|
1
|
Guo W, Hu L, Gao Z, Liu X, Yang X, Wang X. The up-regulation of SPTAN1 expression in Pancreatic adenocarcinoma is associated with tumor immune invasion and poor clinical prognosis. BMC Gastroenterol 2025; 25:5. [PMID: 39762747 PMCID: PMC11706198 DOI: 10.1186/s12876-024-03581-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/05/2024] [Accepted: 12/27/2024] [Indexed: 01/11/2025] Open
Abstract
BACKGROUND Pancreatic adenocarcinoma (PAAD) is a common malignancy with a very low survival rate. More and more studies have shown that SPTAN1 may be involved in the development and progression of a variety of tumors, including rectal cancer, Pancreatic adenocarcinoma, etc., and may affect their prognosis. METHODS Bioinformatics technology was used to analyze the relationship between SPTAN1 expression in PAAD and immune cell infiltration, immune regulatory factors and chemokines, and cell experiments were used to verify the relationship between SPTAN1 knock down and migration, invasion, apoptosis and cycle changes of PAAD cell lines. In addition, immunohistochemical staining of SPTAN1 was performed by tissue microarray (TMA) to study the relationship between high expression of SPTAN1 and clinicopathological features and overall survival rate. RESULTS The expression of SPTAN1 is significantly correlated with immune cell infiltration, immunomodulators, chemokines and their receptors. In addition, it was found that the knock-down of SPTAN1 inhibited the migration and invasion ability of PAAD cell lines, promoted the apoptosis of cell lines, and also affected the changes of cell cycle. Immunohistochemical staining using tissue microarray (TMA) showed that the high expression of SPTAN1 was associated with M stage (P = 0.004) and CA199 (P = 0.012), and the overall survival rate of the high expression group was significantly lower than that of the low expression group (P = 0.043). CONCLUSION Our results suggest that up-regulation of SPTAN1 is related to cell migration, invasion, apoptosis and cycle changes, and is associated with tumor immune invasion and poor prognosis of PAAD.
Collapse
Affiliation(s)
- Wei Guo
- Department of Interventional Vascular Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University, Shanghai, 200082, China
| | - LingYu Hu
- Department of General Surgery, The Second Affiliated Hospital of Jiaxing University, Zhejiang Province, Jiaxing, 314000, China
| | - ZhaoFeng Gao
- Department of General Surgery, The Second Affiliated Hospital of Jiaxing University, Zhejiang Province, Jiaxing, 314000, China
| | - XiaoRong Liu
- Department of General Surgery, The Second Affiliated Hospital of Jiaxing University, Zhejiang Province, Jiaxing, 314000, China
| | - XiaoDan Yang
- Department of General Surgery, The Second Affiliated Hospital of Jiaxing University, Zhejiang Province, Jiaxing, 314000, China.
| | - XiaoGuang Wang
- Department of General Surgery, The Second Affiliated Hospital of Jiaxing University, Zhejiang Province, Jiaxing, 314000, China.
| |
Collapse
|
|
2
|
Abstract
Osteopontin (OPN) is a heavily post-translationally modified protein with a molecular weight of 44-70 kDa, depending on the degree of glycosylation. OPN is involved in various biological processes, including bone remodeling, immune response, cell adhesion, migration, and survival. It is essential for controlling osteoclast and osteoblast activity for maintaining bone mass and bone strength. Additionally, OPN has been linked to cardiovascular, inflammatory illnesses, as well as the onset and progression of cancer. OPN is a multifunctional protein that can interact with a variety of cell surface receptors, such as integrins, CD44, the urokinase-type plasminogen activator receptor (uPAR), as well as extracellular matrix (ECM) components (e.g. collagen and hydroxyapatite). These interactions contribute to its wide range of biological functions in general and has significant implications for bone biology, immunology and cancer, specifically. In this chapter, we summarize the structure of OPN with a focus on its molecular mechanisms of action in various cancers.
Collapse
Affiliation(s)
- Alpana Kumari
- Department of Optometry, University Institute of Allied Health Sciences, Chandigarh University, Gharuan, Mohali, Punjab, India
| | - Dharambir Kashyap
- Department of Medicine, The Brown Centre for Immunotherapy, Melvin and Bren Simon Comprehensive Cancer Center, Indiana University School of Medicine, Indianapolis, IN, United States
| | - Vivek Kumar Garg
- Department of Medical Lab Technology, University Institute of Allied Health Sciences, Chandigarh University, Gharuan, Mohali, Punjab, India.
| |
Collapse
|
|
3
|
Chen Y, Yuan H, Yu Q, Pang J, Sheng M, Tang W. Bioinformatics Analysis and Structure of Gastric Cancer Prognosis Model Based on Lipid Metabolism and Immune Microenvironment. Genes (Basel) 2022; 13:genes13091581. [PMID: 36140749 PMCID: PMC9498347 DOI: 10.3390/genes13091581] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2022] [Revised: 08/28/2022] [Accepted: 08/31/2022] [Indexed: 12/24/2022] Open
Abstract
OBJECTIVES The reprogramming of lipid metabolism is a new trait of cancers. However, the role of lipid metabolism in the tumor immune microenvironment (TIME) and the prognosis of gastric cancer remains unclear. METHODS Consensus clustering was applied to identify novel subgroups. ESTIMATE, TIMER, and MCPcounter algorithms were used to determine the TIME of the subgroups. The underlying mechanisms were elucidated using functional analysis. The prognostic model was established using the LASSO algorithm and multivariate Cox regression analysis. RESULTS Three molecular subgroups with significantly different survival were identified. The subgroup with relatively low lipid metabolic expression had a lower immune score and immune cells. The differentially expressed genes (DEGs) were concentrated in immune biological processes and cell migration via GO and KEGG analyses. GSEA analysis showed that the subgroups were mainly enriched in arachidonic acid metabolism. Gastric cancer survival can be predicted using risk models based on lipid metabolism genes. CONCLUSIONS The TIME of gastric cancer patients is related to the expression of lipid metabolism genes and could be used to predict cancer prognosis accurately.
Collapse
|
|
4
|
Identification of early diagnostic biomarkers via WGCNA in gastric cancer. Biomed Pharmacother 2021; 145:112477. [PMID: 34864309 DOI: 10.1016/j.biopha.2021.112477] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2021] [Revised: 11/14/2021] [Accepted: 11/23/2021] [Indexed: 01/11/2023] Open
Abstract
BACKGROUND Gastric cancer (GC) is the world's second-leading cause of cancer-related mortality, continuing to make it a serious healthcare concern. Even though the prevalence of GC reduces, the prognosis for GC patients remains poor in terms of a lack of reliable biomarkers to diagnose early GC and predict chemosensitivity and recurrence. METHODS AND MATERIAL We integrated the gene expression patterns of gastric cancers from four RNAseq datasets (GSE113255, GSE142000, GSE118897, and GSE130823) from Gene Expression Omnibus (GEO) database to recognize differentially expressed genes (DEGs) between normal and GC samples. A gene co-expression network was built using weighted co-expression network analysis (WGCNA). Furthermore, RT-qPCR was performed to validate the in silico results. RESULTS The red modules in GSE113255, Turquoise in GSE142000, Brown in GSE118897, and the green-yellow module in GSE130823 datasets were found to be highly correlated with the anatomical site of GC. ITGAX, CCL14, ADHFE1, and HOXB13) as the hub gene are differentially expressed in tumor and non-tumor gastric tissues in this study. RT-qPCR demonstrated a high level of the expression of this gene. CONCLUSION The expression levels of ITGAX, CCL14, ADHFE1, and HOXB13 in GC tumor tissues are considerably greater than in adjacent normal tissues. Systems biology approaches identified that these genes could be possible GC marker genes, providing ideas for other experimental studies in the future.
Collapse
|
|
5
|
Schrecker C, Behrens S, Schönherr R, Ackermann A, Pauli D, Plotz G, Zeuzem S, Brieger A. SPTAN1 Expression Predicts Treatment and Survival Outcomes in Colorectal Cancer. Cancers (Basel) 2021; 13:cancers13143638. [PMID: 34298848 PMCID: PMC8305611 DOI: 10.3390/cancers13143638] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2021] [Revised: 07/07/2021] [Accepted: 07/15/2021] [Indexed: 12/24/2022] Open
Abstract
Simple Summary Colorectal cancer (CRC) is a common and deadly form of cancer. Non-erythroid spectrin αII (SPTAN1), a protein of the cytoskeleton, is thought to be involved in CRC development and progression. In this study, we explore whether measuring SPTAN1 levels in resected CRC specimens might help to predict patient survival outcomes and response to chemotherapy. Indeed, we find that higher SPTAN1 protein and mRNA levels in CRC specimens associate with longer patient survival times. Using cell culture experiments, we then show that cells with lower SPTAN1 levels are less susceptible to FOLFOX chemotherapy, a standard treatment regimen for patients with CRC. Overall, our study underscores the importance of cytoskeletal proteins in shaping tumour biology and treatment responses and nominates SPTAN1 as a biomarker to improve patient stratification and refine therapeutic decisions in CRC. Abstract Colorectal cancer (CRC) is a leading cause of cancer-related morbidity and mortality. In a cohort of 189 patients with CRC, we recently showed that expression of the cytoskeletal scaffolding protein non-erythroid spectrin αII (SPTAN1) was lower in advanced metastatic tumours. The aim of the present study was to clarify the association of intratumoural SPTAN1 expression levels with treatment and survival outcomes in patients with CRC. The analysis was based on histologic assessment of SPTAN1 protein levels in our own CRC cohort, and transcriptome data of 573 CRC cases from The Cancer Genome Atlas (TCGA). We first establish that high intratumoural levels of SPTAN1 protein and mRNA associate with favourable survival outcomes in patients with CRC. Next, a response prediction signature applied to the TCGA data reveals a possible link between high SPTAN1 transcript levels and improved patient responses to FOLFOX chemotherapy. Complementary in vitro experiments confirm that SPTAN1 knockdown strains of the colon cancer cell lines HT-29, HCT116 mlh1-2 and Caco-2 are less responsive to FOLFOX chemotherapy compared with SPTAN1-proficient control strains. Taken together, we identify SPTAN1 as a novel prognostic biomarker in CRC and show that SPTAN1 expression levels may predict patient responses to chemotherapy. These investigations illustrate how an affordable, histology-based diagnostic test could directly impact therapeutic decision-making at the bedside.
Collapse
Affiliation(s)
- Christopher Schrecker
- Department of Medicine, Biomedical Research Laboratory, University Hospital Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany; (S.B.); (R.S.); (A.A.); (D.P.); (G.P.); (S.Z.)
- Correspondence: (C.S.); (A.B.); Tel.: +49-69-6301-6218 (A.B.)
| | - Sophia Behrens
- Department of Medicine, Biomedical Research Laboratory, University Hospital Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany; (S.B.); (R.S.); (A.A.); (D.P.); (G.P.); (S.Z.)
| | - Rebecca Schönherr
- Department of Medicine, Biomedical Research Laboratory, University Hospital Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany; (S.B.); (R.S.); (A.A.); (D.P.); (G.P.); (S.Z.)
- Faculty of Medicine, Paracelsus Medical University, Strubergasse 21, 5020 Salzburg, Austria
| | - Anne Ackermann
- Department of Medicine, Biomedical Research Laboratory, University Hospital Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany; (S.B.); (R.S.); (A.A.); (D.P.); (G.P.); (S.Z.)
| | - Daniel Pauli
- Department of Medicine, Biomedical Research Laboratory, University Hospital Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany; (S.B.); (R.S.); (A.A.); (D.P.); (G.P.); (S.Z.)
| | - Guido Plotz
- Department of Medicine, Biomedical Research Laboratory, University Hospital Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany; (S.B.); (R.S.); (A.A.); (D.P.); (G.P.); (S.Z.)
| | - Stefan Zeuzem
- Department of Medicine, Biomedical Research Laboratory, University Hospital Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany; (S.B.); (R.S.); (A.A.); (D.P.); (G.P.); (S.Z.)
| | - Angela Brieger
- Department of Medicine, Biomedical Research Laboratory, University Hospital Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany; (S.B.); (R.S.); (A.A.); (D.P.); (G.P.); (S.Z.)
