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Sikora-Skrabaka M, Walkiewicz KW, Waniczek D, Strzelczyk JK, Nowakowska-Zajdel E. Relationship Between Systemic Inflammatory Response Exponents, Levels of ADAM10, ADAM17 Proteins and Selected Clinical Parameters in Patients with Colorectal Cancer: Original Research Study. Int J Mol Sci 2025; 26:1104. [PMID: 39940871 PMCID: PMC11817235 DOI: 10.3390/ijms26031104] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2024] [Revised: 01/23/2025] [Accepted: 01/24/2025] [Indexed: 02/16/2025] Open
Abstract
Chronic inflammation is a confirmed risk factor for colorectal cancer (CRC). Indicators of systemic inflammatory response (SIR), such as neutrophil-to-lymphocyte ratio (NLR) or platelet-to-lymphocyte ratio (PLR), are easily accessible indicators of the generalized inflammatory response. At the molecular level, inflammation-related carcinogenesis involves proteins from the adamalysin family: ADAM10 and ADAM17. The aim of the study was to assess NLR and PLR and their relationship with selected clinical parameters in CRC patients, as well as the correlation between ADAM10 and ADAM17 in tumor tissue and matched surgical margins with NLR and PLR values. Tumor tissue material matched surgical margins, and blood was collected from 66 patients who underwent surgery because of CRC. The concentrations of ADAM10 and ADAM17 in the collected material were tested using the enzyme-linked immunosorbent assay (ELISA) method. SIR parameters (NLR, PLR) were also determined. The results were statistically analyzed and compared with selected clinical parameters. Results: The study showed that PLR was lower in patients with comorbid cardiovascular diseases (CVD). In patients who underwent preoperative treatment, both the NLR and PLR values were higher than in patients who underwent primary surgery. There was also a negative correlation between ADAM17 concentrations in the surgical margin and PLR values. In conclusion, the presence of additional diseases such as CVD or diabetes mellitus type 2 (DMT2) or the use of preoperative treatment should be taken into account when assessing SIR parameters in CRC patients. Moreover, no clear correlations have been found between ADAM10 and ADAM17 and SIR parameters.
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Affiliation(s)
- Magdalena Sikora-Skrabaka
- Department of Nutrition Related Prevention, Department of Metabolic Diseases Prevention, Faculty of Public Health in Bytom, Medical University of Silesia in Katowice, 41-902 Bytom, Poland;
- Department of Clinical Oncology, No. 4 Provincial Specialist Hospital, 41-902 Bytom, Poland
| | - Katarzyna Weronika Walkiewicz
- Department of Internal Diseases Propaedeutics and Emergency Medicine, Faculty of Public Health in Bytom, Medical University of Silesia, 41-902 Bytom, Poland;
| | - Dariusz Waniczek
- Department of Oncological Surgery, Faculty of Medical Sciences in Zabrze, Medical University of Silesia, 40-515 Katowice, Poland;
| | - Joanna Katarzyna Strzelczyk
- Department of Medical and Molecular Biology, Faculty of Medical Sciences in Zabrze, Medical University of Silesia in Katowice, 41-808 Zabrze, Poland;
| | - Ewa Nowakowska-Zajdel
- Department of Nutrition Related Prevention, Department of Metabolic Diseases Prevention, Faculty of Public Health in Bytom, Medical University of Silesia in Katowice, 41-902 Bytom, Poland;
- Department of Clinical Oncology, No. 4 Provincial Specialist Hospital, 41-902 Bytom, Poland
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Zhang ZX, Peng J, Ding WW. Lipocalin-2 and intestinal diseases. World J Gastroenterol 2024; 30:4864-4879. [PMID: 39679305 PMCID: PMC11612708 DOI: 10.3748/wjg.v30.i46.4864] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/27/2024] [Revised: 09/25/2024] [Accepted: 11/04/2024] [Indexed: 11/21/2024] Open
Abstract
Dysfunction of the intestinal barrier is a prevalent phenomenon observed across a spectrum of diseases, encompassing conditions such as mesenteric artery dissection, inflammatory bowel disease, cirrhosis, and sepsis. In these pathological states, the integrity of the intestinal barrier, which normally serves to regulate the selective passage of substances between the gut lumen and the bloodstream, becomes compromised. This compromised barrier function can lead to a range of adverse consequences, including increased permeability to harmful substances, the translocation of bacteria and their products into systemic circulation, and heightened inflammatory responses within the gut and beyond. Understanding the mechanisms underlying intestinal barrier dysfunction in these diverse disease contexts is crucial for the development of targeted therapeutic interventions aimed at restoring barrier integrity and ameliorating disease progression. Lipocalin-2 (LCN2) expression is significantly upregulated during episodes of intestinal inflammation, making it a pivotal indicator for gauging the extent of such inflammatory processes. Notably, however, LCN2 derived from distinct cellular sources, whether intestinal epithelial cells or immune cells, exhibits notably divergent functional characteristics. Furthermore, the multifaceted nature of LCN2 is underscored by its varying roles across different diseases, sometimes even demonstrating contradictory effects.
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Affiliation(s)
- Zhong-Xu Zhang
- Department of Trauma and Acute Care Surgery, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing 210002, Jiangsu Province, China
| | - Jian Peng
- Department of Trauma and Acute Care Surgery, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing 210002, Jiangsu Province, China
| | - Wei-Wei Ding
- Department of Trauma and Acute Care Surgery, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing 210002, Jiangsu Province, China
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Le P, Gong X, Ung L, Yang H, Keenan BP, Zhang L, He T. A robust ensemble feature selection approach to prioritize genes associated with survival outcome in high-dimensional gene expression data. FRONTIERS IN SYSTEMS BIOLOGY 2024; 4:1355595. [PMID: 39897528 PMCID: PMC11786965 DOI: 10.3389/fsysb.2024.1355595] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Indexed: 02/04/2025]
Abstract
Exploring features associated with the clinical outcome of interest is a rapidly advancing area of research. However, with contemporary sequencing technologies capable of identifying over thousands of genes per sample, there is a challenge in constructing efficient prediction models that balance accuracy and resource utilization. To address this challenge, researchers have developed feature selection methods to enhance performance, reduce overfitting, and ensure resource efficiency. However, applying feature selection models to survival analysis, particularly in clinical datasets characterized by substantial censoring and limited sample sizes, introduces unique challenges. We propose a robust ensemble feature selection approach integrated with group Lasso to identify compelling features and evaluate its performance in predicting survival outcomes. Our approach consistently outperforms established models across various criteria through extensive simulations, demonstrating low false discovery rates, high sensitivity, and high stability. Furthermore, we applied the approach to a colorectal cancer dataset from The Cancer Genome Atlas, showcasing its effectiveness by generating a composite score based on the selected genes to correctly distinguish different subtypes of the patients. In summary, our proposed approach excels in selecting impactful features from high-dimensional data, yielding better outcomes compared to contemporary state-of-the-art models.
