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Ren JX, Chen L, Guo W, Feng KY, Cai YD, Huang T. Patterns of Gene Expression Profiles Associated with Colorectal Cancer in Colorectal Mucosa by Using Machine Learning Methods. Comb Chem High Throughput Screen 2024; 27:2921-2934. [PMID: 37957897 DOI: 10.2174/0113862073266300231026103844] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2023] [Revised: 09/11/2023] [Accepted: 09/30/2023] [Indexed: 11/15/2023]
Abstract
BACKGROUND Colorectal cancer (CRC) has a very high incidence and lethality rate and is one of the most dangerous cancer types. Timely diagnosis can effectively reduce the incidence of colorectal cancer. Changes in para-cancerous tissues may serve as an early signal for tumorigenesis. Comparison of the differences in gene expression between para-cancerous and normal mucosa can help in the diagnosis of CRC and understanding the mechanisms of development. OBJECTIVES This study aimed to identify specific genes at the level of gene expression, which are expressed in normal mucosa and may be predictive of CRC risk. METHODS A machine learning approach was used to analyze transcriptomic data in 459 samples of normal colonic mucosal tissue from 322 CRC cases and 137 non-CRC, in which each sample contained 28,706 gene expression levels. The genes were ranked using four ranking methods based on importance estimation (LASSO, LightGBM, MCFS, and mRMR) and four classification algorithms (decision tree [DT], K-nearest neighbor [KNN], random forest [RF], and support vector machine [SVM]) were combined with incremental feature selection [IFS] methods to construct a prediction model with excellent performance. RESULT The top-ranked genes, namely, HOXD12, CDH1, and S100A12, were associated with tumorigenesis based on previous studies. CONCLUSION This study summarized four sets of quantitative classification rules based on the DT algorithm, providing clues for understanding the microenvironmental changes caused by CRC. According to the rules, the effect of CRC on normal mucosa can be determined.
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Affiliation(s)
- Jing Xin Ren
- School of Life Sciences, Shanghai University, Shanghai, 200444, China
| | - Lei Chen
- College of Information Engineering, Shanghai Maritime University, Shanghai, 201306, China
| | - Wei Guo
- Key Laboratory of Stem Cell Biology, Shanghai Jiao Tong University School of Medicine (SJTUSM) & Shanghai Institutes for Biological Sciences (SIBS), Chinese Academy of Sciences (CAS), Shanghai, 200030, China
| | - Kai Yan Feng
- Department of Computer Science, Guangdong AIB Polytechnic College, Guangzhou, 510507, China
| | - Yu-Dong Cai
- School of Life Sciences, Shanghai University, Shanghai, 200444, China
| | - Tao Huang
- Bio-Med Big Data Center, CAS Key Laboratory of Computational Biology, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, 200031, China
- CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, 200031, China
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Dar MA, Arafah A, Bhat KA, Khan A, Khan MS, Ali A, Ahmad SM, Rashid SM, Rehman MU. Multiomics technologies: role in disease biomarker discoveries and therapeutics. Brief Funct Genomics 2022; 22:76-96. [PMID: 35809340 DOI: 10.1093/bfgp/elac017] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2022] [Revised: 05/21/2022] [Accepted: 06/14/2022] [Indexed: 11/13/2022] Open
Abstract
Medical research has been revolutionized after the publication of the full human genome. This was the major landmark that paved the way for understanding the biological functions of different macro and micro molecules. With the advent of different high-throughput technologies, biomedical research was further revolutionized. These technologies constitute genomics, transcriptomics, proteomics, metabolomics, etc. Collectively, these high-throughputs are referred to as multi-omics technologies. In the biomedical field, these omics technologies act as efficient and effective tools for disease diagnosis, management, monitoring, treatment and discovery of certain novel disease biomarkers. Genotyping arrays and other transcriptomic studies have helped us to elucidate the gene expression patterns in different biological states, i.e. healthy and diseased states. Further omics technologies such as proteomics and metabolomics have an important role in predicting the role of different biological molecules in an organism. It is because of these high throughput omics technologies that we have been able to fully understand the role of different genes, proteins, metabolites and biological pathways in a diseased condition. To understand a complex biological process, it is important to apply an integrative approach that analyses the multi-omics data in order to highlight the possible interrelationships of the involved biomolecules and their functions. Furthermore, these omics technologies offer an important opportunity to understand the information that underlies disease. In the current review, we will discuss the importance of omics technologies as promising tools to understand the role of different biomolecules in diseases such as cancer, cardiovascular diseases, neurodegenerative diseases and diabetes. SUMMARY POINTS
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Benchmark of site- and structure-specific quantitative tissue N-glycoproteomics for discovery of potential N-glycoprotein markers: a case study of pancreatic cancer. Glycoconj J 2021; 38:213-231. [PMID: 33835347 DOI: 10.1007/s10719-021-09994-8] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2020] [Revised: 03/16/2021] [Accepted: 03/19/2021] [Indexed: 02/07/2023]
Abstract
Pancreatic cancer is a highly malignant tumor of the digestive tract that is difficult to diagnose and treat. It is more common in developed countries and has become one of the main causes of death in some countries and regions. Currently, pancreatic cancer generally has a poor prognosis, partly due to the lack of symptoms in the early stages of pancreatic cancer. Therefore, most cases are diagnosed at advanced stage. With the continuous in-depth research of glycoproteomics in precision medical diagnosis, there have been some reports on quantitative analysis of cancer-related cells, plasma or tissues to find specific biomarkers for targeted therapy. This research is based on the developed complete N-linked glycopeptide database search engine GPSeeker, combined with liquid-mass spectrometry and stable diethyl isotope labeling, providing a benchmark of site- and structure-specific quantitative tissue N-glycoproteomics for discovery of potential N-glycoprotein markers. With spectrum-level FDR ≤1%, 20,038 intact N-Glycopeptides corresponding to 4518 peptide backbones, 228 N-glycan monosaccharide compositions 1026 N-glycan putative structures, 4460 N-glycosites and 3437 intact N-glycoproteins were identified. With the criteria of ≥1.5-fold change and p value<0.05, 52 differentially expressed intact N-glycopeptides (DEGPs) were found in pancreatic cancer tussues relative to control, where 38 up-regulated and 14 down-regulated, respectively.
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Zheng S, Liu L, Xue T, Jing C, Xu X, Wu Y, Wang M, Xie X, Zhang B. Comprehensive Analysis of the Prognosis and Correlations With Immune Infiltration of S100 Protein Family Members in Hepatocellular Carcinoma. Front Genet 2021; 12:648156. [PMID: 33815482 PMCID: PMC8013731 DOI: 10.3389/fgene.2021.648156] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2020] [Accepted: 02/24/2021] [Indexed: 01/27/2023] Open
Abstract
S100 protein family members (S100s) are commonly dysregulated in various tumors including hepatocellular carcinoma (HCC). However, the diverse expression, mutation, prognosis and associations with immune infiltration of S100s in HCC have yet to be analyzed. Herein we investigated the roles of S100s in HCC from the Oncomine, Gene Expression Profiling Interactive Analysis (GEPIA), Human Protein Atlas, Kaplan-Meier Plotter, cBioPortal and TIMER databases. Compared with para-cancer tissues, the expression levels of S100A4/S100A6/S100A10/S100A11/S100A13/S100A14/S100P were higher in HCC tissues, while the expression levels of S100A8/S100A9/S100A12 were decreased in tumor tissues. The mRNA levels of S100A2/S100A7/S100A7A/S100A8/S100A9/S100A11 were correlated with advanced tumor stage. Besides, higher mRNA expressions of S100A6/S100A10/S100A11/S100A13/S100A14/S100P were shown to have shorter overall survival (OS), while higher expression of S100A12 was associated with favorable OS. Further, the mutation rate of S100s was investigated, and the high mutation rate (53%) was associated with shorter OS. Additionally, the expressions of S100s were found to be significantly associated with various immune infiltrating cells. Hence, our results showed that S100A6/S100A10/S100A11/S10012/S100A13/S100A14/S100P may be regarded as new prognostic or therapeutic markers and S100s inhibitors may be helpful in the combination of immunotherapies.
