, plays a role in both anoikis resistance and cell migration. In this study, we examined whether p600 is involved in the progression of gastric cancer. METHODS We used both normal gastric mucosal cells and cancer cells laser-microdissected from 42 gastric cancers and their normal counterparts, and compared their p600 mRNA expression levels with quantitative reverse transcriptase-polymerase chain reaction. We inhibited p600 expression in two gastric cancer cell lines with siRNA and examined its effect on the invasiveness and anoikis resistance both in vitro and in vivo. RESULTS Expression of p600 mRNA was significantly higher in gastric cancer cells than in normal mucosal cells (P = 0.027). The invasion assay revealed that invasiveness was significantly reduced by inhibition of p600 (P < 0.01). In vitro experiments revealed that cell viability and colony-formation capacity under anchorage-independent conditions were significantly reduced by inhibition of p600 (P < 0.05). In vivo experiments also showed that the establishment of intraperitoneal disseminated tumors was significantly suppressed by transient inhibition of p600 (P < 0.001). CONCLUSIONS Our results strongly suggest that p600 is involved in gastric cancer progression, and has a potential to be a new molecular target for gastric cancer therapy.
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Affiliation(s)
- Hiroshi Sakai
- Department of Surgery and Oncology, Kyushu University, Fukuoka, Japan
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Rath T, Roderfeld M, Halwe JM, Tschuschner A, Roeb E, Graf J. Cellular sources of MMP-7, MMP-13 and MMP-28 in ulcerative colitis. Scand J Gastroenterol 2010; 45:1186-1196. [PMID: 20568971 DOI: 10.3109/00365521.2010.499961] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
OBJECTIVE Matrix metalloproteinases (MMPs) are considered the predominant proteases in the pathogenesis of mucosal ulcerations associated with inflammatory bowel disease (IBD). Whether the malignancy associated MMP-7 and MMP-13 or the recently cloned MMP-28 convey a certain meaning for intestinal homeostasis and pathogenesis of IBD is currently unknown. We therefore set off to analyze regulation patterns and cellular origins of these MMPs in mucosal tissues of patients with ulcerative colitis (UC). MATERIAL AND METHODS Biopsy samples of affected and healthy tissues were obtained from 35 Norwegian patients with UC. RNA was quantified by quantitative real-time polymerase chain reaction to study MMP gene expression in both pathological and healthy mucosal specimens. Cellular origins were determined by immunohistology using surrogate markers for inflammation, neovascularization, and epithelial structures. Protein expression of MMP-7 and MMP-13 was quantified using enzyme-linked immunosorbent assay. RESULTS MMP-7 and MMP-13 gene expression was significantly increased in UC affected colonic mucosa whereas MMP-28 showed a decreased expression in inflamed mucosa. Endothelial cells and infiltrating leukocytes were identified as the major cellular sources of MMP-7 and MMP-13 in UC. Enterocytes represented the major cellular source of MMP-28 in healthy and inflamed mucosa. CONCLUSIONS MMP-7 and MMP-13 expression in inflammatory and endothelial cells indicate a role of these MMPs for both colitis associated neoangiogenesis and inflammatory changes. Decreased MMP-28 expression in UC is most likely the result of colitis associated epithelial destruction and loss of cryptal architecture.
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Affiliation(s)
- Timo Rath
- Department of Internal Medicine, Division of Gastroenterology, Justus-Liebig-University Giessen, Giessen, Germany
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Fuereder T, Jaeger-Lansky A, Hoeflmayer D, Preusser M, Strommer S, Cejka D, Koehrer S, Crevenna R, Wacheck V. mTOR inhibition by everolimus counteracts VEGF induction by sunitinib and improves anti-tumor activity against gastric cancer in vivo. Cancer Lett 2010; 296:249-56. [PMID: 20471160 DOI: 10.1016/j.canlet.2010.04.015] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2010] [Revised: 04/14/2010] [Accepted: 04/15/2010] [Indexed: 12/20/2022]
Abstract
VEGF receptor blockage has been reported to increase serum VEGF. We hypothesized that mTOR inhibition by everolimus counteracts VEGF induction by sunitinib resulting in an improved anti-tumor activity of sunitinib. In vitro, sunitinib in combination with everolimus did not outperform the respective monotherapies. In vivo, monotherapies reduced tumor growth by 60%, whereas the combination of sunitinib and everolimus led to an almost complete tumor growth inhibition. This superior anti-tumor activity coincided with attenuation of VEGF peaks. In conclusion mTOR inhibition by everolimus counteracts VEGF induction by sunitinib and results in significant reduction of tumor burden and long-lasting tumor growth control.