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Affiliation(s)
- Phi Le
- Division of Hematology/Oncology, Department of Medicine, University of California, San Francisco, San Francisco, CA, United States
| | - Xingyue Gong
- Department of Physiological Nursing, School of Nursing, University of California, San Francisco, San Francisco, CA, United States
| | - Leah Ung
- Division of Hematology/Oncology, Department of Medicine, University of California, San Francisco, San Francisco, CA, United States
| | - Hai Yang
- Division of Hematology/Oncology, Department of Medicine, University of California, San Francisco, San Francisco, CA, United States
| | - Bridget P. Keenan
- Division of Hematology/Oncology, Department of Medicine, University of California, San Francisco, San Francisco, CA, United States
- Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, United States
| | - Li Zhang
- Division of Hematology/Oncology, Department of Medicine, University of California, San Francisco, San Francisco, CA, United States
- Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, United States
- Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA, United States
| | - Tao He
- Department of Mathematics, San Francisco State University, San Francisco, CA, United States
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Fabbi M, Costa D, Russo D, Arenare L, Gaggero G, Signoriello S, Scambia G, Pisano C, Colombo N, Losito NS, Filaci G, Spina A, Califano D, Scognamiglio G, Gadducci A, Mezzanzanica D, Bagnoli M, Ferrini S, Canzonieri V, Chiodini P, Perrone F, Pignata S. Analysis of A Disintegrin and Metalloprotease 17 (ADAM17) Expression as a Prognostic Marker in Ovarian Cancer Patients Undergoing First-Line Treatment Plus Bevacizumab. Diagnostics (Basel) 2022; 12:diagnostics12092118. [PMID: 36140519 PMCID: PMC9498026 DOI: 10.3390/diagnostics12092118] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2022] [Revised: 08/20/2022] [Accepted: 08/29/2022] [Indexed: 11/16/2022] Open
Abstract
To find prognostic factors for advanced ovarian cancer patients undergoing first-line therapy with carboplatin, paclitaxel and bevacizumab, we investigated the expression of a disintegrin and metalloprotease 17 (ADAM17) in cancer tissues. ADAM17 has been involved in ovarian cancer development, progression and cell resistance to cisplatin. Tissue microarrays from 309 ovarian cancer patients enrolled in the MITO16A/MANGO-OV2 clinical trial were analyzed by immunohistochemistry for ADAM17 protein expression. Intensity and extent of staining were combined into a semi-quantitative visual grading system (H score) which was related to clinicopathological characteristics of cases and the clinical outcome of patients by univariate and multivariate Cox regression models. ADAM17 immunostaining was detected in most samples, mainly localized in the tumor cells, with variable intensity across the cohort. Kaplan–Meier survival curves, generated according to the best cut-off value for the ADAM17 H score, showed that high ADAM17 expression was associated with worse prognosis for PFS and OS. However, after the application of a shrinkage procedure to adjust for overfitting hazard ratio estimates, the ADAM17 value as prognostic factor was lost. As subgroup analysis suggested that ADAM17 expression could be prognostically relevant in cases with no residual disease at baseline, further studies in this patient category may be worth planning.
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Affiliation(s)
- Marina Fabbi
- UO Bioterapie, IRCCS Ospedale Policlinico San Martino, 16132 Genoa, Italy
- Correspondence:
| | - Delfina Costa
- UO Oncologia Molecolare e Angiogenesi, IRCCS Ospedale Policlinico San Martino, 16132 Genoa, Italy
| | - Daniela Russo
- Microenvironment Molecular Targets Unit, Istituto Nazionale Tumori IRCCS Fondazione G. Pascale, 80131 Naples, Italy
| | - Laura Arenare
- Clinical Trials Unit, Istituto Nazionale Tumori IRCCS Fondazione G. Pascale, 80131 Naples, Italy
| | - Gabriele Gaggero
- UO Anatomia Patologica Ospedaliera, IRCCS Ospedale Policlinico San Martino, 16132 Genoa, Italy
| | - Simona Signoriello
- Department of Mental Health and Public Medicine, Section of Statistics, Università degli Studi della Campania Luigi Vanvitelli, 80131 Naples, Italy
| | - Giovanni Scambia
- Department of Women and Child Health, Division of Gynecologic Oncology, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy
- Department of Life Science and Public Health, Catholic University of Sacred Heart, Largo Agostino Gemelli, 00168 Rome, Italy
| | - Carmela Pisano
- Urogynecological Medical Oncology, Istituto Nazionale Tumori IRCCS Fondazione G. Pascale, 80131 Naples, Italy
| | - Nicoletta Colombo
- European Institute of Oncology IRCCS, University of Milan-Bicocca, 20126 Milan, Italy
| | - Nunzia Simona Losito
- Pathology Unit, Istituto Nazionale Tumori IRCCS Fondazione G. Pascale, 80131 Naples, Italy
| | - Gilberto Filaci
- UO Bioterapie, IRCCS Ospedale Policlinico San Martino, 16132 Genoa, Italy
- Department of Internal Medicine, University of Genoa, 16132 Genoa, Italy
| | - Anna Spina
- Microenvironment Molecular Targets Unit, Istituto Nazionale Tumori IRCCS Fondazione G. Pascale, 80131 Naples, Italy
| | - Daniela Califano
- Microenvironment Molecular Targets Unit, Istituto Nazionale Tumori IRCCS Fondazione G. Pascale, 80131 Naples, Italy
| | - Giosuè Scognamiglio
- Pathology Unit, Istituto Nazionale Tumori IRCCS Fondazione G. Pascale, 80131 Naples, Italy
| | - Angiolo Gadducci
- Department of Clinical and Experimental Medicine, Division of Gynecology and Obstetrics, University of Pisa, 56127 Pisa, Italy
| | - Delia Mezzanzanica
- Molecular Therapies Unit, Department of Research, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy
| | - Marina Bagnoli
- Molecular Therapies Unit, Department of Research, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy
| | - Silvano Ferrini
- UO Bioterapie, IRCCS Ospedale Policlinico San Martino, 16132 Genoa, Italy
| | - Vincenzo Canzonieri
- Pathology Unit, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, 33081 Aviano, Italy