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Affiliation(s)
- Susu Zheng
- Xiamen Branch, Department of Hepatic Oncology, Zhongshan Hospital, Fudan University, Xiamen, China.,Key Laboratory for Carcinogenesis and Cancer Invasion, Zhongshan Hospital, Shanghai Medical School, The Liver Cancer Institute, The Chinese Ministry of Education, Fudan University, Shanghai, China
| | - Linxia Liu
- School of Nursing and Health Management, Shanghai University of Medicine and Health Sciences, Shanghai, China
| | - Tongchun Xue
- Key Laboratory for Carcinogenesis and Cancer Invasion, Zhongshan Hospital, Shanghai Medical School, The Liver Cancer Institute, The Chinese Ministry of Education, Fudan University, Shanghai, China
| | - Chuyu Jing
- Key Laboratory for Carcinogenesis and Cancer Invasion, Zhongshan Hospital, Shanghai Medical School, The Liver Cancer Institute, The Chinese Ministry of Education, Fudan University, Shanghai, China
| | - Xin Xu
- Key Laboratory for Carcinogenesis and Cancer Invasion, Zhongshan Hospital, Shanghai Medical School, The Liver Cancer Institute, The Chinese Ministry of Education, Fudan University, Shanghai, China
| | - Yanfang Wu
- Xiamen Branch, Department of Hepatic Oncology, Zhongshan Hospital, Fudan University, Xiamen, China
| | - Meixia Wang
- Xiamen Branch, Department of Hepatic Oncology, Zhongshan Hospital, Fudan University, Xiamen, China
| | - Xiaoying Xie
- Xiamen Branch, Department of Hepatic Oncology, Zhongshan Hospital, Fudan University, Xiamen, China.,Key Laboratory for Carcinogenesis and Cancer Invasion, Zhongshan Hospital, Shanghai Medical School, The Liver Cancer Institute, The Chinese Ministry of Education, Fudan University, Shanghai, China
| | - Boheng Zhang
- Xiamen Branch, Department of Hepatic Oncology, Zhongshan Hospital, Fudan University, Xiamen, China.,Key Laboratory for Carcinogenesis and Cancer Invasion, Zhongshan Hospital, Shanghai Medical School, The Liver Cancer Institute, The Chinese Ministry of Education, Fudan University, Shanghai, China.,Center for Evidence-Based Medicine, Shanghai Medical School, Fudan University, Shanghai, China
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Dalal N, Jalandra R, Sharma M, Prakash H, Makharia GK, Solanki PR, Singh R, Kumar A. Omics technologies for improved diagnosis and treatment of colorectal cancer: Technical advancement and major perspectives. Biomed Pharmacother 2020; 131:110648. [PMID: 33152902 DOI: 10.1016/j.biopha.2020.110648] [Citation(s) in RCA: 48] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2020] [Revised: 08/09/2020] [Accepted: 08/16/2020] [Indexed: 12/11/2022] Open
Abstract
Colorectal cancer (CRC) ranks third among the most commonly occurring cancers worldwide, and it causes half a million deaths annually. Alongside mechanistic study for CRC detection and treatment by conventional techniques, new technologies have been developed to study CRC. These technologies include genomics, transcriptomics, proteomics, and metabolomics which elucidate DNA markers, RNA transcripts, protein and, metabolites produced inside the colon and rectum part of the gut. All these approaches form the omics arena, which presents a remarkable opportunity for the discovery of novel prognostic, diagnostic and therapeutic biomarkers and also delineate the underlying mechanism of CRC causation, which may further help in devising treatment strategies. This review also mentions the latest developments in metagenomics and culturomics as emerging evidence suggests that metagenomics of gut microbiota has profound implications in the causation, prognosis, and treatment of CRC. A majority of bacteria cannot be studied as they remain unculturable, so culturomics has also been strengthened to develop culture conditions suitable for the growth of unculturable bacteria and identify unknown bacteria. The overall purpose of this review is to succinctly evaluate the application of omics technologies in colorectal cancer research for improving the diagnosis and treatment strategies.
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Affiliation(s)
- Nishu Dalal
- Gene Regulation Laboratory, National Institute of Immunology, New Delhi 110067, India; Department of Environmental Science, Satyawati College, Delhi University, Delhi 110052, India
| | - Rekha Jalandra
- Gene Regulation Laboratory, National Institute of Immunology, New Delhi 110067, India; Department of Zoology, Maharshi Dayanand University, Rohtak 124001, India
| | - Minakshi Sharma
- Department of Zoology, Maharshi Dayanand University, Rohtak 124001, India
| | - Hridayesh Prakash
- Amity Institute of Virology and Immunology, Amity University, Sector 125, Noida 201313, Uttar Pradesh, India
| | - Govind K Makharia
- Department of Gastroenterology and Human Nutrition, All India Institute of Medical Sciences, New Delhi 110029, India
| | - Pratima R Solanki
- Special Centre for Nanoscience, Jawaharlal Nehru University, New Delhi 110067, India
| | - Rajeev Singh
- Department of Environmental Science, Satyawati College, Delhi University, Delhi 110052, India.
| | - Anil Kumar
- Gene Regulation Laboratory, National Institute of Immunology, New Delhi 110067, India.
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Chern Y, Zhang P, Ju H, Tai IT. Heat shock protein 47 promotes tumor survival and therapy resistance by modulating AKT signaling via PHLPP1 in colorectal cancer. Cancer Biol Med 2020; 17:343-356. [PMID: 32587773 PMCID: PMC7309463 DOI: 10.20892/j.issn.2095-3941.2019.0261] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2019] [Accepted: 12/03/2019] [Indexed: 01/18/2023] Open
Abstract
Objective: Heat shock protein 47 (HSP47) is a collagen-specific molecular chaperone that facilitates collagen maturation. Its role in cancer remains largely unknown. In this study, we investigated the roles of HSP47 in colorectal cancer (CRC) and therapy resistance. Methods: Expression of HSP47 in CRC tissues was examined (1) in paired human CRC/adjacent normal tissues, using real time quantitative reverse transcription polymerase chain reaction (qRT-PCR), The Cancer Genome Atlas (TCGA) database, and 22 independent microarray databases (curated CRC). In vitro studies on several CRC cell lines (HCT116, RKO and CCL228) with modulated HSP47 expression were conducted to assess cell viability and apoptosis (TUNEL assay and caspase-3/-7) during exposure to chemotherapy. AKT signaling and co-immunoprecipitation studies were performed to examine HSP47 and PHLPP1 interaction. In vivo studies using tumor xenografts were conducted to assess the effects of HSP47 modulation on tumor growth and therapy response. Results: HSP47 was upregulated in CRC and was associated with poor prognosis in individuals with CRC. In vitro, HSP47 overexpression supported the survival of CRC cells, whereas its knockdown sensitized cells to 5-fluorouracil (5-FU). HSP47 promoted survival by inhibiting apoptosis, enhancing AKT phosphorylation, and decreasing expression of the AKT-specific phosphatase PHLPP1 when cells were exposed to chemotherapy. These effects were partly results of the interaction between HSP47 and PHLPP1, which decreased PHLPP1 stability and led to more persistent AKT activity. In vivo, HSP47 supported tumor growth despite 5-FU treatment. Conclusions: HSP47 supports the growth of CRC tumors and suppresses the efficacy of chemotherapy via modulation of AKT signaling.