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Affiliation(s)
- Thorsten Fuereder
- Department of Clinical Pharmacology, Medical University Vienna, Austria
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Intrahepatic micrometastases around liver metastases from gastric cancer. ACTA ACUST UNITED AC 2009; 16:493-501. [PMID: 19360371 DOI: 10.1007/s00534-009-0081-y] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2008] [Accepted: 10/20/2008] [Indexed: 12/12/2022]
Abstract
BACKGROUND/PURPOSE We aimed to clarify the association between the presence of micrometastases around liver metastases from gastric cancer and the results of hepatic resection. In addition, we investigated the influence of E-cadherin and matrix metalloproteinase (MMP)-7 expression on the development of micrometastases. METHODS Micrometastases around liver metastases were examined microscopically in 31 metastatic liver tumor specimens resected from 17 patients who had undergone hepatic resection for liver metastases from gastric cancer. E-cadherin and MMP-7 expression in the primary gastric tumor, the liver metastases, and the micrometastases were examined immunohistochemically. RESULTS Hepatic micrometastases were present in around 48% of the liver metastases, accounting for 59% of the patients. The tumor recurrence rate in the remnant liver after hepatic resection was significantly higher, and survival significantly poorer, in patients with such micrometastases than in those without. Micrometastases tended to appear around the liver metastases that had reduced E-cadherin expression. Most of the micrometastases in the lymph ducts and sinusoids showed reduced E-cadherin expression. MMP-7 expression was not correlated with the presence of micrometastases. CONCLUSIONS About half of the hepatic metastases from gastric cancer had seeded off micrometastases, and the presence of these micrometastases was associated with a poorer result of hepatic resection. Reduced E-cadherin expression in metastatic liver tumors may be associated with the development of micrometastases.
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Couto SS, Cao M, Duarte PC, Banach-Petrosky W, Wang S, Romanienko P, Wu H, Cardiff RD, Abate-Shen C, Cunha GR. Simultaneous haploinsufficiency of Pten and Trp53 tumor suppressor genes accelerates tumorigenesis in a mouse model of prostate cancer. Differentiation 2009; 77:103-11. [PMID: 19281769 PMCID: PMC2828345 DOI: 10.1016/j.diff.2008.09.010] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Tumor suppressor gene PTEN is important in the initiation and progression of human prostate carcinoma, whereas the role of TP53 remains controversial. Since Pten/Trp53 double conditional knockout mice show earlier onset and fast progression of prostate cancer when compared to Pten knockout mice, we asked whether heterozygosity of these two tumor suppressor genes was sufficient to accelerate prostatic tumorigenesis. To answer this question we examined prostatic lesion progression of Pten/Trp53 double heterozygous mice and a series of controls such as Pten heterozygous, Pten conditional knockout, Trp53 heterozygous and Trp53 knockout mice. Tissue recombination of adult prostatic epithelium coupled with embryonic rat seminal vesicle mesenchyme was used as a tool to stimulate prostatic epithelial proliferation. In our study, high-grade prostatic intraepithelial neoplasia (PIN) was found with high frequency at 8 weeks post-tissue recombination transplantation. PIN lesions in Pten/Trp53 double heterozygous mice were more severe than those seen in Pten heterozygous alone. Furthermore, morphologic features attributable to Pten or Trp53 loss appeared to be enhanced in double heterozygous tissues. LOH analysis of Pten and Trp53 in genomic DNA collected from high-grade PIN lesions in Pten heterozygous and Pten/Trp53 double heterozygous mice showed an intact wild-type allele for both genes in all samples examined. In conclusion, simultaneous heterozygosity of Pten and Trp53 accelerates prostatic tumorigenesis in this mouse model of prostate cancer independently of loss of heterozygosity of either gene.
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Affiliation(s)
- Suzana S Couto
- Laboratory of Comparative Pathology, Memorial Sloan-Kettering Cancer Center, NY, USA.
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Delassus GS, Cho H, Park J, Eliceiri GL. New pathway links from cancer-progression determinants to gene expression of matrix metalloproteinases in breast cancer cells. J Cell Physiol 2008; 217:739-44. [PMID: 18651563 DOI: 10.1002/jcp.21548] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
AP-2alpha, interleukin-4 (IL-4), E-cadherin, fibulin 1D, p16(INK4alpha), PTEN, RKIP, and S100A4 are determinants (suppressors, except for S100A4) of cancer cell invasiveness and other traits of cancer progression, which are located upstream of matrix metalloproteinases (MMPs) in cell signaling pathways. We will refer to them as upstream cancer-progression determinants (UCPDs, for brevity). MMP-1, MMP-2, MMP-9, MMP-11, MMP-13, MMP-14, MMP-16, and MMP-19 are enhancers of cancer cell invasiveness and other traits of cancer progression, in MDA-MB-231 breast cancer cells. We are interested in pathway links from UCPDs to gene expression of cancer cell MMPs in MDA-MB-231 cells. To test models about these links, wild-type copies of UCPDs were transiently overexpressed and then MMP mRNAs were measured by reverse transcription real-time PCR. The present results show that each of eight UCPDs is linked to the gene expression of a unique set of MMPs. This indicates that the effects are sequence-specific and that each UCPD reaches these MMP expressions through different sets of signaling pathways. We have detected 20 new pathway links, 11 are downregulatory and nine are upregulatory; 15 are new links in any cell, and five are new links in breast cancer. In seven links, three cancer-progression suppressing UCPDs unexpectedly enhance the gene expression of five cancer-progression promoting MMPs.