- Department of Medical, Surgical and Health Sciences, University of Trieste, 34127 Trieste, Italy
| | - Paolo Chiodini
- Department of Mental Health and Public Medicine, Section of Statistics, Università degli Studi della Campania Luigi Vanvitelli, 80131 Naples, Italy
| | - Francesco Perrone
- Clinical Trials Unit, Istituto Nazionale Tumori IRCCS Fondazione G. Pascale, 80131 Naples, Italy
| | - Sandro Pignata
- Urogynecological Medical Oncology, Istituto Nazionale Tumori IRCCS Fondazione G. Pascale, 80131 Naples, Italy
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Adamalizyny jako potencjalne biomarkery w wybranych nowotworach złośliwych przewodu pokarmowego. POSTEP HIG MED DOSW 2021. [DOI: 10.2478/ahem-2021-0020] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Abstrakt
Nowotwory złośliwe przewodu pokarmowego zajmują czołowe miejsce zarówno wśród przyczyn zachorowań jak i zgonów z powodu chorób nowotworowych na świecie. Wciąż poszukuje się potencjalnych biomarkerów, które mogłyby posłużyć jako czynniki predykcyjne i prognostyczne w tych nowotworach. Wśród białek, które mogłyby pełnić taką rolę, wymienia się adamalizyny. Liczne białka z tej rodziny są zaangażowane w wielu etapach nowotworzenia, od procesu różnicowania się pojedynczych komórek, wzrost i progresję guza do tworzenia przerzutów odległych. Dzieje się to m.in. poprzez ścieżki sygnałowe związane z aktywacją insulinopodobnych czynników wzrostu, naskórkowych czynników wzrostu czy oddziaływanie na czynnik martwicy nowotworu TNF-α. Szczególnie istotna w wyjaśnieniu patomechanizmu rozwoju raków gruczołowych przewodu pokarmowego wydaje się ścieżka sygnałowa związana z aktywacją cytokin prozapalnych. Przewlekły stan zapalny jest bowiem dobrze udokumentowanym czynnikiem ryzyka rozwoju tej grupy chorób nowotworowych.
Poznanie roli białek z rodziny adamalizyn w rozwoju i patogenezie nowotworów złośliwych przewodu pokarmowego wymaga wciąż dalszych badań. W artykule podjęto próbę syntezy aktualnej wiedzy na temat wykorzystania wybranych białek z rodziny adamalizyn jako biomarkerów nowotworów złośliwych przewodu pokarmowego.
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Yang G, Cui M, Jiang W, Sheng J, Yang Y, Zhang X. Molecular switch in human diseases-disintegrin and metalloproteinases, ADAM17. Aging (Albany NY) 2021; 13:16859-16872. [PMID: 34182543 PMCID: PMC8266367 DOI: 10.18632/aging.203200] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2021] [Accepted: 05/18/2021] [Indexed: 01/01/2023]
Abstract
The ADAMs (a disintegrin and metalloproteinase) are a family of cell surface proteins with crucial roles in the regulation of cell adhesion, cell proliferation to migration, proteolysis and cell signaling transduction pathways. Among these enzymes, the ADAM17 shows significant effects in the “ectodomain shedding” of its substrates such as cytokines (e.g., tumor necrosis factor α, TNFα), growth factors (e.g., epidermal growth factor, EGF), adhesion proteins (e.g., L-selectin), and their receptors (e.g., IL-6R and TNFα). Several studies focus on the underlying molecular mechanisms of ADAM17 in diseased conditions. Here, we took several different approaches to elucidate the function of ADAM17, the participation of ADAM17 in several human diseases, and the potential as targeted therapy reagents. As more and more studies verify the miRNA-mediated expression variation of ADAM17, the specific regulation network of miRNAs and ADAM17 was exploited in this review as well.
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Affiliation(s)
- Guang Yang
- Jilin Provincial Key Laboratory on Molecular and Chemical Genetic, The Second Hospital of Jilin University, Changchun 130041, P.R. China
| | - Mengying Cui
- Department of Hepatobiliary and Pancreatic Surgery, The Second Hospital of Jilin University, Changchun 130041, P.R. China
| | - Weibo Jiang
- Department of Orthopaedic, The Second Hospital of Jilin University, Changchun 130041, P.R. China
| | - Jiyao Sheng
- Department of Hepatobiliary and Pancreatic Surgery, The Second Hospital of Jilin University, Changchun 130041, P.R. China
| | - Yongsheng Yang
- Department of Hepatobiliary and Pancreatic Surgery, The Second Hospital of Jilin University, Changchun 130041, P.R. China
| | - Xuewen Zhang
- Department of Hepatobiliary and Pancreatic Surgery, The Second Hospital of Jilin University, Changchun 130041, P.R. China
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Loss of Neogenin1 in human colorectal carcinoma cells causes a partial EMT and wound-healing response. Sci Rep 2019; 9:4110. [PMID: 30858446 PMCID: PMC6411945 DOI: 10.1038/s41598-019-40886-y] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2018] [Accepted: 02/15/2019] [Indexed: 02/07/2023] Open
Abstract
Neogenin1 (NEO1) is a receptor of the Deleted in Colorectal Carcinoma (DCC)/Frazzled/UNC-40 family, which regulates axon guidance but can also stabilize epithelial adherens junctions. NEO1 and DCC are also tumor suppressors that can inhibit metastasis by acting as dependence receptors. Given the role of NEO1 in maintaining adherens junctions we tested whether loss of NEO1 also promoted metastasis via an epithelial mesenchymal transition (EMT). Loss of NEO1 disrupted zonula adherens but tight junctions were unaffected. Neo1-depleted epithelial cells exhibited a more migratory morphology, had reduced F-actin rich stress-fibres and more basal lamellipodia. Microtubule density was decreased while microtubule outgrowth was faster. Live imaging showed that Neo1-depleted epithelial islands had increased lateral movement. Western blots and immunostaining revealed increased expression of mesenchymal markers such as Fibronectin and MMP1. Furthermore, RNA-seq analysis showed a striking decrease in expression of genes associated with oxidative phosphorylation, and increased expression of genes associated with EMT, locomotion, and wound-healing. In summary, loss of NEO1 in intestinal epithelial cells produces a partial EMT response, based on gene expression, cellular morphology and behaviour and cytoskeletal distribution. These results suggest that loss of NEO1 in carcinomas may contribute to metastasis by promoting a partial EMT and increased motility.