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Affiliation(s)
- Yijye Chern
- Division of Gastroenterology, Department of Medicine, University of British Columbia, Vancouver V6T 1Z4, Canada
- Michael Smith Genome Sciences Center, British Columbia Cancer Agency, Vancouver V5Z 4S6, Canada
| | - Peter Zhang
- Division of Gastroenterology, Department of Medicine, University of British Columbia, Vancouver V6T 1Z4, Canada
- Michael Smith Genome Sciences Center, British Columbia Cancer Agency, Vancouver V5Z 4S6, Canada
| | - Hyelim Ju
- Division of Gastroenterology, Department of Medicine, University of British Columbia, Vancouver V6T 1Z4, Canada
- Michael Smith Genome Sciences Center, British Columbia Cancer Agency, Vancouver V5Z 4S6, Canada
| | - Isabella T. Tai
- Division of Gastroenterology, Department of Medicine, University of British Columbia, Vancouver V6T 1Z4, Canada
- Michael Smith Genome Sciences Center, British Columbia Cancer Agency, Vancouver V5Z 4S6, Canada
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Lu C, Liu J, Yao M, Li L, Li G. Downregulation of S100 calcium binding protein A12 inhibits the growth of glioma cells. BMC Cancer 2020; 20:261. [PMID: 32228516 PMCID: PMC7106817 DOI: 10.1186/s12885-020-06768-7] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2019] [Accepted: 03/20/2020] [Indexed: 01/27/2023] Open
Abstract
Background S100 calcium binding protein A12 (S100A12) is a member of the S100 protein family and is widely expressed in neutrophil and low expressed in lymphocytes and monocyte. However, the role of S100A12 in glioma has not yet been identified. Methods In the present study, we carried out immunohistochemical investigation of S100A12 in 81 glioma tissues to determine the expression of S100A12 in glioma cells, and evaluate the clinical significance of S100A12 in glioma patients. Futher we knockdown the S100A12 by shRNA, and evaluated cell proliferation, cell migration and cell apoptosis by MTT, colony formation assay, transwell assay,flow cytometry assa and western blot. Results We found that S100A12 was upregulated in tissues of glioma patients and the expression was correlated to WHO stage and tumor size. Further, we found that knockdown S100A12 inhibits the proliferation, migration and invasion of glioma cells through regulating cell apoptosis and EMT. Conclusion S100A12 plays a vital role in glioma progression, and may be an important regulatory molecule for biological behaviors of glioma cell lines.
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Affiliation(s)
- Chunhe Lu
- Department of Neurosurgery, The First Affiliated Hospital of China Medical University, 155 Nanjing North Street, Heping District, Shenyang City, Liaoning Province, P.R. China, 110001
| | - Jia Liu
- Department of Neurosurgery, The First Affiliated Hospital of China Medical University, 155 Nanjing North Street, Heping District, Shenyang City, Liaoning Province, P.R. China, 110001
| | - Mingze Yao
- Department of Neurosurgery, The First Affiliated Hospital of China Medical University, 155 Nanjing North Street, Heping District, Shenyang City, Liaoning Province, P.R. China, 110001
| | - Lun Li
- Department of Neurosurgery, Anshan Hospital of the First Hospital of China Medical University, No.166,Minzhu Street,Tiexi District, Anshan, Liaoning Province, P.R. China, 110001
| | - Guangyu Li
- Department of Neurosurgery, The First Affiliated Hospital of China Medical University, 155 Nanjing North Street, Heping District, Shenyang City, Liaoning Province, P.R. China, 110001.
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Carvalho A, Lu J, Francis JD, Moore RE, Haley KP, Doster RS, Townsend SD, Johnson JG, Damo SM, Gaddy JA. S100A12 in Digestive Diseases and Health: A Scoping Review. Gastroenterol Res Pract 2020; 2020:2868373. [PMID: 32184815 PMCID: PMC7061133 DOI: 10.1155/2020/2868373] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/25/2019] [Revised: 01/05/2020] [Accepted: 01/22/2020] [Indexed: 02/07/2023] Open
Abstract
Calgranulin proteins are an important class of molecules involved in innate immunity. These members of the S100 class of the EF-hand family of calcium-binding proteins have numerous cellular and antimicrobial functions. One protein in particular, S100A12 (also called EN-RAGE or calgranulin C), is highly abundant in neutrophils during acute inflammation and has been implicated in immune regulation. Structure-function analyses reveal that S100A12 has the capacity to bind calcium, zinc, and copper, processes that contribute to nutritional immunity against invading microbial pathogens. S100A12 is a ligand for the receptor for advanced glycation end products (RAGE), toll-like receptor 4 (TLR4), and CD36, which promote cellular and immunological pathways to alter inflammation. We conducted a scoping review of the existing literature to define what is known about the association of S100A12 with digestive disease and health. Results suggest that S100A12 is implicated in gastroenteritis, necrotizing enterocolitis, gastritis, gastric cancer, Crohn's disease, irritable bowel syndrome, inflammatory bowel disease, and digestive tract cancers. Together, these results reveal S100A12 is an important molecule broadly associated with the pathogenesis of digestive diseases.
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Affiliation(s)
- Alexandre Carvalho
- Internal Medicine Program, St. Joseph Mercy Hospital, Ann Arbor, Michigan, USA
| | - Jacky Lu
- Department of Pathology, Microbiology, And Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
| | - Jamisha D. Francis
- Department of Pathology, Microbiology, And Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
| | - Rebecca E. Moore
- Department of Chemistry, Vanderbilt University, Nashville, Tennessee, USA
| | - Kathryn P. Haley
- Department of Biomedical Sciences, Grand Valley State University, Allendale, Michigan, USA
| | - Ryan S. Doster
- Department of Pathology, Microbiology, And Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
- Division of Infectious Diseases, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Steven D. Townsend
- Department of Chemistry, Vanderbilt University, Nashville, Tennessee, USA
| | - Jeremiah G. Johnson
- Department of Microbiology, University of Tennessee, Knoxville, Tennessee, USA
| | - Steven M. Damo
- Department of Life and Physical Sciences, Fisk University, Nashville, Tennessee, USA
- Departments of Biochemistry and Chemistry, Vanderbilt University, Nashville, Tennessee, USA
- Department of Structural Biology, Vanderbilt University, Nashville, Tennessee, USA
| | - Jennifer A. Gaddy
- Department of Pathology, Microbiology, And Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
- Division of Infectious Diseases, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
- Tennessee Valley Healthcare Systems, Department of Veterans Affairs, Nashville, Tennessee, USA
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S100A12 is a promising biomarker in papillary thyroid cancer. Sci Rep 2020; 10:1724. [PMID: 32015423 PMCID: PMC6997206 DOI: 10.1038/s41598-020-58534-1] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2019] [Accepted: 01/15/2020] [Indexed: 02/07/2023] Open
Abstract
S100A12 belongs to the S100 family and acts as a vital regulator in different types of tumors. However, the function of S100A12 in thyroid carcinoma has not yet been investigated. In this study, we analyzed the expression of S100A12 in human papillary thyroid cancer (PTC) samples and two PTC cell lines. In addition, we explored the effects of S100A12 on PTC cell progression in vitro and in vivo. Our results showed that S100A12 was significantly upregulated in PTC specimens. Moreover, silencing S100A12 markedly inhibited PTC cell proliferation, migration, invasion and cell cycle progression. In addition, knockdown of S100A12 significantly reduced the expression of CyclinD1, CDK4 and p-ERK in PTC cells. An in vivo study also showed that silencing S100A12 dramatically suppressed tumor cell growth and decreased Ki67 expression in a xenograft mouse model. This study provides novel evidence that S100A12 serves as an oncogene in PTC. Knockdown of S100A12 suppressed PTC cell proliferation, migration, and invasion and induced G0/G1 phase arrest via the inhibition of the ERK signaling pathway. Therefore, S100A12 may be a potent therapeutic target for PTC.