- Correspondence: (C.S.); (A.B.); Tel.: +49-69-6301-6218 (A.B.)
| |
Collapse
|
|
6
|
Tumor Tissue Oxidative Stress Changes and Na, K-ATPase Evaluation in Head and Neck Squamous Cell Carcinoma. J Membr Biol 2021; 254:475-486. [PMID: 34104985 DOI: 10.1007/s00232-021-00185-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2021] [Accepted: 05/08/2021] [Indexed: 10/21/2022]
Abstract
Changes in metabolism are mechanisms that are largely implicated in the development, progression, and metastasis of head and neck squamous cell carcinoma (HNSCC) and also in resistance to different anticancer therapies. Identification of biomarkers for differentiation between cancerous and normal epithelium, treatment design and prognosis remain a vital issue in the field of head and neck cancer. The present study analyzed the main biochemical changes that occur in HNSCC tumors by through mechanisms involving oxidative stress. The release of substances reactive to thiobarbituric acid was significantly lower in HNSCC tumor tissue as compared to healthy tissue. The assays related to the lipid profile assays showed changes in membrane biophysics of tumor cells due to an increase in total phospholipids and total cholesterol, as well as an increased activity and expression of the α1 subunit of Na, K-ATPase, which is fundamental in the process of carcinogenesis. The modulation of the antioxidant system was also affected, with a decrease in the catalytic activity of the enzymes superoxide dismutase (SOD) and glutathione peroxidase (GPx), as well as a reduction of glutathione (GSH) content and an increase in H2O2 content. A reduction in catalase (CAT) activity was observed. The data presented here are in accordance with important findings described by us in a previous study, involving the same individuals, but with a focus on the damage generated in red blood cells, resulting from tumor installation. Therefore, it was possible to conclude that the biochemical alterations found in HNSCC cells are fundamental for transformation and maintenance of the tumor cell and once it is installed, it is also capable of generating injuries in the patients' red blood cells. Our data demonstrate that this could be a promising biomarker for HNSCC.
Collapse
|
|
7
|
Wei Q, Geng J, Chen Y, Lin H, Wang J, Fang Z, Wang F, Zhang Z. Structure and function of DEAH-box helicase 32 and its role in cancer. Oncol Lett 2021; 21:382. [PMID: 33777205 PMCID: PMC7988694 DOI: 10.3892/ol.2021.12643] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2020] [Accepted: 12/23/2020] [Indexed: 11/06/2022] Open
Abstract
DEAH-box helicase 32 (DHX32) is an RNA helicase with unique structural characteristics that is involved in numerous biological processes associated with RNA, including ribosome biosynthesis, transcription, mRNA splicing and translation. Increasing evidence suggests that abnormal DHX32 expression contributes to cancer initiation and development, due to dysregulated cell proliferation, differentiation, apoptosis and other processes. In the current review, the discovery, structure and function of DHX32, as well as the association between abnormal DHX32 expression and tumors are discussed. DHX32 expression is downregulated in acute lymphoblastic leukemia, but upregulated in solid tumors, including colorectal and breast cancer. Furthermore, DHX32 expression levels are associated with the pathological and clinical features of the cancer. Therefore, DHX32 may serve as a novel liquid biopsy marker for auxiliary diagnosis and prognosis screening, as well as a possible target for cancer therapy. The molecular mechanism underlying the contribution of DHX32 towards the initiation and development of cancer requires further investigation for the development of anticancer treatments based on manipulating DHX32 expression and function.
Collapse
Affiliation(s)
- Qingchun Wei
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, Xiamen, Fujian 361102, P.R. China
| | - Jinting Geng
- Xiamen Key Laboratory of Biomarker Translational Medicine, Center of Medical Laboratory of Xiamen Humanity Hospital, Fujian Medical University, Xiamen, Fujian 361009, P.R. China
| | - Yongquan Chen
- Xiamen Key Laboratory of Biomarker Translational Medicine, Center of Medical Laboratory of Xiamen Humanity Hospital, Fujian Medical University, Xiamen, Fujian 361009, P.R. China
| | - Huayue Lin
- Center of Clinical Laboratory, Xiamen University Affiliated Zhongshan Hospital, Xiamen, Fujian 361104, P.R. China
| | - Jiajia Wang
- Center of Clinical Laboratory, Xiamen University Affiliated Zhongshan Hospital, Xiamen, Fujian 361104, P.R. China
| | - Zanxi Fang
- Center of Clinical Laboratory, Xiamen University Affiliated Zhongshan Hospital, Xiamen, Fujian 361104, P.R. China
| | - Fen Wang
- Center for Cancer and Stem Cell Biology, Institute of Biosciences and Technology, Texas A&M Health Science Center, Houston, TX 77030, USA
| | - Zhongying Zhang
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, Xiamen, Fujian 361102, P.R. China
- Xiamen Key Laboratory of Biomarker Translational Medicine, Center of Medical Laboratory of Xiamen Humanity Hospital, Fujian Medical University, Xiamen, Fujian 361009, P.R. China
| |
Collapse
|
|
8
|
Abstract
Fodrin and its erythroid cell-specific isoform spectrin are actin-associated fibrous proteins that play crucial roles in the maintenance of structural integrity in mammalian cells, which is necessary for proper cell function. Normal cell morphology is altered in diseases such as various cancers and certain neuronal disorders. Fodrin and spectrin are two-chain (αβ) molecules that are encoded by paralogous genes and share many features but also demonstrate certain differences. Fodrin (in humans, typically a heterodimer of the products of the SPTAN1 and SPTBN1 genes) is expressed in nearly all cell types and is especially abundant in neuronal tissues, whereas spectrin (in humans, a heterodimer of the products of the SPTA1 and SPTB1 genes) is expressed almost exclusively in erythrocytes. To fulfill a role in such a variety of different cell types, it was anticipated that fodrin would need to be a more versatile scaffold than spectrin. Indeed, as summarized here, domains unique to fodrin and its regulation by Ca2+, calmodulin, and a variety of posttranslational modifications (PTMs) endow fodrin with additional specific functions. However, how fodrin structural variations and misregulated PTMs may contribute to the etiology of various cancers and neurodegenerative diseases needs to be further investigated.
Collapse
|
|
9
|
The Role of Nonerythroid Spectrin αII in Cancer. JOURNAL OF ONCOLOGY 2019; 2019:7079604. [PMID: 31186638 PMCID: PMC6521328 DOI: 10.1155/2019/7079604] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/18/2019] [Revised: 04/05/2019] [Accepted: 04/09/2019] [Indexed: 12/18/2022]
Abstract
Nonerythroid spectrin αII (SPTAN1) is an important cytoskeletal protein that ensures vital cellular properties including polarity and cell stabilization. In addition, it is involved in cell adhesion, cell-cell contact, and apoptosis. The detection of altered expression of SPTAN1 in tumors indicates that SPTAN1 might be involved in the development and progression of cancer. SPTAN1 has been described in cancer and therapy response and proposed as a potential marker protein for neoplasia, tumor aggressiveness, and therapeutic efficiency. On one hand, the existing data suggest that overexpression of SPTAN1 in tumor cells reflects neoplastic and tumor promoting activity. On the other hand, nuclear SPTAN1 can have tumor suppressing effects by enabling DNA repair through interaction with DNA repair proteins. Moreover, SPTAN1 cleavage products occur during apoptosis and could serve as markers for the efficacy of cancer therapy. Due to SPTAN1's multifaceted functions and its role in adhesion and migration, SPTAN1 can influence tumor growth and progression in both positive and negative directions depending on its specific regulation. This review summarizes the current knowledge on SPTAN1 in cancer and depicts several mechanisms by which SPTAN1 could impact tumor development and aggressiveness.
Collapse
|
|
10
|
Sepulveda AR, J. Del Portillo A. Molecular Basis of Diseases of the Gastrointestinal Tract. MOLECULAR PATHOLOGY 2018:387-415. [DOI: 10.1016/b978-0-12-802761-5.00019-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
|
|
11
|
Li L, Feng R, Xu Q, Zhang F, Liu T, Cao J, Fei S. Expression of the β3 subunit of Na +/K +-ATPase is increased in gastric cancer and regulates gastric cancer cell progression and prognosis via the PI3/AKT pathway. Oncotarget 2017; 8:84285-84299. [PMID: 29137423 PMCID: PMC5663595 DOI: 10.18632/oncotarget.20894] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2017] [Accepted: 08/26/2017] [Indexed: 12/13/2022] Open
Abstract
ATP1B3 encodes the β3 subunit of Na+/K+-ATPase and is located in the q22-23 region of chromosome 3. Na+/K+-ATPase participates in normal cellular activities but also plays a crucial role in carcinogenesis. In the present study, we found that expression of the β3 subunit of Na+/K+-ATPase was increased in human gastric cancer tissues compared with that in normal matched tissues and that this increased expression predicted a poor outcome. ATP1B3 expression was elevated at both the mRNA and protein levels in gastric cancer cell lines relative to those in a normal gastric epithelial cell line. Interestingly, ATP1B3 knockdown significantly inhibited cell proliferation, colony-formation ability, migration, and invasion and increased apoptosis in human gastric carcinoma cell lines. Additionally, knockdown induced cell cycle arrest at the G2/M phase. Furthermore, we demonstrated that ATP1B3 silencing decreased the expression of phosphatidylinositol 3-kinase (PI3K), protein kinase B (AKT) and phosphorylated AKT (p-AKT), indicating that ATP1B3 regulates gastric cancer cell progression via the PI3K/AKT signalling pathway. Hence, the β3 subunit of Na+/K+-ATPase plays an essential role in the tumourigenesis of gastric cancer and may be a potential prognostic and therapeutic target for the treatment of gastric cancer.
Collapse
Affiliation(s)
- Li Li
- Department of Gastroenterology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu 221000, P.R. China
| | - Ru Feng
- Department of Gastroenterology, Xuzhou Medical University, Xuzhou, Jiangsu 221000, P.R. China
| | - Qian Xu
- Department of Gastroenterology, Xuzhou Medical University, Xuzhou, Jiangsu 221000, P.R. China
| | - Feiyue Zhang
- Department of Gastroenterology, Xuzhou Medical University, Xuzhou, Jiangsu 221000, P.R. China
| | - Tong Liu
- Department of Gastroenterology, Xuzhou Medical University, Xuzhou, Jiangsu 221000, P.R. China
| | - Jiang Cao
- Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu 221000, P.R. China
| | - Sujuan Fei
- Department of Gastroenterology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu 221000, P.R. China
| |
Collapse
|
|
12
|
Li X, Dong W, Qu X, Zhao H, Wang S, Hao Y, Li Q, Zhu J, Ye M, Xiao W. Molecular dysexpression in gastric cancer revealed by integrated analysis of transcriptome data. Oncol Lett 2017; 13:3177-3185. [PMID: 28521423 DOI: 10.3892/ol.2017.5798] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2015] [Accepted: 11/30/2016] [Indexed: 02/07/2023] Open
Abstract
Gastric cancer (GC) is often diagnosed in the advanced stages and is associated with a poor prognosis. Obtaining an in depth understanding of the molecular mechanisms of GC has lagged behind compared with other cancers. This study aimed to identify candidate biomarkers for GC. An integrated analysis of microarray datasets was performed to identify differentially expressed genes (DEGs) between GC and normal tissues. Gene ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were then performed to identify the functions of the DEGs. Furthermore, a protein-protein interaction (PPI) network of the DEGs was constructed. The expression levels of the DEGs were validated in human GC tissues using reverse transcription-quantitative polymerase chain reaction (RT-qPCR). A set of 689 DEGs were identified in GC tissues, as compared with normal tissues, including 202 upregulated DEGs and 487 downregulated DEGs. The KEGG pathway analysis suggested that various pathways may play important roles in the pathology of GC, including pathways related to protein digestion and absorption, extracellular matrix-receptor interaction, and the metabolism of xenobiotics by cytochrome P450. The PPI network analysis indicated that the significant hub proteins consisted of SPP1, TOP2A and ARPC1B. RT-qPCR validation indicated that the expression levels of the top 10 most significantly dysexpressed genes were consistent with the illustration of the integrated analysis. The present study yielded a reference list of reliable DEGs, which represents a robust pool of candidates for further evaluation of GC pathogenesis and treatment.