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Affiliation(s)
- Gregory S Delassus
- Department of Pathology, Saint Louis University School of Medicine, St. Louis, Missouri 63104-1028, USA
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Beeghly-Fadiel A, Long JR, Gao YT, Li C, Qu S, Cai Q, Zheng Y, Ruan ZX, Levy SE, Deming SL, Snoddy JR, Shu XO, Lu W, Zheng W. Common MMP-7 polymorphisms and breast cancer susceptibility: a multistage study of association and functionality. Cancer Res 2008; 68:6453-9. [PMID: 18648013 PMCID: PMC2718434 DOI: 10.1158/0008-5472.can-08-0636] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Matrix metalloproteinase-7 (MMP-7) is a small secreted proteolytic enzyme with broad substrate specificity against ECM and non-ECM components. Known to be vital for tumor invasion and metastasis, accumulating evidence also implicates MMP-7 in cancer development. Using data from the Shanghai Breast Cancer Study, we conducted a two-stage study to evaluate the association of MMP-7 single nucleotide polymorphisms (SNPs) with breast cancer risk. Additionally, associated SNPs were characterized by laboratory assays. In stage 1, 11 SNPs were genotyped among 1,079 incident cases and 1,082 community controls using an Affymetrix Genotyping System. Promising SNPs were selected for stage 2 evaluation and genotyped by TaqMan allelic discrimination assays in an independent set of 1,911 cases and 1,811 controls. Three SNPs were selected for stage 2 validation (rs880197, rs10895304, and rs12184413); one had highly consistent results between the two stages of the study. In combined analysis, homozygosity for the variant T allele for rs12184413 was associated with an odds ratio (OR) of 0.7 [95% confidence interval (95% CI), 0.6-0.9] compared with the common C allele. This effect was slightly more pronounced in postmenopausal women (OR, 0.6; 95% CI, 0.4-0.8) than in premenopausal women (OR, 0.8; 95% CI, 0.6-1.1). This SNP is located 3' of the MMP-7 gene, in an area enriched with CTCF binding sites. In silico analysis suggested a regulatory role for this region, and our in vitro assays showed an allelic difference in nuclear protein binding capacity. Results from our study suggest that common MMP-7 genetic polymorphisms may contribute to breast cancer susceptibility.
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Affiliation(s)
- Alicia Beeghly-Fadiel
- Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee
| | - Ji-Rong Long
- Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee
| | - Yu-Tang Gao
- Department of Epidemiology, Shanghai Cancer Institute, Shanghai, China
| | - Chun Li
- Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee
| | - Shimian Qu
- Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee
| | - Qiuyin Cai
- Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee
| | - Ying Zheng
- Shanghai Center for Disease Prevention and Control, Shanghai, China
| | - Zhi-Xian Ruan
- Department of Epidemiology, Shanghai Cancer Institute, Shanghai, China
| | - Shawn E. Levy
- Department of Biomedical Informatics, Vanderbilt University School of Medicine, Nashville, Tennessee
| | - Sandra L. Deming
- Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee
| | - Jay R. Snoddy
- Department of Biomedical Informatics, Vanderbilt University School of Medicine, Nashville, Tennessee
| | - Xiao-ou Shu
- Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee
| | - Wei Lu
- Shanghai Center for Disease Prevention and Control, Shanghai, China
| | - Wei Zheng
- Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee
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Zheng HC, Tsuneyama K, Takahashi H, Miwa S, Sugiyama T, Popivanova BK, Fujii C, Nomoto K, Mukaida N, Takano Y. Aberrant Pim-3 expression is involved in gastric adenoma-adenocarcinoma sequence and cancer progression. J Cancer Res Clin Oncol 2008; 134:481-488. [PMID: 17876606 DOI: 10.1007/s00432-007-0310-1] [Citation(s) in RCA: 63] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2007] [Accepted: 08/28/2007] [Indexed: 12/14/2022]
Abstract
PURPOSE Pim-3, a member of the proto-oncogene Pim family with serine/threonine kinase activity was aberrantly expressed in cancerous lesions of endoderm-derived organs such as liver, pancreas, and colon. The aim of this study was to clarify the role of Pim-3 expression in the tumorigenesis and the development of gastric carcinomas. METHODS Pim-3 expression was immunohistochemically examined on the tissue microarrays containing primary (n = 285) and metastastic (n = 37) sites of gastric carcinomas, in comparison with adenoma (n = 48) and non-cancerous mucosa (n = 84). It was also compared with the clinicopathological parameters of gastric carcinomas. RESULTS Pim-3 expression was enhanced in adenoma (64.6%) and metastasis sites of gastric carcinoma (73.0%), to a lesser degree in primary sites of gastric carcinoma (39.3%) when compared to non-cancerous mucosa (13.1%, p < 0.0001). Pim-3 expression levels were higher in intestinal-type than diffuse-type gastric carcinoma (p = 0.018). Pim-3 expression was closely correlated with sex (p = 0.047), lymphatic (p = 0.019) and venous invasion (p = 0.014). Pim-3 expression was correlated significantly with vascular endothelial growth factor (VEGF, p = 0.009) and extracellular matrix metalloproteinase inducer (EMMPRIN, p = 0.032), both of which are presumed to be involved in neovascularization, a crucial step for metastasis. On the contrary, phosphatase and tensin homology deleted from human chromosome 10 (Pten) negative gastric carcinomas exhibited higher Pim-3 expression than Pten positive ones (p = 0.042). There was no relationship between Pim-3 expression and MVD in gastric carcinomas (p = 0.715). Furthermore, patients with Pim-3 positive gastric cancer, showed a lower cumulative survival rate than those with Pim-3 negative gastric cancer (p = 0.014) and Pim-3 positive was also identified as an independent prognostic factor for gastric carcinoma patients (p = 0.006). CONCLUSIONS Aberrant Pim-3 expression was involved in gastric adenoma-adenocarcinoma sequence and subsequent invasion and metastasis process in gastric cancer. Moreover, Pim-3 may be employed to predict the prognosis of gastric cancer patients. Distinct Pim-3 expression underlies the molecular mechanisms for the differentiation of intestinal-type and diffuse-type carcinomas.