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Joshi H, Vastrad B, Vastrad C. Identification of Important Invasion-Related Genes in Non-functional Pituitary Adenomas. J Mol Neurosci 2019; 68:565-589. [PMID: 30982163 DOI: 10.1007/s12031-019-01318-8] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2018] [Accepted: 03/29/2019] [Indexed: 12/18/2022]
Abstract
Non-functioning pituitary adenomas (NFPAs) are locally invasive with high morbidity. The objective of this study was to diagnose important genes and pathways related to the invasiveness of NFPAs and gain more insights into the underlying molecular mechanisms of NFPAs. The gene expression profiles of GSE51618 were downloaded from the Gene Expression Omnibus database with 4 non-invasive NFPA samples, 3 invasive NFPA samples, and 3 normal pituitary gland samples. Differentially expressed genes (DEGs) are screened between invasive NFPA samples and normal pituitary gland samples, followed by pathway and ontology (GO) enrichment analyses. Subsequently, a protein-protein interaction (PPI) network was constructed and analyzed for these DEGs, and module analysis was performed. In addition, a target gene-miRNA network and target gene-TF (transcription factor) network were analyzed for these DEGs. A total of 879 DEGs were obtained. Among them, 439 genes were upregulated and 440 genes were downregulated. Pathway enrichment analysis indicated that the upregulated genes were significantly enriched in cysteine biosynthesis/homocysteine degradation (trans-sulfuration) and PI3K-Akt signaling pathway, while the downregulated genes were mainly associated with docosahexaenoate biosynthesis III (mammals) and chemokine signaling pathway. GO enrichment analysis indicated that the upregulated genes were significantly enriched in animal organ morphogenesis, extracellular matrix, and hormone activity, while the downregulated genes were mainly associated with leukocyte chemotaxis, dendrites, and RAGE receptor binding. Subsequently, ESR1, SOX2, TTN, GFAP, WIF1, TTR, XIST, SPAG5, PPBP, AR, IL1R2, and HIST1H1C were diagnosed as the top hub genes in the upregulated and downregulated PPI networks and modules. In addition, HS3ST1, GPC4, CCND2, and SCD were diagnosed as the top hub genes in the upregulated and downregulated target gene-miRNA networks, while CISH, ISLR, UBE2E3, and CCNG2 were diagnosed as the top hub genes in the upregulated and downregulated target gene-TF networks. The new important DEGs and pathways diagnosed in this study may serve key roles in the invasiveness of NFPAs and indicate more molecular targets for the treatment of NFPAs.
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Affiliation(s)
- Harish Joshi
- Endocrine and Diabetes Care Center, Hubli, Karnataka, 5800029, India
| | - Basavaraj Vastrad
- Department of Pharmaceutics, SET'S College of Pharmacy, Dharwad, Karnataka, 580002, India
| | - Chanabasayya Vastrad
- Biostatistics and Bioinformatics, Chanabasava Nilaya, Bharthinagar, Dharwad, Karnataka, 580001, India.
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Irigoyen A, Jimenez-Luna C, Benavides M, Caba O, Gallego J, Ortuño FM, Guillen-Ponce C, Rojas I, Aranda E, Torres C, Prados J. Integrative multi-platform meta-analysis of gene expression profiles in pancreatic ductal adenocarcinoma patients for identifying novel diagnostic biomarkers. PLoS One 2018; 13:e0194844. [PMID: 29617451 PMCID: PMC5884535 DOI: 10.1371/journal.pone.0194844] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2017] [Accepted: 03/09/2018] [Indexed: 01/16/2023] Open
Abstract
Applying differentially expressed genes (DEGs) to identify feasible biomarkers in diseases can be a hard task when working with heterogeneous datasets. Expression data are strongly influenced by technology, sample preparation processes, and/or labeling methods. The proliferation of different microarray platforms for measuring gene expression increases the need to develop models able to compare their results, especially when different technologies can lead to signal values that vary greatly. Integrative meta-analysis can significantly improve the reliability and robustness of DEG detection. The objective of this work was to develop an integrative approach for identifying potential cancer biomarkers by integrating gene expression data from two different platforms. Pancreatic ductal adenocarcinoma (PDAC), where there is an urgent need to find new biomarkers due its late diagnosis, is an ideal candidate for testing this technology. Expression data from two different datasets, namely Affymetrix and Illumina (18 and 36 PDAC patients, respectively), as well as from 18 healthy controls, was used for this study. A meta-analysis based on an empirical Bayesian methodology (ComBat) was then proposed to integrate these datasets. DEGs were finally identified from the integrated data by using the statistical programming language R. After our integrative meta-analysis, 5 genes were commonly identified within the individual analyses of the independent datasets. Also, 28 novel genes that were not reported by the individual analyses ('gained' genes) were also discovered. Several of these gained genes have been already related to other gastroenterological tumors. The proposed integrative meta-analysis has revealed novel DEGs that may play an important role in PDAC and could be potential biomarkers for diagnosing the disease.
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Affiliation(s)
- Antonio Irigoyen
- Department of Medical Oncology, Virgen de la Salud Hospital, Toledo, Spain
| | - Cristina Jimenez-Luna
- Institute of Biopathology and Regenerative Medicine (IBIMER), Center of Biomedical Research (CIBM), University of Granada, Granada, Spain
| | - Manuel Benavides
- Department of Medical Oncology, Virgen de la Victoria Hospital, Malaga, Spain
| | - Octavio Caba
- Department of Health Sciences, University of Jaen, Jaen, Spain
| | - Javier Gallego
- Department of Medical Oncology, University General Hospital of Elche, Alicante, Spain
| | - Francisco Manuel Ortuño
- Department of Computer Architecture and Computer Technology, Research Center for Information and Communications Technologies, University of Granada, Granada, Spain
| | | | - Ignacio Rojas
- Department of Computer Architecture and Computer Technology, Research Center for Information and Communications Technologies, University of Granada, Granada, Spain
| | - Enrique Aranda
- Maimonides Institute of Biomedical Research (IMIBIC), Reina Sofia Hospital, University of Cordoba, Cordoba, Spain
| | - Carolina Torres
- Department of Biochemistry and Molecular Biology I, Faculty of Sciences, University of Granada, Granada, Spain
| | - Jose Prados
- Institute of Biopathology and Regenerative Medicine (IBIMER), Center of Biomedical Research (CIBM), University of Granada, Granada, Spain
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Wang X, Han J, Hardie DB, Yang J, Borchers CH. The use of matrix coating assisted by an electric field (MCAEF) to enhance mass spectrometric imaging of human prostate cancer biomarkers. JOURNAL OF MASS SPECTROMETRY : JMS 2016; 51:86-95. [PMID: 26757076 DOI: 10.1002/jms.3728] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/11/2015] [Revised: 10/26/2015] [Accepted: 10/27/2015] [Indexed: 06/05/2023]
Abstract
In this work, we combined a newly developed matrix coating technique - matrix coating assisted by an electric field (MCAEF) and matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS) to enhance the imaging of peptides and proteins in tissue specimens of human prostate cancer. MCAEF increased the signal-to-noise ratios of the detected proteins by a factor of 2 to 5, and 232 signals were detected within the m/z 3500-37500 mass range on a time-of-flight mass spectrometer and with the sinapinic acid MALDI matrix. Among these species, three proteins (S100-A9, S100-A10, and S100-A12) were only observed in the cancerous cell region and 14 proteins, including a fragment of mitogen-activated protein kinase/extracellular signal-regulated kinase kinase kinase 2, a fragment of cAMP-regulated phosphoprotein 19, 3 apolipoproteins (C-I, A-I, and A-II), 2 S100 proteins (A6 and A8), β-microseminoprotein, tumor protein D52, α-1-acid glycoprotein 1, heat shock protein β-1, prostate-specific antigen, and 2 unidentified large peptides at m/z 5002.2 and 6704.2, showed significantly differential distributions at the p < 0.05 (t-test) level between the cancerous and the noncancerous regions of the tissue. Among these 17 species, the distributions of apolipoprotein C-I, S100-A6, and S100-A8 were verified by immunohistological staining. In summary, this study resulted in the imaging of the largest group of proteins in prostate cancer tissues by MALDI-MS reported thus far, and is the first to show a correlation between S100 proteins and prostate cancer in a MS imaging study. The successful imaging of the three proteins only found in the cancerous tissues, as well as those showing differential expressions demonstrated the potential of MCAEF-MALDI/MS for the in situ detection of potential cancer biomarkers. Copyright © 2015 John Wiley & Sons, Ltd.