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Østrup O, Dagenborg VJ, Rødland EA, Skarpeteig V, Silwal-Pandit L, Grzyb K, Berstad AE, Fretland ÅA, Mælandsmo GM, Børresen-Dale AL, Ree AH, Edwin B, Nygaard V, Flatmark K. Molecular signatures reflecting microenvironmental metabolism and chemotherapy-induced immunogenic cell death in colorectal liver metastases. Oncotarget 2017; 8:76290-76304. [PMID: 29100312 PMCID: PMC5652706 DOI: 10.18632/oncotarget.19350] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2017] [Accepted: 06/26/2017] [Indexed: 01/05/2023] Open
Abstract
Background Metastatic colorectal cancer (CRC) is associated with highly variable clinical outcome and response to therapy. The recently identified consensus molecular subtypes (CMS1-4) have prognostic and therapeutic implications in primary CRC, but whether these subtypes are valid for metastatic disease is unclear. We performed multi-level analyses of resectable CRC liver metastases (CLM) to identify molecular characteristics of metastatic disease and evaluate the clinical relevance. Methods In this ancillary study to the Oslo-CoMet trial, CLM and tumor-adjacent liver tissue from 46 patients were analyzed by profiling mutations (targeted sequencing), genome-wide copy number alteration (CNAs), and gene expression. Results Somatic mutations and CNAs detected in CLM were similar to reported primary CRC profiles, while CNA profiles of eight metastatic pairs suggested intra-patient divergence. A CMS classifier tool applied to gene expression data, revealed the cohort to be highly enriched for CMS2. Hierarchical clustering of genes with highly variable expression identified two subgroups separated by high or low expression of 55 genes with immune-related and metabolic functions. Importantly, induction of genes and pathways associated with immunogenic cell death (ICD) was identified in metastases exposed to neoadjuvant chemotherapy (NACT). Conclusions The uniform classification of CLM by CMS subtyping may indicate that novel class discovery approaches need to be explored to uncover clinically useful stratification of CLM. Detected gene expression signatures support the role of metabolism and chemotherapy in shaping the immune microenvironment of CLM. Furthermore, the results point to rational exploration of immune modulating strategies in CLM, particularly by exploiting NACT-induced ICD.
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Affiliation(s)
- Olga Østrup
- Department of Tumor Biology, Institute for Cancer Research, Oslo University Hospital, The Norwegian Radium Hospital, Oslo, Norway
- Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital, The Norwegian Radium Hospital, Oslo, Norway
| | - Vegar Johansen Dagenborg
- Department of Tumor Biology, Institute for Cancer Research, Oslo University Hospital, The Norwegian Radium Hospital, Oslo, Norway
- Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
| | - Einar Andreas Rødland
- Department of Tumor Biology, Institute for Cancer Research, Oslo University Hospital, The Norwegian Radium Hospital, Oslo, Norway
- Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital, The Norwegian Radium Hospital, Oslo, Norway
| | - Veronica Skarpeteig
- Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital, The Norwegian Radium Hospital, Oslo, Norway
| | - Laxmi Silwal-Pandit
- Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital, The Norwegian Radium Hospital, Oslo, Norway
| | - Krzysztof Grzyb
- Department of Pathology, Oslo University Hospital, Rikshospitalet, Oslo, Norway
| | - Audun Elnæs Berstad
- Department of Radiology, Oslo University Hospital, The Norwegian Radium Hospital, Oslo, Norway
| | - Åsmund Avdem Fretland
- Department of Hepato-Pancreato-Biliary Surgery, Oslo University Hospital, Rikshospitalet, Oslo, Norway
- The Intervention Centre, Oslo University Hospital, Rikshospitalet, Oslo, Norway
- Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
| | - Gunhild Mari Mælandsmo
- Department of Tumor Biology, Institute for Cancer Research, Oslo University Hospital, The Norwegian Radium Hospital, Oslo, Norway
- Department of Pharmacy, University of Tromsø - The Arctic University of Norway, Tromsø, Norway
| | - Anne-Lise Børresen-Dale
- Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital, The Norwegian Radium Hospital, Oslo, Norway
- Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
| | - Anne Hansen Ree
- Department of Oncology, Akershus University Hospital, Lørenskog, Norway
- Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
| | - Bjørn Edwin
- Department of Hepato-Pancreato-Biliary Surgery, Oslo University Hospital, Rikshospitalet, Oslo, Norway
- The Intervention Centre, Oslo University Hospital, Rikshospitalet, Oslo, Norway
- Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
| | - Vigdis Nygaard
- Department of Tumor Biology, Institute for Cancer Research, Oslo University Hospital, The Norwegian Radium Hospital, Oslo, Norway
| | - Kjersti Flatmark
- Department of Tumor Biology, Institute for Cancer Research, Oslo University Hospital, The Norwegian Radium Hospital, Oslo, Norway
- Department of Gastroenterological Surgery, Oslo University Hospital, The Norwegian Radium Hospital, Oslo, Norway
- Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
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Ding C, Fan X, Wu G. Peroxiredoxin 1 - an antioxidant enzyme in cancer. J Cell Mol Med 2016; 21:193-202. [PMID: 27653015 PMCID: PMC5192802 DOI: 10.1111/jcmm.12955] [Citation(s) in RCA: 145] [Impact Index Per Article: 16.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2016] [Accepted: 07/17/2016] [Indexed: 12/11/2022] Open
Abstract
Peroxiredoxins (PRDXs), a ubiquitous family of redox‐regulating proteins, are reported of potential to eliminate various reactive oxygen species (ROS). As a major member of the antioxidant enzymes, PRDX1 can become easily over‐oxidized on its catalytically active cysteine induced by a variety of stimuli in vitro and in vivo. In nucleus, oligomeric PRDX1 directly associates with p53 or transcription factors such as c‐Myc, NF‐κB and AR, and thus affects their bioactivities upon gene regulation, which in turn induces or suppresses cell death. Additionally, PRDX1 in cytoplasm has anti‐apoptotic potential through direct or indirect interactions with several ROS‐dependent (redox regulation) effectors, including ASK1, p66Shc, GSTpi/JNK and c‐Abl kinase. PRDX1 is proven to be a versatile molecule regulating cell growth, differentiation and apoptosis. Recent studies have found that PRDX1 and/or PRDX1‐regulated ROS‐dependent signalling pathways play an important role in the progression and metastasis of human tumours, particularly in breast, oesophageal and lung cancers. In this paper, we review the structure, effector functions of PRDX1, its role in cancer and the pivotal role of ROS in anticancer treatment.
