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Cho HS, Mazid MFA, Lee EY, Rayhan MA, Kim HS, Lee BI, You HJ. Two Cysteines in Raf Kinase Inhibitor Protein Make Differential Contributions to Structural Dynamics In Vitro. Molecules 2025; 30:384. [PMID: 39860250 PMCID: PMC11767649 DOI: 10.3390/molecules30020384] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2024] [Revised: 01/11/2025] [Accepted: 01/13/2025] [Indexed: 01/27/2025] Open
Abstract
As a scaffolding protein, Raf kinase binding protein (RKIP) is involved in a variety of cellular pathways, including the Raf-MEK-ERK-cascade. It acts as a negative regulator by binding to its partners, making it an attractive target in the development of therapeutic strategies for cancer. Despite its structural stability as a monomer, RKIP may form a dimer, resulting in the switching of binding partners. It is still unclear how RKIP switches between monomeric and dimeric forms. Here, we identified the role of cysteine 133 in RKIP structural dynamics using recombinant human RKIP (rhRKIP) proteins purified from Escherichia coli BL21(DE3) cells. Mutation of alanine or serine instead of cysteine in RKIP proteins did not affect the biochemical characteristics, while dynamic light scattering and liquid chromatography (LC) quadrupole time-of-flight (Q-TOF) mass spectrometry (MS) suggested distinct peaks in solution, which were identified via LC-MS/MS analyses, and further clarified the role of cysteine in RKIP dimerization. rhRKIP dimer formation was abrogated by a 32-aa peptide mimicking the region between two RKIP proteins for dimerization. In addition, the 32-aa peptide and its short derivatives were investigated for effects on cancer cell viability. Taken together, our findings suggest that it may be possible to regulate RKIP function by controlling its dynamics with reducing agents, which could aid the targeting of cancer cells.
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Affiliation(s)
- Hyun Sang Cho
- Cancer Microenvironment Branch, Division of Cancer Biology, Research Institute, National Cancer Center, Goyang-si 10408, Republic of Korea; (H.S.C.); (E.-Y.L.)
| | - Mohammad Faysal Al Mazid
- Department of Cancer Biomedical Science, National Cancer Center Graduate School of Cancer Science and Policy, National Cancer Center, Goyang-si 10408, Republic of Korea; (M.F.A.M.); (M.A.R.); (B.I.L.)
| | - Eun-Young Lee
- Cancer Microenvironment Branch, Division of Cancer Biology, Research Institute, National Cancer Center, Goyang-si 10408, Republic of Korea; (H.S.C.); (E.-Y.L.)
| | - Md Abu Rayhan
- Department of Cancer Biomedical Science, National Cancer Center Graduate School of Cancer Science and Policy, National Cancer Center, Goyang-si 10408, Republic of Korea; (M.F.A.M.); (M.A.R.); (B.I.L.)
| | - Hyoun Sook Kim
- Targeted Therapy Branch, Division of Precision Medicine, Research Institute, National Cancer Center, Goyang-si 10408, Republic of Korea;
| | - Byung Il Lee
- Department of Cancer Biomedical Science, National Cancer Center Graduate School of Cancer Science and Policy, National Cancer Center, Goyang-si 10408, Republic of Korea; (M.F.A.M.); (M.A.R.); (B.I.L.)
- Targeted Therapy Branch, Division of Precision Medicine, Research Institute, National Cancer Center, Goyang-si 10408, Republic of Korea;
| | - Hye Jin You
- Cancer Microenvironment Branch, Division of Cancer Biology, Research Institute, National Cancer Center, Goyang-si 10408, Republic of Korea; (H.S.C.); (E.-Y.L.)
- Department of Cancer Biomedical Science, National Cancer Center Graduate School of Cancer Science and Policy, National Cancer Center, Goyang-si 10408, Republic of Korea; (M.F.A.M.); (M.A.R.); (B.I.L.)