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Affiliation(s)
- Xiaodong Wang
- University of Victoria-Genome British Columbia Proteomics Centre, #3101-4464 Markham St., Vancouver Island Technology Park, Victoria, BC, V8Z 7X8, Canada
| | - Jun Han
- University of Victoria-Genome British Columbia Proteomics Centre, #3101-4464 Markham St., Vancouver Island Technology Park, Victoria, BC, V8Z 7X8, Canada
| | - Darryl B Hardie
- University of Victoria-Genome British Columbia Proteomics Centre, #3101-4464 Markham St., Vancouver Island Technology Park, Victoria, BC, V8Z 7X8, Canada
| | - Juncong Yang
- University of Victoria-Genome British Columbia Proteomics Centre, #3101-4464 Markham St., Vancouver Island Technology Park, Victoria, BC, V8Z 7X8, Canada
| | - Christoph H Borchers
- University of Victoria-Genome British Columbia Proteomics Centre, #3101-4464 Markham St., Vancouver Island Technology Park, Victoria, BC, V8Z 7X8, Canada
- Department of Biochemistry and Microbiology, University of Victoria, Petch Building Room 207, 3800 Finnerty Rd., Victoria, BC, V8P 5C2, Canada
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Expression and clinical implication of S100A12 in gastric carcinoma. Tumour Biol 2015; 37:6551-9. [PMID: 26638166 DOI: 10.1007/s13277-015-4460-5] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2015] [Accepted: 11/17/2015] [Indexed: 12/14/2022] Open
Abstract
S100 protein family has been implicated in multiple stages of tumorigenesis and progression in which S100A12 is one of the subtypes. However, the role of S100A12 in gastric carcinoma (GC) has not been elucidated yet. This study was aimed to investigate the expression of S100A12 in GC tissues and evaluate the clinical significance of S100A12 in GC patients. S100A12 protein was detected in 207 GC and 52 paired non-cancerous mucosal tissues by immunohistochemistry, while messenger RNA (mRNA) was investigated by Oncomine database analysis. Moreover, survival analysis was performed and the correlation between S100A12 and ubiquitin-specific protease 10 (USP10) and p53 was determined. As for tumor cells, the expression of S100A12 protein and mRNA in GC was proved to be lower than that in non-cancerous mucosa tissues (p < 0.05). Clinicopathological analysis showed that S100A12 protein was negatively associated with tumor size (p = 0.004), depth of invasion (p = 0.022), tumor node metastasis (TNM) stage (p = 0.018), Lauren classification (p < 0.000), and cell differentiation (p < 0.000). In contrast, a positive correlation was found between S100A12 and USP10 protein (p < 0.000). However, no relationship was detected between S100A12 and p53. Moreover, the survival analysis indicated that S100A12 protein was a favorable factor of prognosis of GC (p < 0.05). Although the expression of S100A12 in the stromal cells was detected higher than that in the tumor cells, no relationship between S100A12 protein in stromal cells and the clinicopathological features described above was found (p > 0.05). Our findings suggested that low expression of S100A12 might be served as a new marker in the tumorigenesis and progression of GC.
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Gunaldi M, Okuturlar Y, Gedikbasi A, Akarsu C, Karabulut M, Kural A. Diagnostic importance of S100A9 and S100A12 in breast cancer. Biomed Pharmacother 2015; 76:52-6. [PMID: 26653550 DOI: 10.1016/j.biopha.2015.10.029] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2015] [Revised: 08/30/2015] [Accepted: 10/22/2015] [Indexed: 10/22/2022] Open
Abstract
BACKGROUND The most frequent cause of cancer deaths throughout the world is breast cancer (BC). Therefore, preventing, diagnosing and treating BC has gained importance. S100 protein probably plays an important role in carcinogenesis, cancer development, and metastasis. In this study, we aimed at diagnostic and clinic-pathological importance of serum levels of S100A9 and S100A12 with known cytokine-like pro-inflammatory effects in BC. MATERIAL AND METHOD Serum samples were collected with BC and the control group consisting of healthy individuals. All the samples were analyzed with enzyme-linked immunosorbent assay for serum S100A9 and S100A12 levels before starting the systemic chemotherapy. Clinicopathological characteristics of BC and other blood parameters were compared in relation with serum S100A9 and S100A12 levels. RESULTS While the serum S100A9 levels were found significantly higher as compared to healthy individuals (190.85±32.29 and 92.72±54, respectively) (p=0.001), it was observed that there were no differences in S100A12 (120.50±15.78 and 112.21±10.46, respectively) (p=0.056) levels. As regards the subgroup analysis in BC patients, no statistically significant results were found in body mass index (BMI), smoking, menopause status, histopathologic type, grade, and biological subtype of BC, tumor size, presence of lymph node metastases, lymphovascular invasion (LVI), perineural invasion (PNI) and stage. As regards the blood parameters and serum S100 A9, while only statistically significant results were found with anemia (209.05±33.12 and 181.75±28.21, respectively) (p=0.005), no statistically significant results were found with leukocytosis, thrombocytosis and tumor markers. CONCLUSION In this study, while we found the level of S100A9, which has a potential cytokine-like function in inflammation, significantly higher, we could not find any increase in S100A12 level. Therefore, it is possible that S100A9 can play a key role in inflammation-related BC. Despite of there are no significance relationship between S100A9 and S100A12 clinicopathological features of BC, the determination of S100A9 levels contributes to diagnosis the of BC patients. In future, we suggest that serum S100A9 is investigated as a diagnostic tool even the target marker in BC to suppress inflammation in treatment.