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Affiliation(s)
- Chenbo Ding
- Medical School of Southeast University, Nanjing, China
| | - Xiaobo Fan
- Medical School of Southeast University, Nanjing, China
| | - Guoqiu Wu
- Medical School of Southeast University, Nanjing, China.,Center of Clinical Laboratory Medicine, Zhongda Hospital, Southeast University, Nanjing, China
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10
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Versican: a novel modulator of hepatic fibrosis. J Transl Med 2016; 96:361-74. [PMID: 26752747 DOI: 10.1038/labinvest.2015.152] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2015] [Revised: 10/29/2015] [Accepted: 11/02/2015] [Indexed: 01/17/2023] Open
Abstract
Little is known about the deposition and turnover of proteoglycans in liver fibrosis, despite their abundance in the extracellular matrix. Versican plays diverse roles in modulating cell behavior in other fibroproliferative diseases, but remains poorly described in the liver. Hepatic fibrosis was induced by carbon tetrachloride treatment of C57BL/6 mice over 4 weeks followed by recovery over a 28-day period. Primary mouse hepatic stellate cells (HSCs) were activated in culture and versican was transiently knocked down in human (LX2) and mouse HSCs. Expression of versican, A Disintegrin-like and Metalloproteinase with Thrombospondin-1 motifs (ADAMTS)-1, -4, -5, -8, -9, -15, and -20, and markers of fibrogenesis were studied using immunohistochemistry, real-time quantitative PCR, and western blotting. Immunohistochemistry showed increased expression of versican in cirrhotic human livers and the mouse model of fibrosis. Carbon tetrachloride treatment led to significant increases in versican expression and the proteoglycanases ADAMTS-5, -9, -15, and -20, alongside TNF-α, α-smooth muscle actin (α-SMA), collagen-1, and TGF-β expression. During recovery, expression of many of these genes returned to control levels. However, expression of ADAMTS-5, -8, -9, and -15 showed delayed increases in expression at 28 days of recovery, which corresponded with decreases in versican V0 and V1 cleavage products (G1-DPEAAE(1401) and G1-DPEAAE(441)). Activation of primary HSCs in vitro significantly increased versican, α-SMA, and collagen-1 expression. Transient knockdown of versican in HSCs led to decreases in markers of fibrogenesis and reduced cell proliferation, without inducing apoptosis. Versican expression increases during HSC activation and liver fibrosis, and proteolytic processing occurs during the resolution of fibrosis. Knockdown studies in vitro suggest a possible role of versican in modulating hepatic fibrogenesis.
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Slattery ML, Pellatt DF, Mullany LE, Wolff RK, Herrick JS. Gene expression in colon cancer: A focus on tumor site and molecular phenotype. Genes Chromosomes Cancer 2015; 54:527-41. [PMID: 26171582 DOI: 10.1002/gcc.22265] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2015] [Revised: 05/05/2015] [Accepted: 05/07/2015] [Indexed: 12/28/2022] Open
Abstract
Hundreds to thousands of genes are differentially expressed in tumors when compared to nontumor colonic tissue samples. We evaluated gene expression patterns to better understand differences in colon cancer by tumor site and tumor molecular phenotype. We analyzed RNA-seq data from tumor/normal paired samples from 175 colon cancer patients. We implemented a cross validation strategy with nonparametric tests to identify genes which displayed varying expression characteristics related to paired tumor/nontumor tissue across proximal and distal colon sites and by tumor molecular phenotypes, that is, TP53, KRAS, CpG Island Methylator Phenotype (CIMP), and microsatellite instability (MSI). We used Ingenuity Pathway Analysis (IPA) to determine networks associated with deregulated genes in our data. Genes showed significant differences in expression characteristics at the 0.01 level in both validation groups between tumor subsite (116 genes), CIMP high versus CIMP low (79 genes), MSI versus microsatellite stable (MSS) (49 genes), TP53-mutated versus not mutated (17genes), and KRAS-mutated versus not mutated (1 gene). Deregulated genes for CIMP high and MSI tumors were often down-regulated. In contrast to CIMP high and MSI tumors, genes that were deregulated in TP53 were likely to be up-regulated. ERK1, WNT, growth factors and inflammation-related factors were focal points of both CIMP and MSI IPA networks. The MUC family of genes was up-regulated MSI networks. Numerous genes showed differences in expression between proximal and distal tumors, nontumor proximal and distal tissue, and tumor molecular phenotype. Deregulated mucin genes appear to play an important role in MSI tumors.
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Affiliation(s)
- Martha L Slattery
- Department of Internal Medicine, University of Utah, 383 Colorow, Salt Lake City, Utah, 84117
| | - Daniel F Pellatt
- Department of Internal Medicine, University of Utah, 383 Colorow, Salt Lake City, Utah, 84117
| | - Lila E Mullany
- Department of Internal Medicine, University of Utah, 383 Colorow, Salt Lake City, Utah, 84117
| | - Roger K Wolff
- Department of Internal Medicine, University of Utah, 383 Colorow, Salt Lake City, Utah, 84117
| | - Jennifer S Herrick
- Department of Internal Medicine, University of Utah, 383 Colorow, Salt Lake City, Utah, 84117
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del Rincón SV, Widschwendter M, Sun D, Ekholm-Reed S, Tat J, Teixeira LK, Ellederova Z, Grolieres E, Reed SI, Spruck C. Cks overexpression enhances chemotherapeutic efficacy by overriding DNA damage checkpoints. Oncogene 2015; 34:1961-7. [PMID: 24858038 PMCID: PMC4245389 DOI: 10.1038/onc.2014.137] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2013] [Revised: 03/27/2014] [Accepted: 03/28/2014] [Indexed: 12/12/2022]
Abstract
Cdc kinase subunit (Cks) proteins Cks1 and Cks2 are adaptor-like proteins that bind many cyclin-dependent kinases. A wealth of clinical data has shown that Cks proteins are overexpressed in many types of human cancers and this often correlates with increased tumor aggressiveness. Previously, we showed that Cks overexpression abrogates the intra-S-phase checkpoint, a major barrier to oncogene-mediated transformation. Interestingly, the intra-S-phase checkpoint is crucial for the cellular response to replication stress, a major pathway of apoptosis induction by many chemotherapeutic agents. Here, we demonstrate cancer cells that overexpress Cks1 or Cks2 override the intra-S-phase checkpoint in the presence of replication stress-inducing chemotherapies such as 5-Fluorouracil (5-FU) and methotrexate (MTX) leading to enhanced sensitivity in vitro and in vivo. Furthermore, enforced expression of Cks1 in an MTX-resistant breast cancer cell line was found to restore drug sensitivity. Our results suggest that Cks proteins are important determinants of apoptosis induction of replication stress-inducing chemotherapies such as 5-FU.