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Bustamante A, Baritaki S, Zaravinos A, Bonavida B. Relationship of Signaling Pathways between RKIP Expression and the Inhibition of EMT-Inducing Transcription Factors SNAIL1/2, TWIST1/2 and ZEB1/2. Cancers (Basel) 2024; 16:3180. [PMID: 39335152 PMCID: PMC11430682 DOI: 10.3390/cancers16183180] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2024] [Revised: 09/10/2024] [Accepted: 09/10/2024] [Indexed: 09/30/2024] Open
Abstract
Untreated primary carcinomas often lead to progression, invasion and metastasis, a process that involves the epithelial-to-mesenchymal transition (EMT). Several transcription factors (TFs) mediate the development of EMT, including SNAIL1/SNAIL2, TWIST1/TWIST2 and ZEB1/ZEB2, which are overexpressed in various carcinomas along with the under expression of the metastasis suppressor Raf Kinase Inhibitor Protein (RKIP). Overexpression of RKIP inhibits EMT and the above associated TFs. We, therefore, hypothesized that there are inhibitory cross-talk signaling pathways between RKIP and these TFs. Accordingly, we analyzed the various properties and biomarkers associated with the epithelial and mesenchymal tissues and the various molecular signaling pathways that trigger the EMT phenotype such as the TGF-β, the RTK and the Wnt pathways. We also presented the various functions and the transcriptional, post-transcriptional and epigenetic regulations for the expression of each of the EMT TFs. Likewise, we describe the transcriptional, post-transcriptional and epigenetic regulations of RKIP expression. Various signaling pathways mediated by RKIP, including the Raf/MEK/ERK pathway, inhibit the TFs associated with EMT and the stabilization of epithelial E-Cadherin expression. The inverse relationship between RKIP and the TF expressions and the cross-talks were further analyzed by bioinformatic analysis. High mRNA levels of RKIP correlated negatively with those of SNAIL1, SNAIL2, TWIST1, TWIST2, ZEB1, and ZEB2 in several but not all carcinomas. However, in these carcinomas, high levels of RKIP were associated with good prognosis, whereas high levels of the above transcription factors were associated with poor prognosis. Based on the inverse relationship between RKIP and EMT TFs, it is postulated that the expression level of RKIP in various carcinomas is clinically relevant as both a prognostic and diagnostic biomarker. In addition, targeting RKIP induction by agonists, gene therapy and immunotherapy will result not only in the inhibition of EMT and metastases in carcinomas, but also in the inhibition of tumor growth and reversal of resistance to various therapeutic strategies. However, such targeting strategies must be better investigated as a result of tumor heterogeneities and inherent resistance and should be better adapted as personalized medicine.
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Affiliation(s)
- Andrew Bustamante
- Department of Microbiology, Immunology & Molecular Genetics, David Geffen School of Medicine, Jonsson Comprehensive Cancer Center, University of California at Los Angeles, Los Angeles, CA 90095, USA
| | - Stavroula Baritaki
- Laboratory of Experimental Oncology, Division of Surgery, School of Medicine, University of Crete, 71003 Heraklion, Greece
| | - Apostolos Zaravinos
- Cancer Genetics, Genomics and Systems Biology Laboratory, Basic and Translational Cancer Research Center (BTCRC), Nicosia 1516, Cyprus
- Department of Life Sciences, School of Sciences, European University Cyprus, Nicosia 1516, Cyprus
| | - Benjamin Bonavida
- Department of Microbiology, Immunology & Molecular Genetics, David Geffen School of Medicine, Jonsson Comprehensive Cancer Center, University of California at Los Angeles, Los Angeles, CA 90095, USA
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Gelman IH. Metastasis suppressor genes in clinical practice: are they druggable? Cancer Metastasis Rev 2023; 42:1169-1188. [PMID: 37749308 PMCID: PMC11629483 DOI: 10.1007/s10555-023-10135-w] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/25/2023] [Accepted: 09/01/2023] [Indexed: 09/27/2023]
Abstract
Since the identification of NM23 (now called NME1) as the first metastasis suppressor gene (MSG), a small number of other gene products and non-coding RNAs have been identified that suppress specific parameters of the metastatic cascade, yet which have little or no ability to regulate primary tumor initiation or maintenance. MSG can regulate various pathways or cell biological functions such as those controlling mitogen-activated protein kinase pathway mediators, cell-cell and cell-extracellular matrix protein adhesion, cytoskeletal architecture, G-protein-coupled receptors, apoptosis, and transcriptional complexes. One defining facet of this gene class is that their expression is typically downregulated, not mutated, in metastasis, such that any effective therapeutic intervention would involve their re-expression. This review will address the therapeutic targeting of MSG, once thought to be a daunting task only facilitated by ectopically re-expressing MSG in metastatic cells in vivo. Examples will be cited of attempts to identify actionable oncogenic pathways that might suppress the formation or progression of metastases through the re-expression of specific metastasis suppressors.
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Affiliation(s)
- Irwin H Gelman
- Department of Cancer Genetics & Genomics, Roswell Park Comprehensive Cancer Center, Elm and Carlton Streets, Buffalo, NY, 14263, USA.