Collapse
Affiliation(s)
- Xiaomei Li
- Department of Oncology, The First Affiliated Hospital of PLA General Hospital, Beijing 100048, P.R. China.,Department of Oncology, PLA General Hospital, Beijing 100853, P.R. China
| | - Weiwei Dong
- Department of Oncology, The First Affiliated Hospital of PLA General Hospital, Beijing 100048, P.R. China.,Department of Oncology, PLA General Hospital, Beijing 100853, P.R. China
| | - Xueling Qu
- Department of Oncology, The First Affiliated Hospital of PLA General Hospital, Beijing 100048, P.R. China.,Graduate School Department of Oncology, Medical College of Liaoning, Jinzhou, Liaoning 121001, P.R. China
| | - Huixia Zhao
- Department of Oncology, The First Affiliated Hospital of PLA General Hospital, Beijing 100048, P.R. China
| | - Shuo Wang
- Department of Oncology, The First Affiliated Hospital of PLA General Hospital, Beijing 100048, P.R. China
| | - Yixin Hao
- Department of Oncology, The First Affiliated Hospital of PLA General Hospital, Beijing 100048, P.R. China
| | - Qiuwen Li
- Department of Oncology, The First Affiliated Hospital of PLA General Hospital, Beijing 100048, P.R. China
| | - Jianhua Zhu
- Department of Oncology, The First Affiliated Hospital of PLA General Hospital, Beijing 100048, P.R. China
| | - Min Ye
- Department of Oncology, The First Affiliated Hospital of PLA General Hospital, Beijing 100048, P.R. China
| | - Wenhua Xiao
- Department of Oncology, The First Affiliated Hospital of PLA General Hospital, Beijing 100048, P.R. China
| |
Collapse
|
|
13
|
Zhang C, Min L, Liu J, Tian W, Han Y, Qu L, Shou C. Integrated analysis identified an intestinal-like and a diffuse-like gene sets that predict gastric cancer outcome. Tumour Biol 2016; 37:16317–16335. [PMID: 27858295 DOI: 10.1007/s13277-016-5454-7] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2016] [Accepted: 09/23/2016] [Indexed: 10/20/2022] Open
Abstract
The two major histological types of gastric cancer, intestinal and diffuse subtypes, have distinct epidemiological and pathophysiological features and were also suggested to be of diverse clinical outcomes. Although the gene expression spectrum of gastric cancer subtypes has been reported by previous studies, its linkage with gastric cancer clinical features and outcomes remains elusive. We investigated large-sample online gastric cancer datasets for seeking genes correlated with the clinical diversities between gastric cancer intestinal and diffuse subtypes. Genes differently expressed between the two subtypes were assessed by multiple statistical analysis and were testified on cellular level by quantitative RT-PCR. Related genes were combined to generate a risk signature, and their mutual linkages were also explored. Among genes overexpressed in intestinal subtype, ATPIF1, PRDX2, PRKAR2A, and SMC1A were correlated with positive prognosis. Among genes overexpressed in diffuse subtype, DTNA, GPR161, IDS, RHOQ, and TSHZ2 were correlated with negative prognosis. These nine genes were all novel independent prognostic factors. When used in combination as signatures, these two gene sets displayed strong efficacy for prediction of the prognosis and clinical variables in gastric and colorectal cancer. Hence, these two genes sets were respectively defined as the favorable intestinal-like and adverse diffuse-like gene sets. We identified nine novel genes correlated with the clinical diversity between the intestinal and diffuse subtypes of gastric cancer. The malignant changes from the intestinal to diffuse subtype might be due to the reduction of the four intestinal-like genes, as well as the elevation of the five diffuse-like genes.
Collapse
Affiliation(s)
- Cheng Zhang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Biochemistry and Molecular Biology, Peking University Cancer Hospital and Institute, 52 Fucheng Road, Beijing, 100142, China
| | - Li Min
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Biochemistry and Molecular Biology, Peking University Cancer Hospital and Institute, 52 Fucheng Road, Beijing, 100142, China
| | - Jiafei Liu
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Biochemistry and Molecular Biology, Peking University Cancer Hospital and Institute, 52 Fucheng Road, Beijing, 100142, China
| | - Wei Tian
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Division of Cancer Etiology, Peking University Cancer Hospital & Institute, Beijing, 100142, China
| | - Yong Han
- Department of Pathology, Zhejiang Provincial People's Hospital, Zhejiang, 310014, China
| | - Like Qu
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Biochemistry and Molecular Biology, Peking University Cancer Hospital and Institute, 52 Fucheng Road, Beijing, 100142, China
| | - Chengchao Shou
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Biochemistry and Molecular Biology, Peking University Cancer Hospital and Institute, 52 Fucheng Road, Beijing, 100142, China.
| |
Collapse
|
|
14
|
Robert F, Pelletier J. Perturbations of RNA helicases in cancer. WILEY INTERDISCIPLINARY REVIEWS-RNA 2013; 4:333-49. [PMID: 23658027 DOI: 10.1002/wrna.1163] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
Helicases are implicated in most stages of the gene expression pathway, ranging from DNA replication, RNA transcription, splicing, RNA transport, ribosome biogenesis, mRNA translation, RNA storage and decay. These enzymes utilize energy derived from nucleotide triphosphate hydrolysis to remodel ribonucleoprotein complexes, RNA, or DNA and in this manner affect the information content or output of RNA. Several RNA helicases have been implicated in the oncogenic process--either through altered expression levels, mutations, or due to their role in pathways required for tumor initiation, progression, maintenance, or chemosensitivity. The purpose of this review is to highlight those RNA helicases for which there is significant evidence implicating them in cancer biology.
Collapse
Affiliation(s)
- Francis Robert
- Department of Biochemistry, McGill University, Montreal, Quebec, Canada
| | | |
Collapse
|
|
15
|
Ummanni R, Mundt F, Pospisil H, Venz S, Scharf C, Barett C, Fälth M, Köllermann J, Walther R, Schlomm T, Sauter G, Bokemeyer C, Sültmann H, Schuppert A, Brümmendorf TH, Balabanov S. Identification of clinically relevant protein targets in prostate cancer with 2D-DIGE coupled mass spectrometry and systems biology network platform. PLoS One 2011; 6:e16833. [PMID: 21347291 PMCID: PMC3037937 DOI: 10.1371/journal.pone.0016833] [Citation(s) in RCA: 57] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2010] [Accepted: 01/16/2011] [Indexed: 11/18/2022] Open
Abstract
Prostate cancer (PCa) is the most common type of cancer found in men and among the leading causes of cancer death in the western world. In the present study, we compared the individual protein expression patterns from histologically characterized PCa and the surrounding benign tissue obtained by manual micro dissection using highly sensitive two-dimensional differential gel electrophoresis (2D-DIGE) coupled with mass spectrometry. Proteomic data revealed 118 protein spots to be differentially expressed in cancer (n = 24) compared to benign (n = 21) prostate tissue. These spots were analysed by MALDI-TOF-MS/MS and 79 different proteins were identified. Using principal component analysis we could clearly separate tumor and normal tissue and two distinct tumor groups based on the protein expression pattern. By using a systems biology approach, we could map many of these proteins both into major pathways involved in PCa progression as well as into a group of potential diagnostic and/or prognostic markers. Due to complexity of the highly interconnected shortest pathway network, the functional sub networks revealed some of the potential candidate biomarker proteins for further validation. By using a systems biology approach, our study revealed novel proteins and molecular networks with altered expression in PCa. Further functional validation of individual proteins is ongoing and might provide new insights in PCa progression potentially leading to the design of novel diagnostic and therapeutic strategies.
Collapse
Affiliation(s)
- Ramesh Ummanni
- Department of Oncology, Haematology and Bone Marrow Transplantation with Section Pneumology, Hubertus Wald-Tumor Zentrum, University Hospital Eppendorf, Hamburg, Germany
| | - Frederike Mundt
- Department of Oncology, Haematology and Bone Marrow Transplantation with Section Pneumology, Hubertus Wald-Tumor Zentrum, University Hospital Eppendorf, Hamburg, Germany
| | - Heike Pospisil
- Bioinformatics, University of Applied Sciences Wildau, Wildau, Germany
| | - Simone Venz
- Department of Medical Biochemistry and Molecular Biology, University of Greifswald, Greifswald, Germany
- Interfacultary Institute of Genetics and Functional Genomics, University of Greifswald, Greifswald, Germany
| | - Christian Scharf
- Interfacultary Institute of Genetics and Functional Genomics, University of Greifswald, Greifswald, Germany
- Department of Otorhinolaryngology, Head and Neck Surgery, University of Greifswald, Greifswald, Germany
| | - Christine Barett
- Department of Oncology, Haematology and Bone Marrow Transplantation with Section Pneumology, Hubertus Wald-Tumor Zentrum, University Hospital Eppendorf, Hamburg, Germany
| | - Maria Fälth
- Cancer Genome Research, Deutsches Krebsforschungszentrum, Heidelberg, Germany
| | - Jens Köllermann
- Department of Pathology, University Hospital Eppendorf, Hamburg, Germany
| | - Reinhard Walther
- Department of Medical Biochemistry and Molecular Biology, University of Greifswald, Greifswald, Germany
| | - Thorsten Schlomm
- Prostate Cancer Center, University Hospital Eppendorf, Hamburg, Germany
| | - Guido Sauter
- Department of Pathology, University Hospital Eppendorf, Hamburg, Germany
| | - Carsten Bokemeyer
- Department of Oncology, Haematology and Bone Marrow Transplantation with Section Pneumology, Hubertus Wald-Tumor Zentrum, University Hospital Eppendorf, Hamburg, Germany
| | - Holger Sültmann
- Cancer Genome Research, Deutsches Krebsforschungszentrum, Heidelberg, Germany
| | - A. Schuppert
- Aachen Institute for Advanced Study in Computational Engineering Science, RWTH Aachen University, Aachen, Germany
| | - Tim H. Brümmendorf
- Department of Oncology, Haematology and Bone Marrow Transplantation with Section Pneumology, Hubertus Wald-Tumor Zentrum, University Hospital Eppendorf, Hamburg, Germany
- Medizinische Klinik IV - Hämatologie und Onkologie, RWTH Aachen University, Aachen, Germany
| | - Stefan Balabanov
- Department of Oncology, Haematology and Bone Marrow Transplantation with Section Pneumology, Hubertus Wald-Tumor Zentrum, University Hospital Eppendorf, Hamburg, Germany
- * E-mail:
| |
Collapse
|
|
16
|
Song G, Ouyang G, Mao Y, Ming Y, Bao S, Hu T. Osteopontin promotes gastric cancer metastasis by augmenting cell survival and invasion through Akt-mediated HIF-1alpha up-regulation and MMP9 activation. J Cell Mol Med 2010; 13:1706-1718. [PMID: 19602039 DOI: 10.1111/j.1582-4934.2008.00540.x] [Citation(s) in RCA: 55] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022] Open
Abstract
Osteopontin (OPN) is a secreted, integrin-binding matrix phosphorylated glycoprotein. OPN has been shown to facilitate the progression and metastasis of malignancies and has prognostic value in several types of cancer, including gastric cancer. However, the functional mechanism of OPN mediated metastatic growth in gastric cancer remains unclear. Here, using multiple in vitro and in vivo models, we report that OPN strongly promoted the progression and metastasis of gastric cancer. Immunohistochemical staining revealed that OPN, matrix metalloproteinase (MMP)9 and hypoxia-inducible factor (HIF)-1alpha have statistically significant different expression patterns between well- and poorly differentiated tissue samples (P < 0.05). Correlations existed between OPN and MMP9, and between OPN and HIF-1 (r(1) = 0.872, p(1) < 0.01 and r(2) = 0.878, p(2) < 0.01). Furthermore, OPN dramatically increased colony formation and invasion of gastric cancer cells in vitro and promoted tumour growth and metastasis in vivo. In addition, OPN potently protected gastric cancer cells from serum depletion-induced apoptosis. Further study shows that OPN activated phosphoinositide 3-kinase/Akt survival pathway and up-regulated HIF-1alpha via binding to v3 integrins in gastric cancer cells. Moreover, we found that OPN could activate MMP9 and upregulate MMP2. Taken together, our results suggest that the survival-promoting function is crucial for OPN to promote the development of gastric cancer, and HIF-1 and MMP9 may play key roles during this process. Thus, targeting OPN and its related signalling network may develop an effective therapeutic approach for the management of gastric cancer.