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Affiliation(s)
- Meral Gunaldi
- Department of Medical Oncology, Bakirkoy Dr. Sadi Konuk Education and Research Hospital, Istanbul, Turkey.
| | - Yildiz Okuturlar
- Department of Internal Medicine, Bakirkoy Dr. Sadi Konuk Education and Research Hospital, Istanbul, Turkey
| | - Asuman Gedikbasi
- Department of Biochemistry, Bakirkoy Dr. Sadi Konuk Education and Research Hospital, Istanbul, Turkey
| | - Cevher Akarsu
- Department of General Surgery, Bakirkoy Dr. Sadi Konuk Education and Research Hospital, Istanbul, Turkey
| | - Mehmet Karabulut
- Department of General Surgery, Bakirkoy Dr. Sadi Konuk Education and Research Hospital, Istanbul, Turkey
| | - Alev Kural
- Department of Biochemistry, Bakirkoy Dr. Sadi Konuk Education and Research Hospital, Istanbul, Turkey
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Huang X, Zeng Y, Xing X, Zeng J, Gao Y, Cai Z, Xu B, Liu X, Huang A, Liu J. Quantitative proteomics analysis of early recurrence/metastasis of huge hepatocellular carcinoma following radical resection. Proteome Sci 2014; 12:22. [PMID: 24839399 PMCID: PMC4023177 DOI: 10.1186/1477-5956-12-22] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2013] [Accepted: 04/17/2014] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Hepatic resection is the preferred treatment for huge hepatocellular carcinoma (>10 cm in diameter; H-HCC). However, the patients with H-HCC suffer from poor prognosis due to the early recurrence/metastasis. The underlying mechanism of H-HCC's early recurrence/metastasis is currently not well understood. RESULTS Here, we describe an Isobaric Tags for relative and absolute quantification (iTRAQ)-based quantitative proteomics approach to analyze the early recurrence/metastasis related proteins of H-HCC after radical resection through multidimensional chromatography coupled with tandem mass spectrometry (2DLC-MS/MS). The different protein expression profiles between the early recurrence/metastasis within 6 months(R/M≤6months) and late recurrence/metastasis within 6-12 months after surgery (R/M6-12months) were confirmed and might reveal different underlying molecular mechanisms. We identified 44 and 49 significantly differentially expressed proteins in the R/M≤6months group and the R/M6-12months group compared to the group who had no recurrence within 2 years post surgery (the NR/M group), respectively. Moreover, among those proteins, S100A12 and AMACR were down regulated in the R/M≤6months group but up-regulated in the R/M6-12months group; and this regulation was further confirmed in mRNA and protein level by Q-PCR, Western-Blot and Immunohistochemistry (IHC). CONCLUSIONS This current study presents the first proteomic profile of the early recurrence/metastasis of H-HCC. The results suggest that S100A12 and AMACR might be potential prognostic markers for predicting the early recurrence/metastasis of H-HCC after hepatectomy.
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Affiliation(s)
- Xinhui Huang
- Mengchao Hepatobiliary Hospital of Fujian Medical University, 350025 Fuzhou, People’s Republic of China
- The Liver Center of Fujian Province, Fujian Medical University, 350025 Fuzhou, People’s Republic of China
| | - Yongyi Zeng
- Mengchao Hepatobiliary Hospital of Fujian Medical University, 350025 Fuzhou, People’s Republic of China
- The Liver Center of Fujian Province, Fujian Medical University, 350025 Fuzhou, People’s Republic of China
- Liver Disease Center, The First Affiliated Hospital of Fujian Medical University, 350005 Fuzhou, People’s Republic of China
| | - Xiaohua Xing
- Mengchao Hepatobiliary Hospital of Fujian Medical University, 350025 Fuzhou, People’s Republic of China
- The Liver Center of Fujian Province, Fujian Medical University, 350025 Fuzhou, People’s Republic of China
| | - Jinhua Zeng
- Mengchao Hepatobiliary Hospital of Fujian Medical University, 350025 Fuzhou, People’s Republic of China
- The Liver Center of Fujian Province, Fujian Medical University, 350025 Fuzhou, People’s Republic of China
- Liver Disease Center, The First Affiliated Hospital of Fujian Medical University, 350005 Fuzhou, People’s Republic of China
| | - Yunzhen Gao
- Mengchao Hepatobiliary Hospital of Fujian Medical University, 350025 Fuzhou, People’s Republic of China
- The Liver Center of Fujian Province, Fujian Medical University, 350025 Fuzhou, People’s Republic of China
| | - Zhixiong Cai
- Mengchao Hepatobiliary Hospital of Fujian Medical University, 350025 Fuzhou, People’s Republic of China
- The Liver Center of Fujian Province, Fujian Medical University, 350025 Fuzhou, People’s Republic of China
| | - Bo Xu
- Mengchao Hepatobiliary Hospital of Fujian Medical University, 350025 Fuzhou, People’s Republic of China
- The Liver Center of Fujian Province, Fujian Medical University, 350025 Fuzhou, People’s Republic of China
- Liver Disease Center, The First Affiliated Hospital of Fujian Medical University, 350005 Fuzhou, People’s Republic of China
| | - Xiaolong Liu
- Mengchao Hepatobiliary Hospital of Fujian Medical University, 350025 Fuzhou, People’s Republic of China
- The Liver Center of Fujian Province, Fujian Medical University, 350025 Fuzhou, People’s Republic of China
| | - Aimin Huang
- Mengchao Hepatobiliary Hospital of Fujian Medical University, 350025 Fuzhou, People’s Republic of China
- The Liver Center of Fujian Province, Fujian Medical University, 350025 Fuzhou, People’s Republic of China
- Department of Pathology, School of Basic Medical Science, Fujian Medical University, 350004 Fuzhou, People’s Republic of China
| | - Jingfeng Liu
- Mengchao Hepatobiliary Hospital of Fujian Medical University, 350025 Fuzhou, People’s Republic of China
- The Liver Center of Fujian Province, Fujian Medical University, 350025 Fuzhou, People’s Republic of China
- Liver Disease Center, The First Affiliated Hospital of Fujian Medical University, 350005 Fuzhou, People’s Republic of China
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Álvarez-Chaver P, Otero-Estévez O, Páez de la Cadena M, Rodríguez-Berrocal FJ, Martínez-Zorzano VS. Proteomics for discovery of candidate colorectal cancer biomarkers. World J Gastroenterol 2014; 20:3804-3824. [PMID: 24744574 PMCID: PMC3983438 DOI: 10.3748/wjg.v20.i14.3804] [Citation(s) in RCA: 64] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/25/2013] [Revised: 01/24/2014] [Accepted: 03/10/2014] [Indexed: 02/06/2023] Open
Abstract
Colorectal cancer (CRC) is the second most common cause of cancer-related deaths in Europe and other Western countries, mainly due to the lack of well-validated clinically useful biomarkers with enough sensitivity and specificity to detect this disease at early stages. Although it is well known that the pathogenesis of CRC is a progressive accumulation of mutations in multiple genes, much less is known at the proteome level. Therefore, in the last years many proteomic studies have been conducted to find new candidate protein biomarkers for diagnosis, prognosis and as therapeutic targets for this malignancy, as well as to elucidate the molecular mechanisms of colorectal carcinogenesis. An important advantage of the proteomic approaches is the capacity to look for multiple differentially expressed proteins in a single study. This review provides an overview of the recent reports describing the different proteomic tools used for the discovery of new protein markers for CRC such as two-dimensional electrophoresis methods, quantitative mass spectrometry-based techniques or protein microarrays. Additionally, we will also focus on the diverse biological samples used for CRC biomarker discovery such as tissue, serum and faeces, besides cell lines and murine models, discussing their advantages and disadvantages, and summarize the most frequently identified candidate CRC markers.