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RKIP Pleiotropic Activities in Cancer and Inflammatory Diseases: Role in Immunity. Cancers (Basel) 2021; 13:cancers13246247. [PMID: 34944867 PMCID: PMC8699197 DOI: 10.3390/cancers13246247] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2021] [Revised: 12/06/2021] [Accepted: 12/06/2021] [Indexed: 02/07/2023] Open
Abstract
Simple Summary The human body consists of tissues and organs formed by cells. In each cell there is a switch that allows the cell to divide or not. In contrast, cancer cells have their switch on which allow them to divide and invade other sites leading to death. Over two decades ago, Doctor Kam Yeung, University of Toledo, Ohio, has identified a factor (RKIP) that is responsible for the on/off switch which functions normally in healthy tissues but is inactive or absent in cancers. Since this early discovery, many additional properties have been ascribed to RKIP including its role in inhibiting cancer metastasis and resistance to therapeutics and its role in modulating the normal immune response. This review describes all of the above functions of RKIP and suggesting therapeutics to induce RKIP in cancers to inhibit their growth and metastases as well as inhibit its activity to treat non-cancerous inflammatory diseases. Abstract Several gene products play pivotal roles in the induction of inflammation and the progression of cancer. The Raf kinase inhibitory protein (RKIP) is a cytosolic protein that exerts pleiotropic activities in such conditions, and thus regulates oncogenesis and immune-mediated diseases through its deregulation. Herein, we review the general properties of RKIP, including its: (i) molecular structure; (ii) involvement in various cell signaling pathways (i.e., inhibition of the Raf/MEK/ERK pathway; the NF-kB pathway; GRK-2 or the STAT-3 pathway; as well as regulation of the GSK3Beta signaling; and the spindle checkpoints); (iii) regulation of RKIP expression; (iv) expression’s effects on oncogenesis; (v) role in the regulation of the immune system to diseases (i.e., RKIP regulation of T cell functions; the secretion of cytokines and immune mediators, apoptosis, immune check point inhibitors and RKIP involvement in inflammatory diseases); and (vi) bioinformatic analysis between normal and malignant tissues, as well as across various immune-related cells. Overall, the regulation of RKIP in different cancers and inflammatory diseases suggest that it can be used as a potential therapeutic target in the treatment of these diseases.
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Zhang Y, Zhang PS, Rong ZY, Huang C. One stomach, two subtypes of carcinoma-the differences between distal and proximal gastric cancer. Gastroenterol Rep (Oxf) 2021; 9:489-504. [PMID: 34925847 PMCID: PMC8677565 DOI: 10.1093/gastro/goab050] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/09/2021] [Revised: 07/13/2021] [Accepted: 08/13/2021] [Indexed: 12/13/2022] Open
Abstract
Gastric cancer (GC) is one of the most common malignant tumors of the digestive tract, posing a significant risk to human health. Over the past 10 years, the pathological characteristics and the prognosis of GC have been determined based on the locations of the tumors that were then classified into two types-proximal and distal GC. This review focuses on the differences in epidemiology, etiology, cell source, pathological characteristics, gene expression, molecular markers, manifestations, treatment, prognosis, and prevention between proximal and distal GC to provide guidance and a basis for clinical diagnosis and treatment.
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Affiliation(s)
- Yuan Zhang
- Department of Gastrointestinal Surgery, Shanghai General Hospital, Shanghai Jiao Tong University, Shanghai, P. R. China
| | - Peng-Shan Zhang
- Department of Gastrointestinal Surgery, Shanghai General Hospital, Shanghai Jiao Tong University, Shanghai, P. R. China
| | - Ze-Yin Rong
- Department of Gastrointestinal Surgery, Shanghai General Hospital, Shanghai Jiao Tong University, Shanghai, P. R. China
| | - Chen Huang
- Department of Gastrointestinal Surgery, Shanghai General Hospital, Shanghai Jiao Tong University, Shanghai, P. R. China
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Wang J, Wang J, Gu Q, Yang Y, Ma Y, Zhu J, Zhang Q. [MiR-4443 promotes migration and invasion of breast cancer cells by inhibiting PEBP1 expression]. NAN FANG YI KE DA XUE XUE BAO = JOURNAL OF SOUTHERN MEDICAL UNIVERSITY 2020; 40:1712-1719. [PMID: 33380387 DOI: 10.12122/j.issn.1673-4254.2020.12.03] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
Abstract