Collapse
Affiliation(s)
- Gang Song
- Cancer Research Center, Xiamen University Medical College, Xiamen, China.,The Key Laboratory of Ministry of Education for Cell Biology and Tumor Cell Engineering, School of Life Sciences, Xiamen University, Xiamen, China
| | - Gaoliang Ouyang
- The Key Laboratory of Ministry of Education for Cell Biology and Tumor Cell Engineering, School of Life Sciences, Xiamen University, Xiamen, China
| | - Yubin Mao
- Cancer Research Center, Xiamen University Medical College, Xiamen, China
| | - Yanlin Ming
- The Key Laboratory of Ministry of Education for Cell Biology and Tumor Cell Engineering, School of Life Sciences, Xiamen University, Xiamen, China
| | - Shideng Bao
- The Key Laboratory of Ministry of Education for Cell Biology and Tumor Cell Engineering, School of Life Sciences, Xiamen University, Xiamen, China
| | - Tianhui Hu
- Cancer Research Center, Xiamen University Medical College, Xiamen, China
| |
Collapse
|
|
17
|
Zheng Y, Jia Y, Wang Y, Wang M, Li B, Shi X, Ma X, Xiao D, Sun Y. The hypoxia-regulated transcription factor DEC1 (Stra13, SHARP-2) and its expression in gastric cancer. OMICS-A JOURNAL OF INTEGRATIVE BIOLOGY 2009; 13:301-6. [PMID: 19624270 DOI: 10.1089/omi.2009.0014] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
Abstract
Differentiated embryo-chondrocyte expressed gene 1 (DEC1), as a bHLH transcriptional factor, plays important roles in cell differentiation, proliferation, and apoptosis. The expression of DEC1 and its role in human gastric cancer are unknown. This study was designed to characterize the DEC1 gene profiling of human gastric cancer tissues. The expression of DEC1 in gastric cancer tissues was analyzed by cDNA microarray, reverse-transcriptase polymerase chain reaction (RT-PCR), Western blot, and immunohistochemical studies. Microarray assay demonstrated that DEC1 was one of the upregulated genes in gastric cancer when compared with normal tissues. The expression of DEC1 mRNA was increased in gastric cancer as determined by RT-PCR. An increased DEC1 protein expression in gastric cancer was verified by Western blot analysis. Immunohistochemical studies showed that the 83.02% gastric cancer tissues (44/53) were stained positive for DEC1. The DEC1 expression was increased during the tumor progression from well differentiated (50%, 4/8) to moderately differentiated (76%, 13/17), and poorly differentiated (96%, 27/28) tumor tissues. In contrast, a weak staining for DEC1 (low expression) was observed in 10 % normal tissues (1/10). Statistical analysis found a significant correlation between increased DEC1 expression and poorly differentiated cancer tissues. These data characterized DEC1 expression in gastric cancer and identified a correlation between upregulation of DEC1 expression and differentiation of gastric cancer, suggesting that DEC1 may play an important role in the differentiation and progression of gastric cancer.
Collapse
Affiliation(s)
- Yan Zheng
- Central Laboratory, Jinan Central Hospital affiliated to Shandong University, Jinan, People's Republic of China
| | | | | | | | | | | | | | | | | |
Collapse
|
|
18
|
Akaboshi SI, Watanabe S, Hino Y, Sekita Y, Xi Y, Araki K, Yamamura KI, Oshima M, Ito T, Baba H, Nakao M. HMGA1 is induced by Wnt/beta-catenin pathway and maintains cell proliferation in gastric cancer. THE AMERICAN JOURNAL OF PATHOLOGY 2009; 175:1675-85. [PMID: 19729480 PMCID: PMC2751563 DOI: 10.2353/ajpath.2009.090069] [Citation(s) in RCA: 65] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Accepted: 06/23/2009] [Indexed: 01/12/2023]
Abstract
The development of stomach cancer is closely associated with chronic inflammation, and the Wnt/beta-catenin signaling pathway is activated in most cases of this cancer. High-mobility group A (HMGA) proteins are oncogenic chromatin factors that are primarily expressed not only in undifferentiated tissues but also in various tumors. Here we report that HMGA1 is induced by the Wnt/beta-catenin pathway and maintains proliferation of gastric cancer cells. Specific knockdown of HMGA1 resulted in marked reduction of cell growth. The loss of beta-catenin or its downstream c-myc decreased HMGA1 expression, whereas Wnt3a treatment increased HMGA1 and c-myc transcripts. Furthermore, Wnt3a-induced expression of HMGA1 was inhibited by c-myc knockdown, suggesting that HMGA1 is a downstream target of the Wnt/beta-catenin pathway. Enhanced expression of HMGA1 coexisted with the nuclear accumulation of beta-catenin in about 30% of gastric cancer tissues. To visualize the expression of HMGA1 in vivo, transgenic mice expressing endogenous HMGA1 fused to enhanced green fluorescent protein were generated and then crossed with K19-Wnt1/C2mE mice, which develop gastric tumors through activation of both the Wnt and prostaglandin E2 pathways. Expression of HMGA1-enhanced green fluorescent protein was normally detected in the forestomach, along the upper border of the glandular stomach, but its expression was also up-regulated in cancerous glandular stomach. These data suggest that HMGA1 is involved in proliferation and gastric tumor formation via the Wnt/beta-catenin pathway.
Collapse
Affiliation(s)
- Shin-ichi Akaboshi
- Department of Medical Cell Biology, Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto 860-0811, Japan
| | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
19
|
Zhao Y, Zhou T, Li A, Yao H, He F, Wang L, Si J. A potential role of collagens expression in distinguishing between premalignant and malignant lesions in stomach. Anat Rec (Hoboken) 2009; 292:692-700. [PMID: 19306436 DOI: 10.1002/ar.20874] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Lack of clinical biomarkers for early gastric cancer without specific early symptoms leads to delayed diagnosis, which contributes to high mortality of gastric cancer. Here, we used oligonucleotide microarray to systematically examine differential gene expression among 33 samples from normal, premalignant, and malignant lesions in stomach. A focal adhesion pathway mainly composed of collagen genes was found to have a significantly different expression profile in gastric cancers compared to premalignant lesions. A subset of collagen genes efficiently separated malignant from premalignant tissues, and two representative genes COL11A1 and COL1A1 were validated in 42 tissue samples with quantitative reverse transcription-PCR and in situ hybridization. The data above suggest that focal adhesion pathway may have a role in the pathogenesis of gastric cancer, and the expression profile of collagen genes may be a potential biomarker to distinguish malignant from premalignant lesions in stomach.
Collapse
Affiliation(s)
- Yuan Zhao
- Gastroenterology laboratory, The Institute of Clinic Medical Research, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | | | | | | | | | | | | |
Collapse
|
|
20
|
Liu B, Xiang M, Yu YY, Yang QM, Cai Q, Chen XH, Li JF, Liu BY, Zhu ZG. Influence of down-regulation of RegⅣ expression by small interfering RNA on proliferation and apoptosis of gastric cancer cells. Shijie Huaren Xiaohua Zazhi 2009; 17:549-553. [DOI: 10.11569/wcjd.v17.i6.549] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [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 RegⅣ expression level in human gastric cancer cell lines and the effect of RNA interfering of RegⅣ on proliferation and apoptosis of gastric cancer cells.
METHODS: The expression levels of RegⅣ in nine gastric cancer cell lines were examined by real time PCR, and 3 small interfering RNA (siRNA1, siRNA2, siRNA3) targeting RegⅣ were designed and transfected into gastric cancer cell lines. The changes of RegⅣ mRNA expression level after siRNA interfering were detected by real time PCR. The proliferation was assayed by CCK-8 method. Flow cytometry was used to detect apoptosis of gastric cancer cells.
RESULTS: Compared with gastric mucosa cell line GES-1, the expression level of RegⅣ in gastric cancer cells was 5-fold or higher except MKN-45 and SNU-1. The expression level of RegⅣ in SNU-16 was the highest and was several thousand-fold higher than that in GES-1. SNU-16 was used for siRNA experiment. Three siRNAs showed notably down-regulated expression of RegⅣ mRNA levels with inhibitory rate of 79.3%, 77.4% and 60.4%, respectively in comparison with that in control group. So siRNA1 was used to do cell proliferation assay. After 96 hours' and 120 hours' transfection of siRNA1, the proliferation of SNU-16 cell significantly decreased compared with the control group (P = 0.0057, 0.0173, respectively). The results of flow cytometry revealed that 72 h after transfection with siRNA1, the apoptosis rate of SNU-16 significantly increased.
CONCLUSION: Interfering and down-regulating RegⅣ gene can inhibit proliferation and promote apoptosis of gastric cancer cells, indicating that RegⅣ gene is probably a target for gastric cancer gene therapy.
Collapse
|
|
21
|
Sepulveda AR, Aisner DL. Molecular Basis of Diseases of the Gastrointestinal Tract. MOLECULAR PATHOLOGY 2009:365-393. [DOI: 10.1016/b978-0-12-374419-7.00019-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
|
|
22
|
Goswami RS, Sukhai MA, Thomas M, Reis PP, Kamel-Reid S. Applications of microarray technology to Acute Myelogenous Leukemia. Cancer Inform 2008; 7:13-28. [PMID: 19352456 PMCID: PMC2664704 DOI: 10.4137/cin.s1015] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Microarray technology is a powerful tool, which has been applied to further the understanding of gene expression changes in disease. Array technology has been applied to the diagnosis and prognosis of Acute Myelogenous Leukemia (AML). Arrays have also been used extensively in elucidating the mechanism of and predicting therapeutic response in AML, as well as to further define the mechanism of AML pathogenesis. In this review, we discuss the major paradigms of gene expression array analysis, and provide insights into the use of software tools to annotate the array dataset and elucidate deregulated pathways and gene interaction networks. We present the application of gene expression array technology to questions in acute myelogenous leukemia; specifically, disease diagnosis, treatment and prognosis, and disease pathogenesis. Finally, we discuss several new and emerging array technologies, and how they can be further utilized to improve our understanding of AML.
Collapse
Affiliation(s)
- Rashmi S Goswami
- Division of Applied Molecular Oncology, Princess Margaret Hospital/Ontario Cancer Institute, University Health Network, Toronto, ON, Canada
| | | | | | | | | |
Collapse
|
|
23
|
Abstract
Cardiac glycosides are a diverse family of naturally derived compounds that bind to and inhibit Na+/K+-ATPase. Members of this family have been in clinical use for many years for the treatment of heart failure and atrial arrhythmia, and the mechanism of their positive inotropic effect is well characterized. Exciting recent findings have suggested additional signalling modes of action of Na+/K+-ATPase, implicating cardiac glycosides in the regulation of several important cellular processes and highlighting potential new therapeutic roles for these compounds in various diseases. Perhaps most notably, the increased susceptibility of cancer cells to these compounds supports their potential use as cancer therapies, and the first generation of glycoside-based anticancer drugs are currently in clinical trials.
Collapse
|
|
24
|
Song G, Ming Y, Mao Y, Bao S, Ouyang G. Osteopontin prevents curcumin-induced apoptosis and promotes survival through Akt activation via alpha v beta 3 integrins in human gastric cancer cells. Exp Biol Med (Maywood) 2008; 233:1537-45. [PMID: 18849546 DOI: 10.3181/0805-rm-164] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
Osteopontin (OPN) is a secreted, integrin-binding matrix phosphorylated glycoprotein that is overexpressed in many advanced cancers. However, the functional mechanisms by which OPN contributes to gastric cancer development are poorly understood. Here, we report that curcumin inhibited the growth of SGC7901 cell and induced apoptosis in a concentration- and time-dependent manner, while the acquired expression of OPN in SGC7901 cells dramatically promoted cell survival under serum depletion and prevented curcumin-induced apoptosis. Furthermore, PI3-K inhibitor LY294002 attenuated OPN-mediated Akt activation. Moreover, inhibiting the binding of OPN to alpha(v)beta(3) integrins reduced activation of Akt. Taken together, these results demonstrate that the pro-survival and anti-apoptosis activities of OPN in gastric cancer cells are mediated in part through PI3-K/Akt pathway via alpha(v)beta(3) integrins.
Collapse
Affiliation(s)
- Gang Song
- Key Laboratory of the Ministry of Education for Cell Biology and Tumor Cell Engineering, School of Life Sciences, Xiamen University, Xiamen 361005, China
| | | | | | | | | |
Collapse
|
|
25
|
Ichikawa W, Sasaki Y. Challenges in predicting the clinical outcome in S-1-based chemotherapy for gastric cancer patients. Int J Clin Oncol 2008; 13:206-11. [DOI: 10.1007/s10147-008-0786-y] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2008] [Indexed: 10/22/2022]
|
|
26
|
Tang H, Wang J, Bai F, Zhai H, Gao J, Hong L, Xie H, Zhang F, Lan M, Yao W, Liu J, Wu K, Fan D. Positive correlation of osteopontin, cyclooxygenase-2 and vascular endothelial growth factor in gastric cancer. Cancer Invest 2008; 26:60-7. [PMID: 18181047 DOI: 10.1080/07357900701519279] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Osteopontin (OPN), cyclooxygenase-2 (COX-2) and vascular endothelial growth factor (VEGF) are overexpressed in various experimental models of malignancy. However, the correlation and role of the three molecules in gastric cancer is unclear. In the present study, we found that OPN, COX-2 and VEGF were overexpressed in 53 cancerous tissues with gastric cancer compared with 40 normal mucosa tissues by immunohistochemistry method. Moreover, the results indicated co-expression of OPN, COX-2, and VEGF in gastric cancer. Levels of OPN, COX-2, and VEGF were all significantly correlated with TNM stage, lymph node metastasis and distant metastasis (P < 0.05), while not related to prognosis of patients. In addition, individual levels of OPN, COX-2, and VEGF were all significantly correlated with microvessel density (MVD), valued by CD34 staining directly with r-values of 0.416, 0.400, and 0.566, respectively (P < 0.01). Both OPN and COX-2 levels showed a positive correlation with VEGF (P < 0.05). Meanwhile, expression of COX-2 is in relation to OPN (P < 0.01). Overall, survival for patients with high MVD was significantly lower than for patients with low MVD (P < 0.05). Our findings indicate that OPN, COX-2, and VEGF synergically promote angiogenesis and metastasis in gastric cancer. It may be an important and useful strategy to target these molecules for prevention and therapy of tumor.