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Affiliation(s)
- Sonia V. del Rincón
- Tumor Initiation and Maintenance Program, Cancer Center, Sanford-Burnham Medical Research Institute, La Jolla, California, USA
| | | | - Dahui Sun
- Tumor Initiation and Maintenance Program, Cancer Center, Sanford-Burnham Medical Research Institute, La Jolla, California, USA
| | - Susanna Ekholm-Reed
- Department of Molecular Biology, The Scripps Research Institute, La Jolla, California, USA
| | - John Tat
- Department of Molecular Biology, The Scripps Research Institute, La Jolla, California, USA
| | - Leonardo K. Teixeira
- Department of Molecular Biology, The Scripps Research Institute, La Jolla, California, USA
| | - Zdenka Ellederova
- Tumor Initiation and Maintenance Program, Cancer Center, Sanford-Burnham Medical Research Institute, La Jolla, California, USA
| | - Elise Grolieres
- Tumor Initiation and Maintenance Program, Cancer Center, Sanford-Burnham Medical Research Institute, La Jolla, California, USA
| | - Steven I. Reed
- Department of Molecular Biology, The Scripps Research Institute, La Jolla, California, USA
| | - Charles Spruck
- Tumor Initiation and Maintenance Program, Cancer Center, Sanford-Burnham Medical Research Institute, La Jolla, California, USA
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You H, Lin H, Zhang Z. CKS2 in human cancers: Clinical roles and current perspectives (Review). Mol Clin Oncol 2015; 3:459-463. [PMID: 26137251 DOI: 10.3892/mco.2015.501] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2014] [Accepted: 01/23/2015] [Indexed: 12/23/2022] Open
Abstract
Cyclin-dependent kinase subunit 2 (CKS2) is indicated in the processes of cell cycle and cell proliferation. Through these processes, CKS2 is identified as a cancer gene, but its role has not been well reviewed. The aim of the present study was to summarize the clinicopathological significance and the molecular mechanisms of CKS2 in human cancers. Its expression was upregulated in the majority of the types of cancer studied. CKS2 was shown to have a function in cancers of the digestive tract, genital tract, thyroid, nerve and certain other types of cancer. CKS2 can promote progression of certain cancers via positive control of proliferation, invasion and migration. Downregulation of CKS2 induces cancer cell apoptosis. CKS2 can change a multitude of cellular mechanisms in cancer pathogenesis by regulating the gene translation of numerous validated targets, such as p53, CDK1, cyclin A, cyclin B1, caspase-3 and Bax. In addition, the molecular mechanism that causes aberrant expression of CKS2 was epigenetic modification of miR-26a and the Y-box-binding protein 1 (YB-1) gene. In conclusion, CKS2 is commonly elevated in cancer, most likely due to its ability to promote cancer cell growth, invasion and migration through regulating certain significant genes. Understanding the mechanisms by which CKS2 is involved with cancer pathogenesis will be useful in the development of tumor therapy for patients with cancer.
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Affiliation(s)
- Hanyu You
- Center for Clinical Laboratory, Xiamen University Affiliated Zhongshan Hospital, Xiamen, Fujian 361000, P.R. China
| | - Huayue Lin
- Center for Clinical Laboratory, Xiamen University Affiliated Zhongshan Hospital, Xiamen, Fujian 361000, P.R. China
| | - Zhongying Zhang
- Center for Clinical Laboratory, Xiamen University Affiliated Zhongshan Hospital, Xiamen, Fujian 361000, P.R. China ; State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, Xiamen, Fujian 361005, P.R. China
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Paul Olson TJ, Hadac JN, Sievers CK, Leystra AA, Deming DA, Zahm CD, Albrecht DM, Nomura A, Nettekoven LA, Plesh LK, Clipson L, Sullivan R, Newton MA, Schelman WR, Halberg RB. Dynamic tumor growth patterns in a novel murine model of colorectal cancer. Cancer Prev Res (Phila) 2013; 7:105-13. [PMID: 24196829 DOI: 10.1158/1940-6207.capr-13-0163] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Colorectal cancer often arises from adenomatous colonic polyps. Polyps can grow and progress to cancer, but may also remain static in size, regress, or resolve. Predicting which polyps progress and which remain benign is difficult. We developed a novel long-lived murine model of colorectal cancer with tumors that can be followed by colonoscopy. Our aim was to assess whether these tumors have similar growth patterns and histologic fates to human colorectal polyps to identify features to aid in risk stratification of colonic tumors. Long-lived Apc(Min/+) mice were treated with dextran sodium sulfate to promote colonic tumorigenesis. Tumor growth patterns were characterized by serial colonoscopy with biopsies obtained for immunohistochemistry and gene expression profiling. Tumors grew, remained static, regressed, or resolved over time with different relative frequencies. Newly developed tumors demonstrated higher rates of growth and resolution than more established tumors that tended to remain static in size. Colonic tumors were hyperplastic lesions (3%), adenomas (73%), intramucosal carcinomas (20%), or adenocarcinomas (3%). Interestingly, the level of β-catenin was higher in adenomas that became intratumoral carcinomas than those that failed to progress. In addition, differentially expressed genes between adenomas and intramucosal carcinomas were identified. This novel murine model of intestinal tumorigenesis develops colonic tumors that can be monitored by serial colonoscopy, mirror growth patterns seen in human colorectal polyps, and progress to colorectal cancer. Further characterization of cellular and molecular features is needed to determine which features can be used to risk-stratify polyps for progression to colorectal cancer and potentially guide prevention strategies.
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Affiliation(s)
- Terrah J Paul Olson
- University of Wisconsin-Madison K4/532 Clinical Science Center, 600 Highland Avenue, Madison, WI 53792.