OBJECTIVE To investigate the effect of miR-4443 expression on migration and invasion of breast cancer. METHODS We examined the expression of miR-4443 in breast carcinoma in situ and paired adjacent tissues from 3 breast cancer patients with high-throughput sequencing and verified the results using TCGA database. We also detected miR-4443 expressions using real-time quantitative PCR (RT-qPCR) in low invasive and highly invasive breast cancer cells (MCF-7 and MDA-MB-231 cells, respectively). The changes in apoptosis, migration and invasion of MCF-7 and MDA-MB-231 cells after transfection with miR-4443 mimics, mimics-NC, miR-4443 inhibitor or inhibitor-NC were analyzed using flow cytometry, wound healing assay and Transwell invasion assay. The target gene of miR-4443 was predicted by bioinformatics software and validated by a dual luciferase reporter gene system. RT-qPCR and Western blotting were performed to detect the expression of recombinant human phosphatidyl ethanolamine binding protein 1 (PEBP1) in the transfected cells. RESULTS The expression of miR-4443 was significantly higher in the breast cancer tissues than in the adjacent tissues (P < 0.01), and was significantly up-regulated in MDA-MB-231 cells as compared with MCF-7 cells (P < 0.01). Transfection with miR-4443 mimics or inhibitors did not obviously affect apoptosis rate of the breast cancer cells (P>0.05), but significantly enhanced or weakened the migration and invasion abilities of the cells, respectively (P < 0.01). Bioinformatic analysis identified PEBP1 as the target gene of miR-4443 with a close correlation with metastasis of breast cancer (P < 0.01), and the result was confirmed by double luciferase reporter gene assay. The mRNA and protein expression of PEBP1 were significantly lower in MDA-MB-231 cells than in MCF-7 cells (P < 0.01), and miR-4443 over-expression or knockdown significantly down-regulated or up-regulated PEBP1 expressions in the cells, respectively (P < 0.01). CONCLUSIONS MiR-4443 promotes the migration and invasion of breast cancer cells by inhibiting the expression of PEBP1, suggesting the possibility of suppressing miR-4443 expression as a potential therapeutic strategy for breast cancer.
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Affiliation(s)
- Jinyan Wang
- Department of Oncology, The Affiliated Jiangning Hospital of Nanjing Medical University, Nanjing 211100, China.,Department of Oncology, The Affiliated Jiangning Hospital of Jiangsu Health Vocational College, Nanjing 211100, China
| | - Jinqiu Wang
- Department of Oncology, Dafeng People's Hospital, Yancheng 224199, China
| | - Quan Gu
- Nanjing Medical University, Nanjing 211166, China
| | - Yan Yang
- Department of Oncology, The Affiliated Jiangning Hospital of Nanjing Medical University, Nanjing 211100, China
| | - Yajun Ma
- Department of Oncology, The Affiliated Jiangning Hospital of Nanjing Medical University, Nanjing 211100, China
| | - Jing Zhu
- Department of Oncology, The Affiliated Jiangning Hospital of Nanjing Medical University, Nanjing 211100, China
| | - Quanan Zhang
- Department of Oncology, The Affiliated Jiangning Hospital of Nanjing Medical University, Nanjing 211100, China
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Huang W, Liu J, Hu S, Shi G, Yong Z, Li J, Qiu J, Cao Y, Yuan L. miR-181a Upregulation Promotes Radioresistance of Nasopharyngeal Carcinoma by Targeting RKIP. Onco Targets Ther 2019; 12:10873-10884. [PMID: 31849491 PMCID: PMC6912017 DOI: 10.2147/ott.s228800] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2019] [Accepted: 11/18/2019] [Indexed: 12/13/2022] Open
Abstract
Background Radioresistance is the leading cause of treatment failure for nasopharyngeal carcinoma (NPC). Therefore, screening the critical regulators in radioresistance and revealing the underlying mechanisms is imperative for improvement of therapeutical efficacy in NPC. Materials and methods Our previous study has proved that miR-181a may serve as a pro-radioresistant miRNA. In this study, we explored the expression of miR-181a in NPC, especially in radioresistant NPC samples, by qPCR. Moreover, the clinical significance of miR-181a level was also analyzed. Furthermore, the functions of miR-181a, both in vitro and in vivo, were detected via a serial of assays such as CCK-8, plate clone survival, apoptosis, and xenograft tumor model. The downstream target of miR-181a was also validated by dual luciferase reporter assay and the roles of miR-181a’s target in the regulation of NPC radioresistance were investigated. Results The results revealed that miR-181a was significantly upregulated in NPC, especially in radioresistant NPC. MiR-181a level is positively correlated to lymph node metastasis and advanced TNM stages and negatively associated with overall survival rate in NPC. Ectopic expression of miR-181a in radiosensitive NPC cells, or overexpression of miR-181a inhibitor in radioresistant NPC cells, could enhance or impair the radioresistance of NPC cells supported by the results from both in vitro and in vivo, respectively. Mechanistically, dual luciferase report assay indicated that miR-181a could directly target RKIP. Moreover, both in vitro and in vivo experimental outcomes indicated that RKIP restoration and knockdown could antagonize the effects of miR-181a and miR-181a inhibitor in the regulation of NPC radioresistance. Conclusion Collectively, the findings of this study proved that miR-181a is upregulated and promotes radioresistance by targeting RKIP in NPC. Targeting miR-181a/RKIP axis may be a valid path for reinforcing radiosensitivity and eventually improving the outcomes of clinical treatment in NPC.