Collapse
Affiliation(s)
- Hongwei Tang
- Department of Gastroenterology, General Hospital of Chinese People's Armed Police Forces, Beijing, PR China
| | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
27
|
Dai N, Bao Q, Lu A, Li J. Protein Expression of Osteopontin in Tumor Tissues Is an Independent Prognostic Indicator in Gastric Cancer. Oncology 2007; 72:89-96. [DOI: 10.1159/000111108] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2007] [Accepted: 06/12/2007] [Indexed: 12/16/2022]
|
|
28
|
Higashiyama M, Ito T, Tanaka E, Shimada Y. Prognostic significance of osteopontin expression in human gastric carcinoma. Ann Surg Oncol 2007; 14:3419-27. [PMID: 17896150 DOI: 10.1245/s10434-007-9564-8] [Citation(s) in RCA: 47] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2007] [Revised: 07/21/2007] [Accepted: 07/23/2007] [Indexed: 12/16/2022]
Abstract
BACKGROUND Osteopontin (OPN) is a secreted, integrin-binding glycophosphoprotein that has been implicated in the progression of various solid tumors. To evaluate the clinical significance of OPN in gastric carcinoma, we investigated OPN expression in resected tumors. METHODS Expression of OPN protein by gastric cancer cells was evaluated using western blot analysis. OPN messenger RNA (mRNA) expression in 18 gastric cancers was compared with that in the corresponding normal gastric epithelium by semiquantitative reverse transcription polymerase chain reaction (RT-PCR). Paraffin sections of tumors from 295 patients with gastric cancer were also investigated using immunohistochemistry. RESULTS All four gastric cancer cell lines analyzed using western blotting had almost the same level of OPN protein expression as the positive control (HeLa cells). OPN mRNA was upregulated in 83% (15/18) of the tumors studied. On immunohistochemical staining, 90 tumors were classified as negative (-), whereas 205 were classified as positive (1+, 2+, or 3+). The level of OPN protein expression was significantly associated with the patient's age (p = 0.04), tumor depth (p = 0.03), histological grade (p = 0.008), and hematogenous metastasis (p = 0.007). Kaplan-Meier analysis showed that OPN positivity was significantly associated with a shorter survival time (p = 0.027). Furthermore, multivariate analysis revealed that OPN positivity was an independent risk factor for hematogenous metastasis (p = 0.034). CONCLUSIONS The present findings suggest that increased tumor expression of OPN is an important determinant of shorter survival time and that OPN positivity may be useful for predicting the risk of hematogenous metastasis in gastric cancer patients.
Collapse
Affiliation(s)
- Motoshige Higashiyama
- Department of Surgery, Kyoto University, Kawaracho Shogoin Sakyo-ku, Kyoto, 606-8507, Japan
| | | | | | | |
Collapse
|
|
29
|
Tang H, Wang J, Bai F, Hong L, Liang J, Gao J, Zhai H, Lan M, Zhang F, Wu K, Fan D. Inhibition of osteopontin would suppress angiogenesis in gastric cancer. Biochem Cell Biol 2007; 85:103-10. [PMID: 17464350 DOI: 10.1139/o06-208] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Osteopontin (OPN) plays an important role in tumorigenesis, tumor invasion, and metastasis in many types of cancers, including gastric cancer. Recently, much interest has been focused on the role of OPN in tumor angiogenesis. Our previous studies have shown that OPN is overexpressed, and associated with mean microvessel density in, the tissue samples of patients with gastric cancer. In the present study, we aimed to further determine and provide evidence for the role of OPN in gastric-cancer-associated angiogenesis by diminishing OPN expression in gastric cancer cells using the small interference RNA method, and then evaluate the effects of OPN on gastric cancer-associated angiogenesis by in vivo and in vitro assays. Our results revealed that reduced OPN production by gastric cancer cells would reduce the proliferation, migration, and tube formation of human umbilical vein endothelial cells, and lead to a lower microvessel density, i.e., angiogenesis, in transplanted tumors of mice. These data confirm the positive role of OPN in gastric-cancer-associated angiogenesis.
Collapse
Affiliation(s)
- Hongwei Tang
- State Key Laboratory of Cancer Biology and Institute of Digestive Disease, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, Shannxi Province, China
| | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
30
|
Galamb O, Sipos F, Molnar B, Szoke D, Spisak S, Tulassay Z. Evaluation of malignant and benign gastric biopsy specimens by mRNA expression profile and multivariate statistical methods. CYTOMETRY. PART B, CLINICAL CYTOMETRY 2007; 72:299-309. [PMID: 17366642 DOI: 10.1002/cyto.b.20189] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
BACKGROUND mRNA expression array and multivariate statistical analysis of gastric biopsies can yield insight into the molecular biology basis of local alterations, supporting expression-based identification of morphological alterations. METHODS From 11 patients with erosive gastritis(EG), 5 with adenocarcinoma (GC), 11 with atrophic gastritis (AG) gastric biopsies were collected, total RNA isolated, T7 amplification and expression analysis of 1047 mRNAs was performed using commercial glass arrays (Clontech, USA). After microarray quality control, applicable data were available from 7 EG, 4 GC, and 5 AG. Multivariate statistical and cell functional analysis were performed. Real-time RT-PCR and immunohistochemistry were used for validation. RESULTS GC was characterized by overregulated v-raf, v-erb-a, BCL2-associated- athanogene, immediate-early-response-3, Polo-like kinase, CDK-2, cyclin-C, Pin1 genes, and downregulated ADP-ribosyltransferase, sialophorin and DCC. AG cases had increased PDGF-receptor, TGF-beta-receptor-3, and decreased death-associated-protein-3, beta-1-catenin, topoisomerase-1 levels. In EG upregulation of IGF-receptor-1, CD9, transferrin receptor, integrins, and underexpression of keratin-5, caspase-4 was found. Discriminant analysis could reclassify all samples correctly using four parameters. CONCLUSIONS mRNA expression array analysis of gastric biopsies yields previously known and new data in the evaluation of local gastric alterations.
Collapse
Affiliation(s)
- Orsolya Galamb
- 2nd Department of Internal Medicine, University Semmelweis, Faculty of Medicine, Budapest, Hungary.
| | | | | | | | | | | |
Collapse
|
|
31
|
Abstract
Gastric cancer is the second most common cancer worldwide. Treatment of localized gastric cancer relies primarily on surgical intervention, although growing evidence suggests that the addition of chemoradiation may improve disease-free intervals and overall survival. In this regard, the current high rates of recurrence and subsequent poor survival have prompted an ever-increasing use of multimodal strategies, even for early-stage disease. However, these therapies are often limited by debilitating toxicities and varying degrees of response efficacy. As a result, pharmacogenomics, the study of specific genetic and molecular signatures that may be predictive of treatment outcomes, has gained considerable interest. For example, studies have demonstrated that the expression of enzymes involved in the metabolism or conjugation of commonly used chemotherapy agents, such as fluoropyrimidines and cisplatin, can serve as surrogate markers predictive of chemotherapy response. Polymorphisms in the genes encoding these enzymes have also been identified and may further account for altered expression patterns, resulting in varied clinical responses. Future work is necessary to further refine the list of molecular genetic markers and to identify novel markers for prognostic and predictive purposes. Technologies such as microarray analysis may be useful in identifying new molecular genetic markers, and further work may determine whether these markers can be employed to help stratify patients into different multimodal treatment regimens.
Collapse
Affiliation(s)
- Casandra Anderson
- Department of General Oncologic Surgery, City of Hope National Medical Center, Duarte, California 91010, USA
| | | | | |
Collapse
|
|
32
|
Murtaza I, Marra G, Schlapbach R, Patrignani A, Künzli M, Wagner U, Sabates J, Dutt A. A preliminary investigation demonstrating the effect of quercetin on the expression of genes related to cell-cycle arrest, apoptosis and xenobiotic metabolism in human CO115 colon-adenocarcinoma cells using DNA microarray. Biotechnol Appl Biochem 2006; 45:29-36. [PMID: 16640504 DOI: 10.1042/ba20060044] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
The role of the natural dietary flavonoid chemical quercetin (an antioxidant) in the prevention and treatment of colon cancer is receiving a great deal of attention. However, little is known about the molecular mechanisms of action of this flavonoid. In the present study, whole genome DNA microarrays were used to evaluate the effect of quercetin on gene expression in the CO115 colon-adenocarcinoma cell line with the completely deleted chromosome 18 harbouring the SMAD4 tumour-suppressor gene related to colon carcinogenesis. The study demonstrated that quercetin, widely present in fruit and vegetables, inhibited the growth of CO115 cells at 100 microM concentration in both the G(1)/S and the G(2)/M phases by modulating cell-cycle and apoptosis-related genes. Differential changes in accumulation of transcripts analysed for cells treated with 100 microM quercetin for 24 and 48 h in three independent repeated experiments revealed 5060-7000 differentially expressed genes. This means that quercetin probably does have a broad modulatory effect on gene expression in colon cancer. Out of these differentially expressed genes, the expression of 35 and 23 unique set of genes involved in cell-cycle control, apoptosis and xenobiotic metabolism were significantly altered after 24 and 48 h quercetin treatment respectively. Our results represent a novel aspect of the biological profile of quercetin that induces cell-cycle arrest through modulation of cell-cycle-related and apoptosis genes. The present study demonstrates a new step in elucidating the underlying molecular mechanisms of the antitumour action of quercetin, which could become a chemopreventive or chemotherapeutic agent for colon cancer.
Collapse
Affiliation(s)
- Imtiyaz Murtaza
- Biochemistry and Molecular Biotechnology Laboratory, Division of PHT, SK University of Agricultural Sciences and Technology, Shalimar Campus, Srinagar, Kashmir, India.
| | | | | | | | | | | | | | | |
Collapse
|
|
33
|
Yu CD, Xu SH, Mou HZ, Jiang ZM, Zhu CH, Liu XL. Function and chromosome location of differentially expressed genes in gastric cancer. ACTA ACUST UNITED AC 2006; 33:397-404. [PMID: 16722334 DOI: 10.1016/s0379-4172(06)60066-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
Using Affymetrix U133A oligonucleotide microarrays, screening was done for genes that were differentially expressed in gastric cancer (T) and normal gastric mucosa (C), and their chromosome location was characterized by bioinformatics. A total of 270 genes were found to have a difference in expression levels of more than eight times. Of them 157 were up-regulated (Signal Log Ratio [SLR] > or = 3), and 113 were down-regulated (SLR< or = -3). Except for, four genes with unknown localization, a vast majority of the genes were sporadically distributed over every chromosome. However, chromosome 1 contained the most differentially expressed genes (26 genes, or 9.8%), followed by chromosomes 11 and 19 (both 24 genes, or 9.1%). These genes were also more likely to be on the short-arm of the chromosome (q), which had 173 (65%). When these genes were classified according to their functions, it was found that most (67 genes, 24.8%) belonged to the enzymes and their regulators groups. The next group was the signal transduction genes group (43 genes, 15.9%). The rest of the top three groups were nucleic acid binding genes (17, 6.3%), transporter genes (15, 5.5%), and protein binding genes (12, 4.4%). These made up 56.9% of all the differentially expressed genes. There were also 50 genes of unknown function (18.5%). Therefore it was concluded that differentially expressed genes in gastric cancer seemed to be sporadically distributed across the genome, but most were found on chromosomes 1, 11 and 19. The five groups associated genes abnormality were important genes for further study on gastric cancer.