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17
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Wang K, Huang C, Nice EC. Proteomics, genomics and transcriptomics: their emerging roles in the discovery and validation of colorectal cancer biomarkers. Expert Rev Proteomics 2014; 11:179-205. [PMID: 24611605 DOI: 10.1586/14789450.2014.894466] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
Colorectal cancer (CRC) is the second most common cancer in females and the third in males. Since CRC is often diagnosed at an advanced stage when prognosis is poor, identification of biomarkers for early diagnosis is urgently required. Recent advances in proteomics, genomics and transcriptomics have facilitated high-throughput profiling of data generated from CRC-related genes and proteins, providing a window of information for biomarker discovery and validation. However, transfer of candidate biomarkers from bench to bedside remains a dilemma. In this review, we will discuss emerging proteomic technologies and highlight various sample types utilized for proteomics-based identification of CRC biomarkers. Moreover, recent breakthroughs in genomics and transcriptomics for the identification of CRC biomarkers, with particular emphasis on the merits of emerging methylomic and miRNAomic strategies, will be discussed. Integration of proteomics, genomics and transcriptomics will facilitate the discovery and validation of CRC biomarkers leading to the emergence of personalized medicine.
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Affiliation(s)
- Kui Wang
- The State Key Laboratory of Biotherapy, West China Hospital, Sichuan University , Chengdu, 610041 , P.R. China
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18
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Luo Y, Wang L, Wang J. Developing proteomics-based biomarkers for colorectal neoplasms for clinical practice: opportunities and challenges. Proteomics Clin Appl 2014; 7:30-41. [PMID: 23255431 DOI: 10.1002/prca.201200071] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2012] [Revised: 10/30/2012] [Accepted: 11/20/2012] [Indexed: 12/17/2022]
Abstract
Colorectal cancer (CRC) arises from the normal colon epithelium through the accumulation of genetic mutations and epigenetic alterations that are associated with progression along the histological adenoma-adenocarcinoma sequence. Elucidating the molecular alterations underlying disease progression will not only provide insight into the behavior of the tumors, but also could lead to the discovery of useful biomarkers for diagnosis, monitoring treatment responsiveness, or predicting disease outcomes. In the past a few years, there have been several evaluating differentially expressed protein biomarkers by employing proteomics technologies coupled with mass spectrometry. In the current review, we will briefly summarize the results from selected recent studies using tissue or serum samples from CRC patients in the past 5 years and discuss the opportunities and challenges in translating these findings from the research setting to clinical practice.
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Affiliation(s)
- Yanxin Luo
- Department of Colorectal Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, PR China
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Martínez-Aguilar J, Chik J, Nicholson J, Semaan C, McKay MJ, Molloy MP. Quantitative mass spectrometry for colorectal cancer proteomics. Proteomics Clin Appl 2014; 7:42-54. [PMID: 23027722 DOI: 10.1002/prca.201200080] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2012] [Revised: 09/05/2012] [Accepted: 09/12/2012] [Indexed: 12/15/2022]
Abstract
This review documents the uses of quantitative MS applied to colorectal cancer (CRC) proteomics for biomarker discovery and molecular pathway profiling. Investigators are adopting various labeling and label-free MS approaches to quantitate differential protein levels in cells, tumors, and plasma/serum. We comprehensively review recent uses of this technology to examine mouse models of CRC, CRC cell lines, their secretomes and subcellular fractions, CRC tumors, CRC patient plasma/serum, and stool samples. For biomarker discovery these approaches are uncovering proteins with potential diagnostic and prognostic utility, while in vitro cell culture experiments are characterizing proteomic and phosphoproteomic responses to disrupted signaling pathways due to mutations or to inhibition of drugable enzymes.
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Affiliation(s)
- Juan Martínez-Aguilar
- Australian Proteome Analysis Facility (APAF), Department of Chemistry & Biomolecular Sciences, Macquarie University, Sydney, Australia
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Petriz BA, Franco OL. Application of Cutting-Edge Proteomics Technologies for Elucidating Host–Bacteria Interactions. ADVANCES IN PROTEIN CHEMISTRY AND STRUCTURAL BIOLOGY 2014; 95:1-24. [DOI: 10.1016/b978-0-12-800453-1.00001-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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Rucevic M, Hixson D, Josic D. Mammalian plasma membrane proteins as potential biomarkers and drug targets. Electrophoresis 2011; 32:1549-64. [PMID: 21706493 DOI: 10.1002/elps.201100212] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Defining the plasma membrane proteome is crucial to understand the role of plasma membrane in fundamental biological processes. Change in membrane proteins is one of the first events that take place under pathological conditions, making plasma membrane proteins a likely source of potential disease biomarkers with prognostic or diagnostic potential. Membrane proteins are also potential targets for monoclonal antibodies and other drugs that block receptors or inhibit enzymes essential to the disease progress. Despite several advanced methods recently developed for the analysis of hydrophobic proteins and proteins with posttranslational modifications, integral membrane proteins are still under-represented in plasma membrane proteome. Recent advances in proteomic investigation of plasma membrane proteins, defining their roles as diagnostic and prognostic disease biomarkers and as target molecules in disease treatment, are presented.
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Affiliation(s)
- Marijana Rucevic
- COBRE Center for Cancer Research Development, Rhode Island Hospital, Providence, RI, USA
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22
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Global expression study in colorectal cancer on proteins with alkaline isoelectric point by two-dimensional difference gel electrophoresis. J Proteomics 2011; 74:858-73. [PMID: 21385629 DOI: 10.1016/j.jprot.2011.02.030] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2011] [Revised: 02/24/2011] [Accepted: 02/26/2011] [Indexed: 01/01/2023]
Abstract
Colorectal cancer is one of the leading causes of cancer death worldwide. To identify candidates for biomarkers and therapeutic targets, we investigated the proteome of colorectal cancer tissues. Using 2D-DIGE in combination with our original large format electrophoresis apparatus, we compared surgically resected normal and tumor tissues from 53 patients with colorectal cancer. We focused on proteins with an alkaline pI using IPG gels for the alkaline range. We observed 1687 protein spots, and found 100 spots with statistical (p<0.01) and significant (>2-fold) differences between the normal and the tumor tissue groups. Among these 100 protein spots, five showed a different intensity between tumor tissues from the stage-II and the stage-III patients. MS experiments revealed that these 100 protein spots corresponded to 58 unique proteins. These included six proteins which had not been previously reported to be associated with colorectal cancer. Among these proteins, five were not reported in any type of malignancy. IEF/western blotting confirmed the differences in protein expression between the normal and the tumor tissues. These results may provide an insight for biomarker development and drug target discovery in colorectal cancer.