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Affiliation(s)
- Hua-Chuan Zheng
- Department of Diagnostic Pathology, Graduate School of Medical and Pharmaceutical Sciences, University of Toyama, Toyama, 930-0194, Japan
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Low expression of FHIT and PTEN correlates with malignancy of gastric carcinomas: tissue-array findings. Appl Immunohistochem Mol Morphol 2008; 15:432-40. [PMID: 18091387 DOI: 10.1097/01.pai.0000213127.96590.2d] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
To clarify the roles of FHIT (fragile histidine triad) and PTEN (phosphatase and tensin homology deleted from human chromosome 10) expression in the genesis and progression of gastric cancers, we examined expression of FHIT and PTEN on tissue microarray containing gastric normal mucosa (n=49), adenoma (n=49), noncancerous mucosa adjacent to carcinoma (n=84) and carcinoma (n=249) by immunohistochemistry. Their expression was compared with clinicopathologic parameters of tumors, including expression of p53 and cysteine protease protein 32 as well as survival time of patients with carcinoma. The results showed expression of FHIT and PTEN were lower in gastric carcinoma than those in normal mucosa, noncancerous mucosa adjacent to carcinoma and adenoma of the stomach (P<0.05). FHIT and PTEN expression showed a significantly negative association with depth of invasion, lymphatic invasion, and lymph node metastasis, liver metastasis, and Union Internationale Contre le Cancer staging of gastric carcinoma (P<0.05). Intestinal-type gastric carcinomas highly expressed FHIT and PTEN protein, compared with diffuse-type ones (P<0.05). Expression of FHIT and PTEN were positively related with expression of p53 and cysteine protease protein 32 in gastric carcinoma (P<0.05), as well as favorable prognosis of the patients with the tumors (P<0.05). There was positive relationship between FHIT and PTEN expression in gastric carcinoma (P<0.05). It was suggested that down-regulated expression of FHIT and PTEN contributed to gastric carcinogenesis possibly by involving in the imbalance between apoptosis and proliferation of cells. Their altered expression underlay the molecular basis of invasion, metastasis, differentiation of gastric carcinoma.
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32
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Zheng HC, Takahashi H, Li XH, Hara T, Masuda S, Guan YF, Takano Y. Downregulated parafibromin expression is a promising marker for pathogenesis, invasion, metastasis and prognosis of gastric carcinomas. Virchows Arch 2007; 452:147-55. [PMID: 18080135 PMCID: PMC2233709 DOI: 10.1007/s00428-007-0551-z] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2007] [Revised: 11/09/2007] [Accepted: 11/10/2007] [Indexed: 11/21/2022]
Abstract
Parafibromin is a protein encoded by the hyperparathyroidism 2 oncosuppressor gene and its downregulated expression is involved in pathogenesis of parathyroid carcinomas. To clarify the roles of parafibromin expression in tumourigenesis and progression of gastric carcinomas, it was examined by immunohistochemistry (IHC) on tissue microarray containing gastric carcinomas (n = 508), adenomas (n = 45) and gastritis (n = 49) with a comparison of its expression with clinicopathological parametres of carcinomas. Gastric carcinoma cell lines (MKN28, AGS, MKN45, KATO-III and HGC-27) were studied for parafibromin expression by IHC and western blot. Parafibromin expression was localised in the nucleus of gastric epithelial cells, adenoma, carcinoma cells and cell lines. Its expression was gradually decreased from gastritis to gastric carcinoma, through gastric adenomas (p < 0.05) and inversely correlated with tumour size, depth of invasion, lymphatic invasion, lymph node metastasis and Union Internationale Contre le Cancer (UICC) staging (p < 0.05) but not with sex or venous invasion (p > 0.05). Parafibromin was strongly expressed in older carcinoma patients compared with younger ones (p < 0.05). There was stronger positivity of parafibromin in intestinal-type than diffuse-type carcinomas (p < 0.05). Univariate analysis indicated cumulative survival rate of patients with positive parafibromin expression to be higher than without its expression (p < 0.05). Multivariate analysis showed that age, tumour size, depth of invasion, lymphatic invasion, lymph node metastasis, UICC staging and Lauren’s classification but not sex, venous invasion or parafibromin expression were independent prognostic factors for carcinomas(p < 0.05). Downregulated parafibromin expression possibly contributed to pathogenesis, growth, invasion and metastasis of gastric carcinomas. It was considered as a promising marker to indicate the aggressive behaviours and prognosis of gastric carcinomas.