Collapse
MESH Headings
- Adenocarcinoma/genetics
- Adenocarcinoma/metabolism
- Chromosome Mapping
- Chromosomes, Human, Pair 1
- Chromosomes, Human, Pair 11
- Chromosomes, Human, Pair 19
- Female
- GTP-Binding Proteins/metabolism
- Gene Expression Profiling
- Gene Expression Regulation, Neoplastic
- Humans
- Male
- Middle Aged
- Oligonucleotide Array Sequence Analysis
- RNA, Neoplasm/genetics
- Receptors, Estrogen/metabolism
- Receptors, LDL/metabolism
- Signal Transduction
- Stomach Neoplasms/genetics
- Stomach Neoplasms/metabolism
Collapse
Affiliation(s)
- Chuan-Ding Yu
- Zhejiang Cancer Research Institute, Hangzhou, China.
| | | | | | | | | | | |
Collapse
|
|
34
|
Abstract
Several attempts to classify gastric cancer (GCA) have been made over the past decades. Most successful, and widely used, is the classification by Laurén, which distinguishes, by microscopical morphology alone, two main cancer pathogeneses, diffuse (DGCA) and intestinal (IGCA) subtypes, which appear clearly as dissimilar clinical and epidemiological entities. Here we review the main differences in epidemiology, histopathology, and molecular pathology of the two main subtypes of gastric carcinomas based on Laurén classification. In clinical practice, however, clinical staging, particularly in predicting the survival, still remains superior to all classifications of gastric cancer independent of cancer type. The existence of local precursor lesions or conditions of IGCA tumours, i.e. Helicobacter pylori gastritis, atrophic gastritis (AG), intestinal metaplasia (IM), adenoma, dysplasia, and intramucosal neoplasia, is firmly established. The links of DGCA with intestinal-type epithelium, AG or IM are poor, or do not exist. So far, H. pylori gastritis is the only universal precursor condition for DGCA. It implies that AG and achlorhydria are of minor significance and infrequent in the development of DGCA but are important steps in that of IGCA. Despite an increasing body of data, the overall view on molecular pathology of GCA remains fragmentary. No consistent differences in the molecular pathology of GCA subtypes to meet the Laurén classification have been established. With the exception of TP53, no gene mutation occurring regularly in both histological types of GCA has been reported. Chromosomal aberrations and loss of heterozygosity seem to be non-specific and do not follow any consistent route in the progression of GCA. Microsatellite instability is more commonly found in IGCA than in DGCA. The present epigenetic data suggest that most of the decrease (or loss) of gene expression may be explained by promoter hypermethylation which is more often found in IGCA. In DGCA specific genes such as CDH1 are more often hypermethylated. Compared with GCA, in premalignant condition lesions gene mutations and chromosomal aberrations are infrequent. Epigenetic dysregulation might also represent a major mechanism for altered gene expression in premalignant stages in gastric carcinogenesis.
Collapse
Affiliation(s)
- Matti Vauhkonen
- Department of Medicine, Helsinki University Central Hospital (HUCH), Jorvi Hospital, Espoo, Finland
| | | | | |
Collapse
|
|
35
|
Chen JQ, Contreras RG, Wang R, Fernandez SV, Shoshani L, Russo IH, Cereijido M, Russo J. Sodium/potasium ATPase (Na+, K+-ATPase) and ouabain/related cardiac glycosides: a new paradigm for development of anti- breast cancer drugs? Breast Cancer Res Treat 2005; 96:1-15. [PMID: 16322895 DOI: 10.1007/s10549-005-9053-3] [Citation(s) in RCA: 76] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2005] [Accepted: 08/11/2005] [Indexed: 11/30/2022]
Abstract
Prolonged exposure to 17beta-estradiol (E2) is a key etiological factor for human breast cancer. The biological effects and carcinogenic effects of E2 are mediated via estrogen receptors (ERs), ERalpha and ERbeta. Anti-estrogens, e.g. tamoxifen, and aromatase inhibitors have been used to treat ER-positive breast cancer. While anti-estrogen therapy is initially successful, a major problem is that most tumors develop resistance and the disease ultimately progresses, pointing to the need of developing alternative drugs targeting to other critical targets in breast cancer cells. We have identified that Na+, K+-ATPase, a plasma membrane ion pump, has unique/valuable properties that could be used as a potentially important target for breast cancer treatment: (a) it is a key player of cell adhesion and is involved in cancer progression; (b) it serves as a versatile signal transducer and is a target for a number of hormones including estrogens and (d) its aberrant expression and activity are implicated in the development and progression of breast cancer. There are several lines of evidence indicating that ouabain and related digitalis (the potent inhibitors of Na+, K+-ATPase) possess potent anti-breast cancer activity. While it is not clear how the suggested anti-cancer activity of these drugs work, several observations point to ouabain and digitalis as being potential ER antagonists. We critically reviewed many lines of evidence and postulated a novel concept that Na+, K+-ATPase in combination with ERs could be important targets of anti-breast cancer drugs. Modulators, e.g. ouabain and related digitalis could be useful to develop valuable anti-breast cancer drugs as both Na+, K+-ATPase inhibitors and ER antagonists.
Collapse
Affiliation(s)
- Jin-Qiang Chen
- Breast Cancer Research Laboratory, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
| | | | | | | | | | | | | | | |
Collapse
|
|
36
|
Galamb O, Sipos F, Fischer K, Tulassay Z, Molnar B. The results of the expression array studies correlate and enhance the known genetic basis of gastric and colorectal cancer. CYTOMETRY. PART B, CLINICAL CYTOMETRY 2005; 68:1-17. [PMID: 16208682 DOI: 10.1002/cyto.b.20069] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
Gastric and colorectal cancers belong to the most frequent cancer types in the world today. This fact emphasizes the importance of identification of useful diagnostic and prognostic markers, in the earliest stage of the disease. The examination of gene expression profile in gastric and colorectal cancer may develop the bases of early diagnosis and of individual therapeutic strategies. In the microarray examinations done so far for these types of cancers, the expression of hundreds and thousands of genes were studied, however, both the sample collection and the results showed wide variations. The diversity of expression array methods and data analysis makes the comparison of microarray results difficult. Beside the exposition of the practical aspects of the chip technology, our aims are the systematization of data that are currently available in the international scientific literature and the description of the results in a comprehensive way. Microarray results show that the gene expression pattern, detected in gastric and colon cancers, highly depends on the histological type and heterogeneity of the sample, array type, and softwares, used for data analysis. Recent experiments point out not just the changes of the alterations of tumor suppression, apoptosis, cell-cycle regulation, and signal transduction, but tumor cell metabolism and cell-microenvironment interactions also. Results show connection to and make more complete the already known molecular background of gastric and colorectal cancers. Based on the accumulation of recent and further data, such kind of multifunctional diagnostic microarrays that can be suited for completing the conventional histological diagnostics and subtypization will certainly become available in the near future.
Collapse
Affiliation(s)
- Orsolya Galamb
- II Department of Medicine, Semmelweis University, Faculty of Medicine Budapest, Hungary.
| | | | | | | | | |
Collapse
|
|
37
|
van Baal JWPM, Milano F, Rygiel AM, Bergman JJGHM, Rosmolen WD, van Deventer SJH, Wang KK, Peppelenbosch MP, Krishnadath KK. A comparative analysis by SAGE of gene expression profiles of Barrett's esophagus, normal squamous esophagus, and gastric cardia. Gastroenterology 2005; 129:1274-81. [PMID: 16230080 DOI: 10.1053/j.gastro.2005.07.026] [Citation(s) in RCA: 62] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/13/2005] [Accepted: 07/06/2005] [Indexed: 12/16/2022]
Abstract
BACKGROUND & AIMS The metaplastic process in which the normal squamous epithelium of the distal esophagus is replaced by columnar-lined epithelium, known as Barrett's esophagus (BE), is poorly understood. The aim of this study was to define, analyze, and compare transcription profiles of BE, normal cardia epithelium, and squamous epithelium to gain more insight into the process of metaplasia and to identify uniquely expressed genes in these epithelia. METHODS Serial analysis of gene expression was applied for obtaining transcription libraries of biopsy specimens taken from a BE-affected patient with intestinal type of metaplasia and from normal squamous and gastric cardia epithelia. Validation of results by reverse-transcription polymerase chain reaction and immunoblotting was performed using tissues of 20 patients with BE. RESULTS More than 120,000 tags were sequenced. Between BE and squamous 776, and between BE and gastric cardia 534 tags were significantly differentially expressed (P < .05, pairwise comparison). In contrast, squamous compared with gastric cardia epithelia showed significant differential expression of 1316 tags. The most up-regulated genes in BE compared with squamous epithelium were trefoil factors, annexin A10, and galectin-4. Each of the epithelia showed a unique cytokeratin expression profile. CONCLUSIONS This study provides a comparison of the transcriptomes of BE, squamous epithelium, and gastric cardia epithelium. BE proves to be an incompletely differentiated type of epithelium that shows similarities to both normal squamous and gastric cardia epithelia. In addition, several uniquely expressed genes are identified. These results are a major advancement in understanding the process of metaplasia that leads to BE.
Collapse
Affiliation(s)
- Jantine W P M van Baal
- Laboratory of Experimental Internal Medicine, Academic Medical Center, Amsterdam, The Netherlands.
| | | | | | | | | | | | | | | | | |
Collapse
|
|
38
|
Terada N, Ohno N, Yamakawa H, Ohara O, Ohno S. Topographical significance of membrane skeletal component protein 4.1 B in mammalian organs. Anat Sci Int 2005; 80:61-70. [PMID: 15960311 DOI: 10.1111/j.1447-073x.2005.00094.x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
The polarized architecture of epithelial cells is a fundamental determinant of cell structures and functions. Both formation and orientation of proper epithelial polarity are needed for cell-cell or cell-matrix adhesion, signal transduction and cytoskeletal interactions of multimolecular complexes at apical, lateral and basal cell membranes. These cell membrane domains are usually segregated by some junctional complexes. Recent molecular genetic studies on the anchor structure between myelin sheaths and axons have indicated the specific molecular organization for polarization of axolemma and the myelin sheaths at paranodes, termed 'septate-like junctions'. It was also speculated that other mammalian organs may use a similar junctional system. The protein 4.1 B was originally found to be localized in paranodes and juxtaparanodes of myelinated nerve fibers. Our recent immunohistochemical studies on protein 4.1B have indicated its significance for the cell-cell and/or cell-matrix adhesion in various rodent organs. The protein 4.1 family of proteins have been supposed to possess variable molecular domains relating to cell adhesion, ion balance, receptor responses and signal transduction. Therefore, more precise studies on the molecular structure and the functional domains of protein 4.1B, as well as on its changes under physiological and pathological conditions, may provide a clue for organogenesis in various mammalian organs.
Collapse
Affiliation(s)
- Nobuo Terada
- Department of Anatomy, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Tamaho, Japan.
| | | | | | | | | |
Collapse
|
|
39
|
Gologan A, Graham DY, Sepulveda AR. Molecular markers in Helicobacter pylori-associated gastric carcinogenesis. Clin Lab Med 2005; 25:197-222. [PMID: 15749238 DOI: 10.1016/j.cll.2004.12.002] [Citation(s) in RCA: 43] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
Helicobacter pylori infection is a known risk factor of gastric carcino-genesis. This article presents early molecular alterations associated with H. pylori chronic gastritis and advances in the molecular characterization of preneoplastic intestinal metaplasia (IM) and premalignant gastric mucosal lesions. H. pylori infection induces changes in gene expression, genomic instability and accumulation of gene mutations in the stomach epithelium. Mutations, including LOH and microsatellite instability, and gene hypermethylation are seen not only in gastric cancer, but are already detectable in IM and gastric dysplasia/adenoma. Recent reports using microarray expression analysis identified several gastric epithelial genes that are regulated by H. pylori. Among the many genes showing altered epithelial expression in response to H. pylori, some might be useful as markers to assess gastric cancer risk. Profiles of mutagenesis and gene expression in IM and dysplasia/adenoma have been characterized and represent potential markers of preneoplastic and premalignant lesions during gastric carcinogenesis.
Collapse
Affiliation(s)
- Adrian Gologan
- Department of Pathology, University of Pittsburgh Medical Center, PUH-A610, 200 Lothrop Street, Pittsburgh, PA 15213-2582, USA
| | | | | |
Collapse
|
|
40
|
Yu CD, Xu SH, Mou HZ, Jiang ZM, Zhu CH, Liu XL. Gene expression profile differences in gastric cancer, pericancerous epithelium and normal gastric mucosa by gene chip. World J Gastroenterol 2005; 11:2390-7. [PMID: 15832406 PMCID: PMC4305623 DOI: 10.3748/wjg.v11.i16.2390] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To study the difference of gene expression in gastric cancer (T), pericancerous epithelium (P) and normal tissue of gastric mucosa (C), and to screen an associated novel gene in early gastric carcinogenesis by oligonucleotide microarray.
METHODS: U133A (Affymetrix, Santa Clara, CA) gene chip was used to detect the gene expression profile difference in T, P and C, respectively. Bioinformatics was used to analyze the detected results.
RESULTS: When gastric cancer was compared with normal gastric mucosa, 766 genes were found, with a difference of more than four times in expression levels. Of the 766 genes, 530 were up-regulated (Signal Log Ratio [SLR]>2), and 236 were down-regulated (SLR<-2). When pericancerous epithelium was compared with normal gastric mucosa, 64 genes were found, with a difference of more than four times in expression levels. Of the 64 genes, 50 were up-regulated (SLR>2), and 14 were down-regulated (SLR<-2). Compared with normal gastric mucosa, a total of 143 genes with a difference in expression levels (more than four times, either in cancer or in pericancerous epithelium) were found in gastric cancer (T) and pericancerous epithelium (P). Of the 143 genes, 108 were up-regulated (SLR>2), and 35 were down-regulated (SLR<-2).