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Proteomics of colorectal cancer: Overview of discovery studies and identification of commonly identified cancer-associated proteins and candidate CRC serum markers. J Proteomics 2010; 73:1873-95. [DOI: 10.1016/j.jprot.2010.06.004] [Citation(s) in RCA: 75] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2010] [Revised: 06/02/2010] [Accepted: 06/15/2010] [Indexed: 02/09/2023]
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Wild N, Andres H, Rollinger W, Krause F, Dilba P, Tacke M, Karl J. A combination of serum markers for the early detection of colorectal cancer. Clin Cancer Res 2010; 16:6111-21. [PMID: 20798228 DOI: 10.1158/1078-0432.ccr-10-0119] [Citation(s) in RCA: 96] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
PURPOSE Fecal occult blood testing is recommended as first-line screening to detect colorectal cancer (CRC). We evaluated markers and marker combinations in serum as an alternative to improve the detection of CRC. EXPERIMENTAL DESIGN Using penalized logistic regression, 6 markers were selected for evaluation in 1,027 samples (301 CRC patients, 143 patients with adenoma, 266 controls, 141 disease controls, and 176 patients with other cancer). The diagnostic performance of each marker and of marker combinations was assessed. RESULTS To detect CRC from serum samples, we tested 22 biomarkers. Six markers were selected for a marker combination, including the known tumor markers CEA (carcinoembryonic antigen) and CYFRA 21-1 as well as novel markers or markers that are less routinely used for the detection of CRC: ferritin, osteopontin (OPN), anti-p53, and seprase. CEA showed the best sensitivity at 95% specificity with 43.9%, followed by seprase (42.4%), CYFRA 21-1 (35.5%), OPN (30.2%), ferritin (23.9%), and anti-p53 (20.0%). A combination of these markers gave 69.6% sensitivity at 95% specificity and 58.7% at 98% specificity. Focusing on International Union against Cancer (UICC) stages 0-III reduced the sensitivity slightly to 68.0% and 53.3%, respectively. In a subcollective, with matched stool samples (75 CRC cases and 234 controls), the sensitivity of the marker combination was comparable with fecal immunochemical testing (FIT) with 82.4% and 68.9% versus 81.8% and 72.7% at 95% and 98% specificity, respectively. CONCLUSIONS The performance of the serum marker combination is comparable with FIT. This provides a novel tool for CRC screening to trigger a follow-up colonoscopy for a final diagnosis.
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Affiliation(s)
- Norbert Wild
- Department of New Technologies, Roche Diagnostics GmbH, Penzberg, Germany.
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Scatena R, Bottoni P, Pontoglio A, Giardina B. Revisiting the Warburg effect in cancer cells with proteomics. The emergence of new approaches to diagnosis, prognosis and therapy. Proteomics Clin Appl 2010; 4:143-158. [DOI: 10.1002/prca.200900157] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/30/2023]
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Ang CS, Rothacker J, Patsiouras H, Burgess AW, Nice EC. Murine fecal proteomics: a model system for the detection of potential biomarkers for colorectal cancer. J Chromatogr A 2009; 1217:3330-40. [PMID: 19875126 DOI: 10.1016/j.chroma.2009.10.007] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2009] [Revised: 09/30/2009] [Accepted: 10/02/2009] [Indexed: 12/18/2022]
Abstract
Tumor related products shed into the feces offer a potential source of biomarkers for the detection of colorectal cancer (CRC). Using SDS-PAGE followed by nanoflow reversed-phased LC-MS/MS to analyse fecal samples from Apc(Min/+) mice (that develop spontaneous multiple intestinal neoplasia with age) we have identified 336 proteins (115 proteins of murine origin, 201 from fecal bacteria, 18 associated with food intake and 2 of apparent parasitic origin). 75% of the murine proteins identified in this study are predicted to be extracellular or associated with the cell plasma membrane. Of these proteins, a number of the murine homologues of colorectal cancer associated proteins (CCAP) such as hemoglobin, haptoglobin, hemopexin, alpha-2-macroglobulin and cadherin-17 have been identified, demonstrating the potential of fecal proteomics for detecting potential biomarkers and paving the way for subsequent MS/MS based biomarker studies on similar human samples.
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Affiliation(s)
- Ching-Seng Ang
- Ludwig Institute for Cancer Research, Melbourne Tumour Biology Branch, PO Box 2008, Royal Melbourne Hospital, Australia
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Scatena R, Bottoni P, Pontoglio A, Mastrototaro L, Giardina B. Glycolytic enzyme inhibitors in cancer treatment. Expert Opin Investig Drugs 2008; 17:1533-45. [PMID: 18808312 DOI: 10.1517/13543784.17.10.1533] [Citation(s) in RCA: 123] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
BACKGROUND The radio- and chemotherapeutics currently used for the treatment of cancer are widely known to be characterized by a low therapeutic index. An interesting approach to overcoming some of the limits of these techniques is the exploitation of the so-called Warburg effect, which typically characterizes neoplastic cells. Interestingly, this feature has already been utilized with good results, but only for diagnostic purposes (PET and SPECT). From a pharmacological point of view, drugs able to perturb cancer cell metabolism, specifically at the level of glycolysis, may display interesting therapeutic activities in cancer. OBJECTIVE The pharmacological actions of these glycolytic enzyme inhibitors, based primarily on ATP depletion, could include: i) amelioration of drug selectivity by exploiting the particular glycolysis addiction of cancer cell; ii) inhibition of energetic and anabolic processes; iii) reduction of hypoxia-linked cancer-cell resistance; iv) reduction of ATP-dependent multi-drug resistance; and v) cytotoxic synergism with conventional cancer treatments. CONCLUSION Several glycolytic inhibitors are currently in preclinical and clinical development. Their clinical value as anticancer agents, above all in terms of therapeutic index, strictly depends on a careful reevaluation of the pathophyiological role of the unique metabolism of cancer cells in general and of Warburg effect in particular.
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Affiliation(s)
- Roberto Scatena
- Catholic University, Department of Laboratory Medicine, Largo A. Gemelli 8, 00168 Rome, Italy.
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Karl J, Wild N, Tacke M, Andres H, Garczarek U, Rollinger W, Zolg W. Improved diagnosis of colorectal cancer using a combination of fecal occult blood and novel fecal protein markers. Clin Gastroenterol Hepatol 2008; 6:1122-8. [PMID: 18928937 DOI: 10.1016/j.cgh.2008.04.021] [Citation(s) in RCA: 49] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/08/2007] [Revised: 04/08/2008] [Accepted: 04/13/2008] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Annual testing for fecal occult blood is recommended as first-line screening for the detection of colorectal cancer (CRC), but is affected by limited sensitivity. We initiated a proteomics-based search for novel biomarkers to improve the sensitivity of detection of CRC in stool samples. METHODS Six markers, including immunologic fecal occult blood test (iFOBT), were evaluated in a collective of 551 samples (186 CRC, 113 advanced adenoma, and 252 control patients) to establish the diagnostic performance of each marker and marker combinations. RESULTS We tested the known stool markers hemoglobin (iFOBT), hemoglobin-haptoglobin, calprotectin, carcinoembryogenic antigen, and the novel fecal markers tissue inhibitor of metalloproteinase-1 (TIMP-1) and S100A12. The best diagnostic performance was found for S100A12 with an area under the curve of 0.95, followed by TIMP-1 (0.92), hemoglobin-haptoglobin (0.92), hemoglobin (0.91), calprotectin (0.90), and carcinoembryogenic antigen (0.66). By using Bayes logistic regression as a mathematic model, the highest sensitivity (88%) for the detection of CRC at 95% specificity was obtained with the marker pair S100A12 and hemoglobin-haptoglobin. Increasing the specificity to 98%, the combination of S100A12, hemoglobin-haptoglobin, and TIMP-1 resulted in a sensitivity of 82%, with the highest increase of sensitivity found in early tumor stages (international union against cancer stage I: 74% sensitivity vs 57% of the best single marker). CONCLUSIONS Depending on the specificity selected, a marker pair, S100A12 and hemoglobin-haptoglobin, or a triple combination including TIMP-1, allowed the detection of CRC at significantly higher rates than can be obtained with iFOBT alone.
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Affiliation(s)
- Johann Karl
- Department of New Technologies, Professional Diagnostics, Roche Diagnostics GmbH, Penzberg, Germany.
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From Our Sister Journal: Proteomics 4/2008. Proteomics 2008. [DOI: 10.1002/pmic.200890007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022]
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