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Affiliation(s)
- Hua-Chuan Zheng
- Department of Biochemistry and Molecular Biology, College of Basic Medicine, China Medical University, Shenyang, China.
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Chang D, Wang TY, Li HC, Wei JC, Song JX. Prognostic significance of PTEN expression in esophageal squamous cell carcinoma from Linzhou City, a high incidence area of northern China. Dis Esophagus 2007; 20:491-6. [PMID: 17958724 DOI: 10.1111/j.1442-2050.2007.00695.x] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Decreased expression of tumor suppressor gene PTEN has been reported to be a poor prognostic indicator in a variety of human malignant tumors. The purpose of this study was to clarify the roles of PTEN in esophageal squamous cell carcinoma (ESCC) and the prognostic significance of PTEN protein expression. Sixty-four patients from a high incidence area of northern China who underwent esophagectomy for ESCC between January 1998 and December 1999 enrolled in this study. PTEN expression was assessed by immunohistochemistry in 64 primary cancers and 64 paired normal esophageal epithelium tissues. The positive rate and staining grade of PTEN protein expression was lower in the esophageal cancers than in paired adjacent normal esophageal epithelium (P < 0.001). PTEN expression correlated with tumor differentiation (P = 0.001), tumor infiltration depth (P = 0.015) and pTNM staging (P = 0.048). The 5-year survival rate in patients with PTEN positive expression was 82% compared to 39% in patients with PTEN negative expression (P = 0.0019). Our results show that the expression of PTEN is decreased in ESCC compared to normal esophageal epithelium. Therefore, PTEN may play an important role in carcinogenesis and the progression of ESCC in a high incidence area of northern China, and PTEN could serve as an important factor to predict clinical outcome and prognosis.
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Affiliation(s)
- D Chang
- Department of Thoracic Surgery, Beijing Friendship Hospital, Capital Medical University, Beijing, China.
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Oh JH, Kim A, Park JM, Kim SH, Chung AS. Ultraviolet B-induced matrix metalloproteinase-1 and -3 secretions are mediated via PTEN/Akt pathway in human dermal fibroblasts. J Cell Physiol 2007; 209:775-85. [PMID: 16972255 DOI: 10.1002/jcp.20754] [Citation(s) in RCA: 43] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
Matrix Metalloproteinases (MMPs) are crucial enzymes for ultraviolet irradiation-induced photoaging in human skin. Ultraviolet B (UVB) stimulates dermal fibroblasts to increase MMP-1 and -3 expression and extracellular matrix (ECM) degradation in photoaging. We investigated whether phosphatase and tensin homolog (PTEN)/Akt pathway is involved in secretions of MMP-1 and -3 in human dermal fibroblasts. The increase in MMP-1 and -3 expression and secretion occurred along with the increase in PTEN and Akt phosphorylation by UVB irradiation in a dose- and time-dependent manner. However, treatment with a casein kinase 2 inhibitor, 5,6-dichloro-1-beta-D-ribofuranosyl-benzimidazole, inhibited their phosphorylations and MMP-1 and -3 secretions. Transfection of wild-type PTEN (Wt-PTEN) decreased basal and UVB-induced MMP-1 and -3 secretions, as well as activator protein-1 (AP-1) activity, while transfection of small interference RNA of PTEN (siRNA-PTEN), phosphatase-inactive PTEN (C124S-PTEN), or lipid phosphatase-inactive PTEN (G129E-PTEN) increased basal or UVB-induced MMP-1 and -3 secretions and AP-1 activity. Transfection of constitutively active Akt (Myr-Akt) also increased basal or UVB-induced MMP-1 and -3 secretions, as well as AP-1 activity. However, transfection of kinase-inactive Akt (K179M-Akt) decreased their secretions, but showed no significant change of AP-1 activity without UVB irradiation, and a significant increase of AP-1 activity with UVB irradiation. Treatment with the phosphatidylinositol 3-kinase inhibitors, LY294002 or wortmannin, downregulated basal and UVB-induced MMP-1 and -3 secretions. In conclusion, UVB irradiation increases PTEN and Akt phosphorylation in human dermal fibroblasts, and these inhibition of PTEN and activation of Akt by phosphorylation are involved in UVB-induced MMP-1 and -3 secretions partly through upregulation of AP-1 activity.