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Przemyslaw L, Boguslaw HA, Elzbieta S, Malgorzata SM. ADAM and ADAMTS family proteins and their role in the colorectal cancer etiopathogenesis. BMB Rep 2013; 46:139-50. [PMID: 23527857 PMCID: PMC4133867 DOI: 10.5483/bmbrep.2013.46.3.176] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023] Open
Abstract
The ADAM and ADAMTS families, also called adamalysins belong to an important group of extracellular matrix proteins. The ADAMs family belong to both the transmembrane and secreted proteins, while ADAMTS family only contains secreted forms. Adamalysins play an important role in the cell phenotype regulation via their activities in signaling pathways, cell adhesion and migration. The human proteome contains 21 ADAM, and 19 ADAMTS proteins, which are involved in extracellular matrix remodeling, shedding of various substrates such as: adhesion ligands, growth factors, their receptors and diverse cytokines. Recent studies provide evidence that adamalysins play a crucial role in colorectal cancer (CRC) etiopathogenesis. It seems possible that adamalysins might be used as CRC prediction markers or potential pharmaceutical targets. [BMB Reports 2013; 46(3): 139-150]
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Extensive quantitative remodeling of the proteome between normal colon tissue and adenocarcinoma. Mol Syst Biol 2013; 8:611. [PMID: 22968445 PMCID: PMC3472694 DOI: 10.1038/msb.2012.44] [Citation(s) in RCA: 192] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2012] [Accepted: 08/08/2012] [Indexed: 12/15/2022] Open
Abstract
In-depth proteomic analysis of microdissected colorectal cancer identifies extensive alterations in the cell-surface and nuclear proteomes between normal mucosa and adenocarcinoma, but observes strikingly little proteomic change between cancer and metastases. ![]()
First large-scale proteomic analysis of microdissected tissue from archival formalin-fixed and paraffin-embedded material. Quantitation of 7576 proteins between patient-matched samples of normal colonic mucosa, primary cancer, and nodal metastasis. Expression levels of 1808 proteins changed significantly between normal and cancer tissues. Total Protein Approach (TPA)—a new way to determine protein copy numbers per cell without protein standards. We report a proteomic analysis of microdissected material from formalin-fixed and paraffin-embedded colorectal cancer, quantifying >7500 proteins between patient matched normal mucosa, primary carcinoma, and nodal metastases. Expression levels of 1808 proteins changed significantly between normal and cancer tissues, a much larger fraction than that reported in transcript-based studies. Tumor cells exhibit extensive alterations in the cell-surface and nuclear proteomes. Functionally similar changes in the proteome were observed comparing rapidly growing and differentiated CaCo-2 cells. In contrast, there was minimal proteomic remodeling between primary cancer and metastases, suggesting that no drastic proteome changes are necessary for the tumor to propagate in a different tissue context. Additionally, we introduce a new way to determine protein copy numbers per cell without protein standards. Copy numbers estimated in enterocytes and cancer cells are in good agreement with CaCo-2 and HeLa cells and with the literature data. Our proteomic data set furthermore allows mapping quantitative changes of functional protein classes, enabling novel insights into the biology of colon cancer.
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Mehta S, Shelling A, Muthukaruppan A, Lasham A, Blenkiron C, Laking G, Print C. Predictive and prognostic molecular markers for cancer medicine. Ther Adv Med Oncol 2011; 2:125-48. [PMID: 21789130 DOI: 10.1177/1758834009360519] [Citation(s) in RCA: 144] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Over the last 10 years there has been an explosion of information about the molecular biology of cancer. A challenge in oncology is to translate this information into advances in patient care. While there are well-formed routes for translating new molecular information into drug therapy, the routes for translating new information into sensitive and specific diagnostic, prognostic and predictive tests are still being developed. Similarly, the science of using tumor molecular profiles to select clinical trial participants or to optimize therapy for individual patients is still in its infancy. This review will summarize the current technologies for predicting treatment response and prognosis in cancer medicine, and outline what the future may hold. It will also highlight the potential importance of methods that can integrate molecular, histopathological and clinical information into a synergistic understanding of tumor progression. While these possibilities are without doubt exciting, significant challenges remain if we are to implement them with a strong evidence base in a widely available and cost-effective manner.
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Affiliation(s)
- Sunali Mehta
- School of Medical Sciences, University of Auckland, Auckland, New Zealand
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18
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Zhang R, Pan X, Huang Z, Weber GF, Zhang G. Osteopontin enhances the expression and activity of MMP-2 via the SDF-1/CXCR4 axis in hepatocellular carcinoma cell lines. PLoS One 2011; 6:e23831. [PMID: 21909361 PMCID: PMC3166084 DOI: 10.1371/journal.pone.0023831] [Citation(s) in RCA: 66] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2011] [Accepted: 07/26/2011] [Indexed: 12/14/2022] Open
Abstract
Background and Aims Osteopontin, SDF-1α, and MMP-2 are important secreted molecules involved in the pathophysiology of human hepatocellular carcinoma (HCC). This study investigates the effect of the SDF-1α/CXCR4 axis on expression and activity of MMP-2 induced by osteopontin. Methods The expression of CXCR4, SDF-1α, MMP-2 and their associated cellular signaling cascades, involving Akt and MAP Kinases, were determined by Western blotting. The activities of MMP-2 and MMP-9 were assayed by gel zymography. The role of the osteopontin receptors integrin αvβ3 and CD44v6 was evaluated using neutralizing antibodies. We also established CXCR4-deficient SMMC7721 cell lines by transfection with miRNA-CXCR4 plasmids and determined cell invasion activity in a transwell assay. Results In comparison with untreated cells, recombinant human osteopontin (rhOPN) up-regulated CXCR4, SDF-1α, and MMP-2 expression about 5-, 4-, and 6-fold on the protein levels through binding to integrin αvβ3 and CD44v6 in hepatocellular carcinoma cells (SMMC7721 and HepG2). Inhibition of the SDF-1α/CXCR4 axis down-regulated the rhOPN-induced MMP-2 expression and activity. rhOPN also activated Akt, p38 and JNK. Down-regulation of CXCR4 decreased the rhOPN-induced invasion in SMMC7721 cells. Conclusion These results indicate that rhOPN up-regulates MMP-2 through the SDF-1α/CXCR4 axis, mediated by binding to integrin αvβ3 and CD44v6 and activating the PI-3K/Akt and JNK pathways in HepG2 and SMMC7721 cells. Therefore, the osteopontin-SDF-1α/CXCR4-MMP-2 system may be a new therapeutic target for treating HCC progression.