CONCLUSION: To apply a gene chip could find 143 genes associated with the genes of gastric cancer in pericancerous epithelium, although there were no pathological changes in the tissue slices. More interesting, six genes of pericancerous epithelium were up-regulated in comparison with genes of gastric cancer and three genes were down-regulated in comparison with genes of gastric cancer. It is suggested that these genes may be related to the carcinogenesis and development of early gastric cancer.
Collapse
Affiliation(s)
- Chuan-Ding Yu
- Zhejiang Cancer Research Institute, No. 38 Guangji Road, Hangzhou 310022, Zhejiang Province, China.
| | | | | | | | | | | |
Collapse
|
|
41
|
Liu X, Krishnan A, Mondry A. An entropy-based gene selection method for cancer classification using microarray data. BMC Bioinformatics 2005; 6:76. [PMID: 15790388 PMCID: PMC1087831 DOI: 10.1186/1471-2105-6-76] [Citation(s) in RCA: 95] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2004] [Accepted: 03/24/2005] [Indexed: 12/04/2022] Open
Abstract
BACKGROUND Accurate diagnosis of cancer subtypes remains a challenging problem. Building classifiers based on gene expression data is a promising approach; yet the selection of non-redundant but relevant genes is difficult. The selected gene set should be small enough to allow diagnosis even in regular clinical laboratories and ideally identify genes involved in cancer-specific regulatory pathways. Here an entropy-based method is proposed that selects genes related to the different cancer classes while at the same time reducing the redundancy among the genes. RESULTS The present study identifies a subset of features by maximizing the relevance and minimizing the redundancy of the selected genes. A merit called normalized mutual information is employed to measure the relevance and the redundancy of the genes. In order to find a more representative subset of features, an iterative procedure is adopted that incorporates an initial clustering followed by data partitioning and the application of the algorithm to each of the partitions. A leave-one-out approach then selects the most commonly selected genes across all the different runs and the gene selection algorithm is applied again to pare down the list of selected genes until a minimal subset is obtained that gives a satisfactory accuracy of classification. The algorithm was applied to three different data sets and the results obtained were compared to work done by others using the same data sets. CONCLUSION This study presents an entropy-based iterative algorithm for selecting genes from microarray data that are able to classify various cancer sub-types with high accuracy. In addition, the feature set obtained is very compact, that is, the redundancy between genes is reduced to a large extent. This implies that classifiers can be built with a smaller subset of genes.
Collapse
Affiliation(s)
- Xiaoxing Liu
- Bioinformatics Institute, 30, Biopolis Street, #07-01, (S) 138671, Singapore
| | - Arun Krishnan
- Bioinformatics Institute, 30, Biopolis Street, #07-01, (S) 138671, Singapore
| | - Adrian Mondry
- Bioinformatics Institute, 30, Biopolis Street, #07-01, (S) 138671, Singapore
| |
Collapse
|
|
42
|
Dicken BJ, Bigam DL, Cass C, Mackey JR, Joy AA, Hamilton SM. Gastric adenocarcinoma: review and considerations for future directions. Ann Surg 2005; 241:27-39. [PMID: 15621988 PMCID: PMC1356843 DOI: 10.1097/01.sla.0000149300.28588.23] [Citation(s) in RCA: 501] [Impact Index Per Article: 25.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
OBJECTIVE This update reviews the epidemiology and surgical management, and the controversies of gastric adenocarcinoma. We provide the relevance of outcome data to surgical decision-making and discuss the application of gene-expression analysis to clinical practice. SUMMARY BACKGROUND DATA Gastric cancer mortality rates have remained relatively unchanged over the past 30 years, and gastric cancer continues to be one of the leading causes of cancer-related death. Well-conducted studies have stimulated changes to surgical decision-making and technique. Microarray studies linked to predictive outcome models are poised to advance our understanding of the biologic behavior of gastric cancer and improve surgical management and outcome. METHODS We performed a review of the English gastric adenocarcinoma medical literature (1980-2003). This review included epidemiology, pathology and staging, surgical management, issues and controversies in management, prognostic variables, and the application of outcome models to gastric cancer. The results of DNA microarray analysis in various cancers and its predictive abilities in gastric cancer are considered. RESULTS Prognostic studies have provided valuable data to better the understanding of gastric cancer. These studies have contributed to improved surgical technique, more accurate pathologic characterization, and the identification of clinically useful prognostic markers. The application of microarray analysis linked to predictive models will provide a molecular understanding of the biology driving gastric cancer. CONCLUSIONS Predictive models generate important information allowing a logical evolution in the surgical and pathologic understanding and therapy for gastric cancer. However, a greater understanding of the molecular changes associated with gastric cancer is needed to guide surgical and medical therapy.
Collapse
Affiliation(s)
- Bryan J Dicken
- Department of Surgery, University of Alberta & Cross Cancer Institute, Edmonton, Alberta, Canada
| | | | | | | | | | | |
Collapse
|
|
43
|
Kim NS, Hahn Y, Oh JH, Lee JY, Oh KJ, Kim JM, Park HS, Kim S, Song KS, Rho SM, Yoo HS, Kim YS. Gene cataloging and expression profiling in human gastric cancer cells by expressed sequence tags. Genomics 2005; 83:1024-45. [PMID: 15177556 DOI: 10.1016/j.ygeno.2003.12.002] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2003] [Accepted: 12/04/2003] [Indexed: 12/14/2022]
Abstract
To understand the molecular mechanism associated with gastric carcinogenesis, we identified genes expressed in gastric cancer cell lines and tissues. Of 97,609 high-quality ESTs sequenced from 36 cDNA libraries, 92,545 were coalesced into 10,418 human Unigene clusters (Build 151). The gene expression profile was produced by counting the cluster frequencies in each library. Although the profiles of highly expressed genes varied greatly from library to library, those genes related to cell structure formation, heat shock proteins, the glycolysis pathway, and the signaling pathway were highly represented in human gastric cancer cell lines and in primary tumors. Conversely, the genes encoding immunoglobulins, ribosomal proteins, and digestive proteins were down-regulated in gastric cancer cell lines and tissues compared to normal tissues. The transcription levels of some of these genes were confirmed by RT-PCR. We found that genes related to cell adhesion, apoptosis, and cytoskeleton formation were particularly up-regulated in the gastric cancer cell lines established from malignant ascites compared to those from primary tumors. This comprehensive molecular profiling of human gastric cancer should be useful for elucidating the genetic events associated with human gastric cancer.
Collapse
Affiliation(s)
- Nam-Soon Kim
- Laboratory of Human Genomics, Korea Research Institute of Bioscience and Biotechnology, Daejeon 305-333, South Korea
| | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
44
|
Kim JM, Sohn HY, Yoon SY, Oh JH, Yang JO, Kim JH, Song KS, Rho SM, Yoo HS, Kim YS, Kim JG, Kim NS. Identification of Gastric Cancer–Related Genes Using a cDNA Microarray Containing Novel Expressed Sequence Tags Expressed in Gastric Cancer Cells. Clin Cancer Res 2005. [DOI: 10.1158/1078-0432.473.11.2] [Citation(s) in RCA: 34] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
Abstract
Purpose: Gastric cancer is one of the most frequently diagnosed malignancies in the world, especially in Korea and Japan. To understand the molecular mechanism associated with gastric carcinogenesis, we attempted to identify novel gastric cancer–related genes using a novel 2K cDNA microarray.
Experimental Design: A 2K cDNA microarray was fabricated from 1,995 novel expressed sequence tags (ESTs) showing no hits or a low homology with ESTs in public databases from our 143,452 ESTs collected from gastric cancer cell lines and tissues. An analysis of the gene expression for human gastric cancer cell lines to a normal cell line was done using this cDNA microarray. Data for the different expressed genes were verified using semiquantitative reverse transcription-PCR, Western blotting, and immunohistochemical staining in the gastric cell lines and tissues.
Results: Forty genes were identified as either up-regulated or down-regulated genes in human gastric cancer cells. Among these, genes such as SKB1, NT5C3, ZNF9, p30, CDC20, and FEN1, were confirmed to be up-regulated genes in nine gastric cell lines and in 25 pairs of tissue samples from patients by semiquantitative reverse transcription-PCR. On the other hand, genes such as MT2A and CXX1 were identified as down-regulated genes. In particular, the SKB1, CDC20, and FEN1 genes were overexpressed in ≥68% of tissues and the MT2A gene was down-expressed in 72% of the tissues. Western blotting and immunohistochemical analyses for CDC20 and SKB1 showed overexpression and localization changes of the corresponding protein in human gastric cancer tissues.
Conclusions: Novel genes that are related to human gastric cancer were identified using cDNA microarray developed in our laboratory. In particular, CDC20 and MT2A represent a potential biomarker of human gastric cancer. These newly identified genes should provide a valuable resource for understanding the molecular mechanism associated with tumorigenesis of gastric carcinogenesis and for the discovery of potential diagnostic markers of gastric cancer.
Collapse
Affiliation(s)
- Jeong-Min Kim
- 1Genome Research Center, Korea Research Institute of Bioscience and Biotechnology
- 5Department of Microbiology, College of Natural Sciences, Kyungpook National University, Daegu, Korea
| | - Ho-Yong Sohn
- 4Department of Food and Nutrition, Andong National University, Andong, Korea; and
| | - Sun Young Yoon
- 1Genome Research Center, Korea Research Institute of Bioscience and Biotechnology
| | - Jung-Hwa Oh
- 1Genome Research Center, Korea Research Institute of Bioscience and Biotechnology
| | - Jin Ok Yang
- 1Genome Research Center, Korea Research Institute of Bioscience and Biotechnology
| | - Joo Heon Kim
- 2Department of Pathology, Eulji University School of Medicine; and
| | - Kyu Sang Song
- 3Department of Pathology, College of Medicine, Chungnam National University, Daejeon, Korea
| | - Seung-Moo Rho
- 2Department of Pathology, Eulji University School of Medicine; and
| | - Hyan Sook Yoo
- 1Genome Research Center, Korea Research Institute of Bioscience and Biotechnology
| | - Yong Sung Kim
- 1Genome Research Center, Korea Research Institute of Bioscience and Biotechnology
| | - Jong-Guk Kim
- 5Department of Microbiology, College of Natural Sciences, Kyungpook National University, Daegu, Korea
| | - Nam-Soon Kim
- 1Genome Research Center, Korea Research Institute of Bioscience and Biotechnology
| |
Collapse
|
|
45
|
Koon N, Zaika A, Moskaluk CA, Frierson HF, Knuutila S, Powell SM, El-Rifai W. Clustering of molecular alterations in gastroesophageal carcinomas. Neoplasia 2004; 6:143-9. [PMID: 15140403 PMCID: PMC1502088 DOI: 10.1593/neo.03385] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
Gene expression levels are regulated at many levels. Integration of genome-wide analyses for the study of DNA and RNA provides a unique tool to detect genetic alterations in the cancer genome. In this study, we generated and integrated DNA amplification data from comparative genomic hybridization (CGH) and serial analyses of gene expression (SAGE) in order to obtain a molecular profile of gastroesophageal junction (GEJ) carcinomas. DNA amplifications mapped to specific chromosomal regions and were frequently seen at 1q, 4q, 5q, 6p, 7p, 8q, 17q, and 20q. Using SAGE, we obtained over 156,432 tags from GEJ adenocarcinomas and normal gastric mucosa. These tags were assigned to UniGene clusters. Chromosomal positions for overexpressed genes were obtained to produce a GEJ carcinoma transcriptome map. A total of 123 genes was significantly overexpressed (more than fivefold; P <.01) in one or more SAGE libraries. This gene overexpression map was integrated and compared to the chromosomal CGH ideogram. Several chromosomal arms that had frequent DNA amplifications showed frequent gene expression alterations such as chromosomes 1 (15 genes), 2 (9 genes), 6 (6 genes), 11 (6 genes), 12 (8 genes), and 17 (13 genes). Despite the relatively large DNA amplification regions, overexpressed genes frequently mapped and clustered to small chromosomal regions at early-replicating (Giemsa light) bands such as 1q21.3 (nine genes), 6p21.3 (five genes), and 17q21 (eight genes). These results provide a comprehensive tool to search for DNA amplifications and overexpressed genes in GEJ carcinoma. The observed phenomenon of the presence of large amplification areas, yet clustering of overexpressed genes to relatively small loci, may suggest a high organization of chromatin and cancer-related genes in the nucleus.