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Affiliation(s)
- Jang-Hee Oh
- Department of Biological Sciences, Korea Advanced Institute of Science and Technology, 373-1 Guseong-dong, Yuseong-gu, Daejeon 305-701, South Korea
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Zheng H, Takahashi H, Murai Y, Cui Z, Nomoto K, Miwa S, Tsuneyama K, Takano Y. Pathobiological characteristics of intestinal and diffuse-type gastric carcinoma in Japan: an immunostaining study on the tissue microarray. J Clin Pathol 2006; 60:273-7. [PMID: 16714395 PMCID: PMC1860577 DOI: 10.1136/jcp.2006.038778] [Citation(s) in RCA: 117] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
AIM To investigate the pathobiological features of intestinal and diffuse-type gastric carcinomas in the Japanese population. METHODS The expression of fragile histine triad (FHIT), phosphatase and tensin homology deleted from human chromosome 10 (PTEN), caspase-3, Ki-67, mutant p53, matrix metalloproteinase (MMP)-2, MMP-9, and extracellular matrix metalloproteinase inducer (EMMPRIN) on tissue microarrays of gastric carcinomas by immunostaining was examined in comparison with the clinicopathological characteristics between intestinal and diffuse-type cases. RESULTS Intestinal-type carcinoma frequently occurred in old men, whereas the diffuse type comparatively occurred more in young women (p<0.05). The diffuse-type carcinoma was more inclined to invasion into muscularis propria, lymphatic invasion and lymph node metastasis, and belonged to higher International Union against Cancer (UICC) staging (p<0.05) compared with intestinal-type counterparts. Expression of FHIT, PTEN, Ki-67, caspase-3, mutant p53 and EMPPRIN was higher in intestinal-type carcinomas than in diffuse-type carcinomas (p<0.05). Kaplan-Meier analysis indicated that patients with intestinal-type carcinomas had a higher cumulative survival rate (p<0.05). CONCLUSION Intestinal-type gastric carcinomas with a more favourable prognosis frequently show high levels of proliferation and apoptosis, and always accompany strong expression of FHIT, PTEN and mutant p53 and EMMPRIN. EMMPRIN expression might underlie the molecular basis of liver metastasis and higher proliferation of intestinal-type gastric carcinomas in Japan. Lauren's classification thus proved pathologically relevant for the clinical treatment of gastric carcinomas.
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Affiliation(s)
- Huachuan Zheng
- Department of Pathology School of Medicine, University of Toyama, Toyama, Japan.
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Zheng H, Tsuneyama K, Cheng C, Takahashi H, Cui Z, Nomoto K, Murai Y, Takano Y. Expression of KAI1 and tenascin, and microvessel density are closely correlated with liver metastasis of gastrointestinal adenocarcinoma. J Clin Pathol 2006; 60:50-6. [PMID: 16698949 PMCID: PMC1860584 DOI: 10.1136/jcp.2006.036699] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Abstract
AIM To seek good markers to predict invasion and metastasis of gastrointestinal adenocarcinoma (GIA). METHODS Expression of KAI1 and tenascin were examined on tissue microarrays containing gastric adenocarcinoma (n = 98), colorectal adenocarcinoma (n = 125), gastric adjacent non-cancerous mucosa (n = 95) and colorectal adjacent non-cancerous mucosa (n = 112) by immunostaining. Microvessel density (MVD) in GIA was labelled using anti-CD34 antibody by immunostaining. Expression of KAI1 and tenascin, and MVD were compared with clinicopathological features of tumours, including PTEN (phosphatase and tensin homology deleted from human chromosome 10) and EMMPRIN (extracellular matrix metalloproteinase inducer) expression. RESULTS KAI1 expression was higher in GIAs than in their adjacent non-cancerous mucosa (p<0.05). KAI1 and tenascin expression showed a significantly negative association with liver metastasis of GIA (p<0.05), but not with depth of invasion, venous invasion or lymph node metastasis (p>0.05). A significantly negative relationship was observed between EMMPRIN and tenascin expression in GIA (p<0.05). MVD was positively correlated with depth of invasion, venous invasion, lymph node metastasis and liver metastasis of tumours (p<0.05), whereas it was negatively correlated with PTEN expression (p<0.05). CONCLUSIONS Up-regulated KAI1 expression may play an important part in malignant transformation of gastrointestinal epithelial cells. Reduced expression of KAI1 and tenascin might underlie the molecular basis of liver metastasis of GIA. Angiogenesis is a key event in the invasion and metastasis of GIA. These markers might be used to indicate liver metastasis of GIA in clinicopathological practice.