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Affiliation(s)
- Rihua Zhang
- Department of Gastroenterology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Xiaolin Pan
- Department of Gastroenterology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Zuhu Huang
- Department of Infection Diseases, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Georg F. Weber
- University of Cincinnati Academic Health Center, College of Pharmacy, Cincinnati, Ohio, United States of America
| | - Guoxin Zhang
- Department of Gastroenterology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
- * E-mail:
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Lin AY, Chua MS, Choi YL, Yeh W, Kim YH, Azzi R, Adams GA, Sainani K, van de Rijn M, So SK, Pollack JR. Comparative profiling of primary colorectal carcinomas and liver metastases identifies LEF1 as a prognostic biomarker. PLoS One 2011; 6:e16636. [PMID: 21383983 PMCID: PMC3044708 DOI: 10.1371/journal.pone.0016636] [Citation(s) in RCA: 53] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2010] [Accepted: 01/03/2011] [Indexed: 12/19/2022] Open
Abstract
Purpose We sought to identify genes of clinical significance to predict survival and the risk for colorectal liver metastasis (CLM), the most common site of metastasis from colorectal cancer (CRC). Patients and Methods We profiled gene expression in 31 specimens from primary CRC and 32 unmatched specimens of CLM, and performed Significance Analysis of Microarrays (SAM) to identify genes differentially expressed between these two groups. To characterize the clinical relevance of two highly-ranked differentially-expressed genes, we analyzed the expression of secreted phosphoprotein 1 (SPP1 or osteopontin) and lymphoid enhancer factor-1 (LEF1) by immunohistochemistry using a tissue microarray (TMA) representing an independent set of 154 patients with primary CRC. Results Supervised analysis using SAM identified 963 genes with significantly higher expression in CLM compared to primary CRC, with a false discovery rate of <0.5%. TMA analysis showed SPP1 and LEF1 protein overexpression in 60% and 44% of CRC cases, respectively. Subsequent occurrence of CLM was significantly correlated with the overexpression of LEF1 (chi-square p = 0.042), but not SPP1 (p = 0.14). Kaplan Meier analysis revealed significantly worse survival in patients with overexpression of LEF1 (p<0.01), but not SPP1 (p = 0.11). Both univariate and multivariate analyses identified stage (p<0.0001) and LEF1 overexpression (p<0.05) as important prognostic markers, but not tumor grade or SPP1. Conclusion Among genes differentially expressed between CLM and primary CRC, we demonstrate overexpression of LEF1 in primary CRC to be a prognostic factor for poor survival and increased risk for liver metastasis.
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Affiliation(s)
- Albert Y Lin
- Department of Medicine, Santa Clara Valley Medical Center, San Jose, California, United States of America.
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Zhu ZZ, Liu B, Wang AZ, Jia HR, Jin XX, He XL, Hou LF, Zhu GS. Association of p53 codon 72 polymorphism with liver metastases of colorectal cancers positive for p53 overexpression. J Zhejiang Univ Sci B 2009; 9:847-52. [PMID: 18988302 DOI: 10.1631/jzus.b0820100] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
OBJECTIVE To evaluate the association between p53 codon 72 polymorphism (R72P) and the risk of colorectal liver metastases. METHODS The p53 R72P genotype was identified by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method in 78 consecutive colorectal cancer patients with liver metastases and 214 age- and sex-matched cases with nonmetastatic colorectal cancer. RESULTS The R allele of the p53 R72P polymorphism was more frequently found in metastatic cases than in nonmetastatic cases (P=0.075). Carriers of the 72R allele had a 2.25-fold (95% CI (confidence interval)=1.05 to approximately 4.83) increased risk of liver metastases. On the stratification analysis, 72R-carrying genotype conferred a 3.46-fold (95% CI=1.02 to approximately 11.72) and a 1.05-fold (95% CI=0.36 to approximately 3.08) increased risk of liver metastases for p53 overexpression-positive and negative colorectal cancers, respectively. CONCLUSION These results demonstrate for the first time that the 72R allele of the p53 polymorphism has an increased risk for liver metastases in colorectal cancers positive for p53 overexpression.
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Affiliation(s)
- Zhong-Zheng Zhu
- Department of Pathology, No. 113 Hospital of People's Liberation Army, Ningbo 315040, China.
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Upregulation of the cycline kinase subunit CKS2 increases cell proliferation rate in gastric cancer. J Cancer Res Clin Oncol 2008; 135:761-9. [PMID: 19034516 DOI: 10.1007/s00432-008-0510-3] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2008] [Accepted: 10/27/2008] [Indexed: 01/25/2023]
Abstract
PURPOSE CKS2 was identified as an upregulated gene in gastric cancer via our DNA microarray. This study was to verify the upregulation of CKS2 in many gastric cancer patients and to examine the CKS2-mediated cellular response. METHODS CKS2 upregulation was analyzed using reverse transcriptase PCR, real-time PCR, and immunohistochemical and clinicopathological analyses. GFP-CKS2 or CKS2-siRNA was used to analyze the cellular localization and proliferation. RESULTS The strong upregulation of mRNA and protein levels of CKS2 was identified. In CKS2-overexpressing cells, tumor suppressor p53 and p21(cip1) were downregulated and cell growth was increased. In contrast, CKS2-siRNA-transfected cells showed an increased tumor suppressor expression and decreased cell growth. CONCLUSIONS We showed that CKS2 was significantly upregulated in gastric cancers and a high level of CKS2 was highly correlated with histologic tumor differentiation and pathological grade of the tumor size, lymph node, and metastasis stage. We suggest that the cell cycle regulator CKS2 might be deeply involved in gastric cancer progression.
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Ptitsyn AA, Weil MM, Thamm DH. Systems biology approach to identification of biomarkers for metastatic progression in cancer. BMC Bioinformatics 2008; 9 Suppl 9:S8. [PMID: 18793472 PMCID: PMC2537559 DOI: 10.1186/1471-2105-9-s9-s8] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Metastases are responsible for the majority of cancer fatalities. The molecular mechanisms governing metastasis are poorly understood, hindering early diagnosis and treatment. Previous studies of gene expression patterns in metastasis have concentrated on selection of a small number of "signature" biomarkers. RESULTS We propose an alternative approach that puts into focus gene interaction networks and molecular pathways rather than separate genes. We have reanalyzed expression data from a large set of primary solid and metastatic tumors originating from different tissues using the latest available tools for normalization, identification of differentially expressed genes and pathway analysis. Our studies indicate that regardless of the tissue of origin, all metastatic tumors share a number of common features related to changes in basic energy metabolism, cell adhesion/cytoskeleton remodeling, antigen presentation and cell cycle regulation. Analysis of multiple independent datasets indicates significantly reduced oxidative phosphorylation in metastases compared to primary solid tumors. CONCLUSION Our methods allow identification of robust, although not necessarily highly expressed biomarkers. A systems approach relying on groups of interacting genes rather than single markers is also essential for understanding the cellular processes leading to metastatic progression. We have identified metabolic pathways associated with metastasis that may serve as novel targets for therapeutic intervention.
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Affiliation(s)
- Andrey A Ptitsyn
- Center for Bioinformatics, Department of Microbiology, Immunology and Pathology, Colorado State University, Colorado, USA.
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