Collapse
Affiliation(s)
- Natalie Koon
- Digestive Health Center of Excellence University of Virginia Health System, Charlottesville, VA 22908-0708, USA
| | - Alexander Zaika
- Digestive Health Center of Excellence University of Virginia Health System, Charlottesville, VA 22908-0708, USA
| | - Christopher A Moskaluk
- Department of Pathology, University of Virginia Health System, Charlottesville, VA 22908-0708, USA
| | - Henry F Frierson
- Department of Pathology, University of Virginia Health System, Charlottesville, VA 22908-0708, USA
| | - Sakari Knuutila
- Department of Medical Genetics, University of Helsinki, Helsinki, Finland
| | - Steven M Powell
- Digestive Health Center of Excellence University of Virginia Health System, Charlottesville, VA 22908-0708, USA
| | - Wa'el El-Rifai
- Digestive Health Center of Excellence University of Virginia Health System, Charlottesville, VA 22908-0708, USA
| |
Collapse
|
|
46
|
Kimura Y, Noguchi T, Kawahara K, Kashima K, Daa T, Yokoyama S. Genetic alterations in 102 primary gastric cancers by comparative genomic hybridization: gain of 20q and loss of 18q are associated with tumor progression. Mod Pathol 2004; 17:1328-37. [PMID: 15154013 DOI: 10.1038/modpathol.3800180] [Citation(s) in RCA: 78] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Gastric cancer is one of the most common cancers. Molecular events in the carcinogenesis of gastric cancer remain, however, largely undefined. We investigated changes in DNA copy number in 102 gastric cancers by CGH. We found changes in DNA copy number in all cases, with frequent (> or =30% of patients) gains at 20q, 8q, 20p, 7q, 17q, 5p, and 13q. Frequent (> or =20%) losses were found at 19p, 18q, 5q, 21q, 4p, 4q, 15q, and 17p. The mean number of total alterations was significantly lower in grade 3 and scirrhous-type carcinomas (10.81 in grade 3 vs 13.98 in grade 1 and grade 2, 9.31 in scirrhous-type vs 13.18 in medullary- and intermediate-type). The mean number of losses and total alterations were higher in tumors at pT2, pT3 and pT4 (4.68 and 12.77 in pT2, pT3, and pT4 vs 2.55 and 9.22 in pT1). The mean number of losses was higher in carcinomas with lymph node metastasis (4.83). The mean number of gains and total alterations were higher in carcinomas with venous invasion (8.44 and 13.28). Several chromosomal alterations were linked in a statistically significant manner to specific clinicopathological parameters. Gain of 17q, 20p, and 20q and loss of 4p were associated with the pattern of the cancer-stroma relationship; loss of 18q was associated with pT category; gain of 5p was associated with pN category; loss of 4q and loss of 21q were associated with lymphatic invasion; gain of 7p and loss of 4q and 18q were associated with venous invasion; and loss of 18q was associated with pathological stage. These data suggest that gain of 20q and loss of 18q might play an important role in the development and progression of gastric cancer. Moreover, some genes on 20q and 18q might be target genes of gastric cancer.
Collapse
Affiliation(s)
- Yasuhiko Kimura
- Department of Oncological Science (Pathology), Faculty of Medicine, Oita University, Oita 879-5593 , Japan.
| | | | | | | | | | | |
Collapse
|
|
47
|
Abdelhaleem M. Do human RNA helicases have a role in cancer? Biochim Biophys Acta Rev Cancer 2004; 1704:37-46. [PMID: 15238243 DOI: 10.1016/j.bbcan.2004.05.001] [Citation(s) in RCA: 43] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2004] [Accepted: 05/06/2004] [Indexed: 11/24/2022]
Abstract
Human RNA helicases (HRH) represent a large family of enzymes that play important roles in RNA processing. The biochemical characteristics and biological functions of the majority of HRH are still to be determined. However, there are examples of dysregulation of HRH expression in various types of cancer. In addition, some HRH have been shown to be involved in the regulation of, or the molecular interaction with, molecules implicated in cancer. Other helicases take part in fusion transcripts resulting from cancer-associated chromosomal translocation. These findings raise the question of whether HRH can contribute to cancer development/progression. In this review, I summarize the cancer-related features of HRH.
Collapse
Affiliation(s)
- Mohamed Abdelhaleem
- Division of Haematopathology, Department of Paediatric Laboratory Medicine, Hospital for Sick Children, University of Toronto, Room 3691 Atrium, 555 University Avenue, Toronto, ON M5G 1X8, Canada.
| |
Collapse
|
|
48
|
Oue N, Hamai Y, Mitani Y, Matsumura S, Oshimo Y, Aung PP, Kuraoka K, Nakayama H, Yasui W. Gene expression profile of gastric carcinoma: identification of genes and tags potentially involved in invasion, metastasis, and carcinogenesis by serial analysis of gene expression. Cancer Res 2004; 64:2397-405. [PMID: 15059891 DOI: 10.1158/0008-5472.can-03-3514] [Citation(s) in RCA: 227] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Gastric carcinoma (GC) is one of the most common malignancies worldwide. To better understand the genetic basis of this disease, we performed serial analysis of gene expression (SAGE) on four primary GC samples and one associated lymph node metastasis. We obtained a total of 137,706 expressed tags (Gene Expression Omnibus accession number GSE 545, SAGE Hiroshima gastric cancer tissue), including 38,903 that were unique. Comparing tags from our GC libraries containing different stages and different histologies, we found several genes and tags that are potentially involved in invasion, metastasis, and carcinogenesis. Among these, we selected 27 genes and measured mRNA expression levels in an additional 46 GC samples by quantitative reverse transcription-PCR. Frequently overexpressed genes (tumor/normal ratio > 2) were COL1A1 (percentage of cases with overexpression, 78.3%), CDH17 (73.9%), APOC1 (67.4%), COL1A2 (58.7%), YF13H12 (52.2%), CEACAM6 (50.0%), APOE (50.0%), REGIV (47.8%), S100A11 (41.3%), and FUS (41.3%). Among these genes, mRNA expression levels of CDH17 and APOE were associated with depth of tumor invasion (P = 0.0060 and P = 0.0139, respectively), and those of FUS and APOE were associated with degree of lymph node metastasis (P = 0.0416 and P = 0.0006, respectively). In addition, mRNA expression levels of FUS, COL1A1, COL1A2, and APOE were associated with stage (P = 0.0414, P = 0.0156, P = 0.0395, and P = 0.0125, respectively). Quantitative reverse transcription-PCR analysis also showed a high level of REGIV expression (>100 arbitrary units) in 14 of 46 GC samples (30.4%) but not in noncancerous tissues. We detected V5-tagged RegIV protein in the culture media of cells transfected with pcDNA-RegIV-V5 by Western blot. Our results provide a list of candidate genes that are potentially involved in invasion, metastasis, and carcinogenesis of GC. REGIV may serve as a specific biomarker for GC.
Collapse
Affiliation(s)
- Naohide Oue
- Department of Molecular Pathology, Hiroshima University Graduate School of Biomedical Sciences, Hiroshima, Japan
| | | | | | | | | | | | | | | | | |
Collapse
|
|
49
|
van Erk MJ, Teuling E, Staal YCM, Huybers S, van Bladeren PJ, Aarts JMMJG, van Ommen B. Time- and dose-dependent effects of curcumin on gene expression in human colon cancer cells. J Carcinog 2004; 3:8. [PMID: 15140256 PMCID: PMC421747 DOI: 10.1186/1477-3163-3-8] [Citation(s) in RCA: 72] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2004] [Accepted: 05/12/2004] [Indexed: 12/31/2022] Open
Abstract
BACKGROUND: Curcumin is a spice and a coloring food compound with a promising role in colon cancer prevention. Curcumin protects against development of colon tumors in rats treated with a colon carcinogen, in colon cancer cells curcumin can inhibit cell proliferation and induce apoptosis, it is an anti-oxidant and it can act as an anti-inflammatory agent. The aim of this study was to elucidate mechanisms and effect of curcumin in colon cancer cells using gene expression profiling. METHODS: Gene expression changes in response to curcumin exposure were studied in two human colon cancer cell lines, using cDNA microarrays with four thousand human genes. HT29 cells were exposed to two different concentrations of curcumin and gene expression changes were followed in time (3, 6, 12, 24 and 48 hours). Gene expression changes after short-term exposure (3 or 6 hours) to curcumin were also studied in a second cell type, Caco-2 cells. RESULTS: Gene expression changes (>1.5-fold) were found at all time points. HT29 cells were more sensitive to curcumin than Caco-2 cells. Early response genes were involved in cell cycle, signal transduction, DNA repair, gene transcription, cell adhesion and xenobiotic metabolism. In HT29 cells curcumin modulated a number of cell cycle genes of which several have a role in transition through the G2/M phase. This corresponded to a cell cycle arrest in the G2/M phase as was observed by flow cytometry. Functional groups with a similar expression profile included genes involved in phase-II metabolism that were induced by curcumin after 12 and 24 hours. Expression of some cytochrome P450 genes was downregulated by curcumin in HT29 and Caco-2 cells. In addition, curcumin affected expression of metallothionein genes, tubulin genes, p53 and other genes involved in colon carcinogenesis. CONCLUSIONS: This study has extended knowledge on pathways or processes already reported to be affected by curcumin (cell cycle arrest, phase-II genes). Moreover, potential new leads to genes and pathways that could play a role in colon cancer prevention by curcumin were identified.
Collapse
Affiliation(s)
- Marjan J van Erk
- Wageningen University, Division of Toxicology, Tuinlaan 5, 6703 HE Wageningen, the Netherlands
- Wageningen University/TNO Centre for Food Toxicology, PO Box 8000, 6700 EA Wageningen, the Netherlands
| | - Eva Teuling
- Wageningen University, Division of Toxicology, Tuinlaan 5, 6703 HE Wageningen, the Netherlands
| | - Yvonne CM Staal
- Wageningen University, Division of Toxicology, Tuinlaan 5, 6703 HE Wageningen, the Netherlands
| | - Sylvie Huybers
- Wageningen University, Division of Toxicology, Tuinlaan 5, 6703 HE Wageningen, the Netherlands
| | - Peter J van Bladeren
- Wageningen University/TNO Centre for Food Toxicology, PO Box 8000, 6700 EA Wageningen, the Netherlands
- Nestlé Research Centre, PO Box 44, CH-1000 Lausanne 26, Switzerland
| | - Jac MMJG Aarts
- Wageningen University, Division of Toxicology, Tuinlaan 5, 6703 HE Wageningen, the Netherlands
- Wageningen University/TNO Centre for Food Toxicology, PO Box 8000, 6700 EA Wageningen, the Netherlands
| | - Ben van Ommen
- TNO Nutrition and Food Research, PO Box 360, 3700 AJ Zeist, the Netherlands
| |
Collapse
|
|
50
|
Meireles SI, Cristo EB, Carvalho AF, Hirata R, Pelosof A, Gomes LI, Martins WK, Begnami MD, Zitron C, Montagnini AL, Soares FA, Neves EJ, Reis LFL. Molecular classifiers for gastric cancer and nonmalignant diseases of the gastric mucosa. Cancer Res 2004; 64:1255-65. [PMID: 14973074 DOI: 10.1158/0008-5472.can-03-1850] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
High incidence of gastric cancer-related death is mainly due to diagnosis at an advanced stage in addition to the lack of adequate neoadjuvant therapy. Hence, new tools aimed at early diagnosis would have a positive impact in the outcome of the disease. Using cDNA arrays having 376 genes either identified previously as altered in gastric tumors or known to be altered in human cancer, we determined expression signature of 99 tissue fragments representing normal gastric mucosa, gastritis, intestinal metaplasia, and adenocarcinomas. We first validated the array by identifying molecular markers that are associated with intestinal metaplasia, considered as a transition stage of gastric adenocarcinomas of the intestinal type as well as markers that are associated with diffuse type of gastric adenocarcinomas. Next, we applied Fisher's linear discriminant analysis in an exhaustive search of trios of genes that could be used to build classifiers for class distinction. Many classifiers could distinguish between normal and tumor samples, whereas, for the distinction of gastritis from tumor and for metaplasia from tumor, fewer classifiers were identified. Statistical validations showed that trios that discriminate between normal and tumor samples are powerful classifiers to distinguish between tumor and nontumor samples. More relevant, it was possible to identify samples of intestinal metaplasia that have expression signature resembling that of an adenocarcinoma and can now be used for follow-up of patients to determine their potential as a prognostic test for malignant transformation.
Collapse
Affiliation(s)
- Sibele I Meireles
- Ludwig Institute for Cancer Research, Rua Prof. Antonio Prudente 109, São Paulo, SP 01509-010, Brazil
| | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|