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Affiliation(s)
- Huachuan Zheng
- Department of Pathology, Faculty of Medicine, University of Toyama, Toyama, Japan
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Elsamman E, Fukumori T, Ewis AA, Ali N, Kajimoto K, Shinohara Y, Ishikawa M, Takahashi M, Nishitani MA, Baba Y, Kanayama HO. Differences in gene expression between noninvasive and invasive transitional cell carcinoma of the human bladder using complementary deoxyribonucleic acid microarray: Preliminary results. Urol Oncol 2006; 24:109-15. [PMID: 16520272 DOI: 10.1016/j.urolonc.2005.07.011] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2005] [Revised: 07/23/2005] [Accepted: 07/25/2005] [Indexed: 11/15/2022]
Abstract
This study was performed to identify differences in gene expression between superficial noninvasive and invasive transitional cell carcinoma (TCC) of the bladder in human beings. We used complementary deoxyribonucleic acid microarrays containing 14,551 different genes to analyze gene expression among 6 cases of superficial and 6 cases of invasive TCC of the bladder to identify differences in gene expression, which might explain differences in the biology and clinical outcomes of these histologic subtypes of TCC. Quantitative real-time polymerase chain reaction was performed for selected genes to validate the microarray data. Significant up-regulation of 40 genes was associated with cases of superficial noninvasive, but not in invasive, TCC of the urinary bladder. This effect included genes involved in epithelial cell dedifferentiation and keratinization, as well as genes related to cell cycle, cell adhesion, transcription, and apoptosis. Conversely, significant up-regulation of 34 genes was associated with cases of invasive TCC, but not in superficial TCC, including genes related to extracellular matrix degradation, immune responses, cell cycling, and angiogenesis. This study shows the usefulness of complementary deoxyribonucleic acid microarray technology for identifying differences in gene expression among different histotypes of bladder cancer.
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Affiliation(s)
- Essam Elsamman
- Department of Urology, The University of Tokushima School of Medicine, Tokushima, Japan
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Jung Y, Bang S, Choi K, Kim E, Kim Y, Kim J, Park J, Koo H, Moon RT, Song K, Lee I. TC1 (C8orf4) enhances the Wnt/beta-catenin pathway by relieving antagonistic activity of Chibby. Cancer Res 2006; 66:723-8. [PMID: 16424001 DOI: 10.1158/0008-5472.can-05-3124] [Citation(s) in RCA: 47] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
The Wnt/beta-catenin pathway has been implicated in human cancers. Here, we show that TC1 (C8orf4), a small protein present in vertebrates, functions as a positive regulator of the pathway. TC1 interacts with Chibby (Cby) and thereby enhances the signaling pathway by relieving the antagonistic function of Cby on the beta-catenin-mediated transcription. Upon coexpression in mammalian cells, TC1 redistributes from nucleolus to nuclear speckles, where it colocalizes with Cby. TC1 up-regulates the expression of beta-catenin target genes that are implicated in invasiveness and aggressive behavior of cancers, such as metalloproteinases, laminin gamma2, and others. Our data indicate that TC1 is a novel upstream regulator of the Wnt/beta-catenin pathway that enhances aggressive behavior of cancers.
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Affiliation(s)
- Yusun Jung
- Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, 388-1 Poongnap-Dong, Songpa-Gu, Seoul 138-736, Korea
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Ii M, Yamamoto H, Adachi Y, Maruyama Y, Shinomura Y. Role of matrix metalloproteinase-7 (matrilysin) in human cancer invasion, apoptosis, growth, and angiogenesis. Exp Biol Med (Maywood) 2006; 231:20-27. [PMID: 16380641 DOI: 10.1177/153537020623100103] [Citation(s) in RCA: 308] [Impact Index Per Article: 16.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Matrix metalloproteinase (MMP)-7, also known as matrilysin, is a "minimal domain MMP" that exhibits proteolytic activity against components of the extracellular matrix (ECM). Matrilysin is frequently overexpressed in human cancer tissues and is associated with cancer progression. Tumorigenesis is a multistep process involving cell growth, invasion, metastasis, and angiogenesis. Matrilysin has been shown to play important roles not only in degradation of ECM proteins, but also in the regulation of several biochemical processes such as activation, degradation, and shedding of non-ECM proteins. This minire-view provides a summary of the current literature on the roles of matrilysin in tumorigenesis with a focus on the roles of modifications of non-ECM proteins by matrilysin and other related MMPs in tumorigenesis. Proteolysis of insulin-like growth factor binding protein by matrilysin results in increased bioavailability of insulin-like growth factors and enhanced cellular proliferation. Matrilysin has also been implicated in the ectodomain shedding of several cell surface molecules. Heparin-binding epidermal growth factor precursor (proHB-EGF) is cleaved by matrilysin into mature HB-EGF, which promotes cellular proliferation. Membrane-bound Fas ligand (FasL) is cleaved into soluble FasL, which increases apoptosis of cells adjacent to tumor cells. E-cadherin is converted to soluble E-cadherin to promote invasion. Tumor necrosis factor (TNF)-alpha precursor is cleaved to release soluble TNF-alpha to increase apoptosis. We propose that these matrilysin-mediated pathways provide the necessary and logical mechanisms to promote cancer progression.
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Affiliation(s)
- Masanori Ii
- First Department of Internal Medicine, Sapporo Medical University, School of Medicine, South-1, West-16, Chuo-ku, Sapporo 060-8543, Japan.
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Doucas H, Garcea G, Neal CP, Manson MM, Berry DP. Changes in the Wnt signalling pathway in gastrointestinal cancers and their prognostic significance. Eur J Cancer 2005; 41:365-79. [PMID: 15691635 DOI: 10.1016/j.ejca.2004.11.005] [Citation(s) in RCA: 60] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2004] [Revised: 10/08/2004] [Accepted: 11/12/2004] [Indexed: 12/24/2022]
Abstract
Many steps in the Wnt signalling pathway may be altered during the process of carcinogenesis. This Review focuses on the changes observed in gastrointestinal cancers. A literature search was undertaken and the currently available data summarised. Understanding the alterations to this signalling pathway may help to reveal future targets for therapeutic agents. In addition, since in some tumours, levels of components of the Wnt pathway have been found to correlate with clinical stage, their potential use as prognostic indicators is highlighted.
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Affiliation(s)
- H Doucas
- Department of Cancer Biomarkers and Prevention Group, Biocentre, Leicester LE1 7RH, UK.
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Akahane T, Akahane M, Shah A, Connor CM, Thorgeirsson UP. TIMP-1 inhibits microvascular endothelial cell migration by MMP-dependent and MMP-independent mechanisms. Exp Cell Res 2005; 301:158-67. [PMID: 15530852 DOI: 10.1016/j.yexcr.2004.08.002] [Citation(s) in RCA: 81] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2004] [Revised: 08/03/2004] [Indexed: 11/19/2022]
Abstract
It was reported over a decade ago that tissue inhibitor of metalloproteinases-1 (TIMP-1) suppresses angiogenesis in experimental models but the mechanism is still incompletely understood. This in vitro study focused on the molecular basis of TIMP-1-mediated inhibition of endothelial cell (EC) migration, a key step in the angiogenic process. Both recombinant human TIMP-1 and the synthetic MMP inhibitors, GM6001 and MMP-2-MMP-9 Inhibitor III, suppressed migration of human dermal microvascular endothelial cells (HDMVEC) in a dose-dependent fashion. The MMP-dependent inhibition of migration was associated with increased expression of the junctional adhesion proteins, VE-cadherin and PECAM-1, and VE-cadherin accumulation at cell-cell junctions. TIMP-1 also caused MMP-independent dephosphorylation of focal adhesion kinase (FAK) (pY397) and paxillin, which was associated with reduced number of F-actin stress fibers and focal adhesions. Moreover, TIMP-1 stimulated expression of PTEN that has been shown to reduce phosphorylation of FAK and inhibit cell migration. Our data suggest that TIMP-1 inhibits HDMVEC migration through MMP-dependent stimulation of VE-cadherin and MMP-independent stimulation of PTEN with subsequent dephosphorylation of FAK and cytoskeletal remodeling.
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Affiliation(s)
- Takemi Akahane
- Laboratory of Cellular Carcinogenesis and Tumor Promotion, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-4255, USA
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Liao XF, Yi JL, Li XR, Deng W, Yang ZF, Tian G. Angiogenesis in rabbit hepatic tumor after transcatheter arterial embolization. World J Gastroenterol 2004; 10:1885-9. [PMID: 15222029 PMCID: PMC4572223 DOI: 10.3748/wjg.v10.i13.1885] [Citation(s) in RCA: 32] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
AIM: To investigate the effect of transcatheter arterial embolization (TAE) on angiogenesis of hepatic tumor.
METHODS: Twenty New Zealand White rabbits were randomly divided into two groups of 10 each and VX2 carcinoma was implanted in the left medial lobes of the livers. Fourteen days later, a silicon catheter was inserted into the left hepatic artery of rabbit with VX2 hepatic tumor and infusion was performed via the hepatic artery using Lipiodol (the TAE group) or saline (the control group). Rabbits were sacrificed 7 d after treatment and tumor tissues were excised. Expression of vascular endothelial growth factor (VEGF) protein and microvessel density (MVD) of tumors were examined using immunohistochemistry. The staining intensity of VEGF was evaluated with a computer-assisted image-analyzer. Reverse transcription-polymerase chain reaction (RT-PCR) was used to detect the VEGF mRNA expression of tumors.
RESULTS: MVD was higher in the TAE group compared with the control group (28.6 ± 10.6 vs 16.3 ± 6.9, P < 0.01). Expression of VEGF protein was enhanced after TAE. The staining intensity of VEGF in the TAE group was 0.162 ± 0.018, significantly higher than in the control group (0.142 ± 0.01, P < 0.01). At mRNA level, VEGF165 mRNA was significantly higher in the TAE group compared with the control group (2.58 ± 0.42 vs 1.99 ± 0.21, P < 0.001). MVD was well correlated to VEGF expression in both the TAE group (r = 0.69, P < 0.05) and the control group (r = 0.72, P < 0.05).
CONCLUSION: TAE promotes the development of neovascularization of residual tumors through up-regulation of VEGF expression, possibly due to hypoxic insult.
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Affiliation(s)
- Xiao-Feng Liao
- Department of General Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China.
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