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Affiliation(s)
- Wei Huang
- Department of Nuclear Medicine, The Third Xiangya Hospital, Central South University, Changsha, Hunan, People's Republic of China.,Research Center of Carcinogenesis and Targeted Therapy, Xiangya Hospital, Central South University, Changsha, Hunan, People's Republic of China
| | - Jie Liu
- Department of Pathology, Changsha Central Hospital, Changsha, Hunan, People's Republic of China
| | - Shanbiao Hu
- Department of Urological Organ Transplantation, The Second Xiangya Hospital of Central South University, Changsha, Hunan, People's Republic of China
| | - Guangqing Shi
- Department of Nuclear Medicine, The Third Xiangya Hospital, Central South University, Changsha, Hunan, People's Republic of China
| | - Zhong Yong
- Department of Nuclear Medicine, The Third Xiangya Hospital, Central South University, Changsha, Hunan, People's Republic of China
| | - Jian Li
- Department of Nuclear Medicine, The Third Xiangya Hospital, Central South University, Changsha, Hunan, People's Republic of China
| | - Juan Qiu
- Department of Nuclear Medicine, The Third Xiangya Hospital, Central South University, Changsha, Hunan, People's Republic of China
| | - Yan Cao
- Department of Nuclear Medicine, The Third Xiangya Hospital, Central South University, Changsha, Hunan, People's Republic of China
| | - Li Yuan
- Department of Nuclear Medicine, The Third Xiangya Hospital, Central South University, Changsha, Hunan, People's Republic of China
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Abdi E, Latifi‐Navid S, Zahri S, Yazdanbod A, Pourfarzi F. Risk factors predisposing to cardia gastric adenocarcinoma: Insights and new perspectives. Cancer Med 2019; 8:6114-6126. [PMID: 31448582 PMCID: PMC6792520 DOI: 10.1002/cam4.2497] [Citation(s) in RCA: 75] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2019] [Revised: 07/17/2019] [Accepted: 08/01/2019] [Indexed: 12/12/2022] Open
Abstract
Recent decades have seen an alarming increase in the incidence of cardia gastric adenocarcinoma (CGA) while noncardia gastric adenocarcinoma (NCGA) has decreased. In 2012, 260 000 CGA cases (age-standardised rate (ASR); 3.3/100 000) and 691 000 NCGA cases (ASR; 8.8/100 000) were reported worldwide. Compared with women, men had greater rates for both the subsites, especially for CGA. Recently, four molecular subtypes of GC have been proposed by the Cancer Genome Atlas (TCGA) and the Asian Cancer Research Group (ACRG); however, these classifications do not take into account predisposing germline variants and their possible interaction with somatic alterations in carcinogenesis. The etiology of adenocarcinoma of the cardia and the gastroesophageal junction (GEJ) is not known. It is thought that CGA is distinct from adenocarcinomas located in the esophagus or distal stomach, both epidemiologically and biologically. Moreover, CGA is often identified in the advanced stage having a poor prognosis. Therefore, understanding the risk and the role of predisposing factors in etiology of CGA can inform clinical practice and counseling for risk reduction. In this paper, we showed that GC family history, lifestyle, demographics, gastroesophageal reflux disease, Helicobacter pylori infection, and multiple genetic and epigenetic risk factors as well as several predisposing conditions may underlie susceptibility to CGA. However, several genome-wide association studies (GWASs) should be conducted to identify novel high-penetrance genes and pathways as well as causal germline variants predisposing to CGA. They must include different ethnic groups, especially from high-incidence countries for CGA, because some risk loci are ancestry-specific. In parallel, statistical methods can be developed to identify cancer predisposition genes (CPGs) from tumor sequencing data. It is also necessary to find novel long noncoding RNAs related to the risk of CGA. Taken altogether, new cancer risk prediction models, including all genetic and nongenetic factors influencing risk, should be developed to facilitate risk assessment, disease prevention, and early diagnosis and intervention of CGA in the future.
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Affiliation(s)
- Esmat Abdi
- Department of BiologyFaculty of SciencesUniversity of Mohaghegh ArdabiliArdabilIran
| | - Saeid Latifi‐Navid
- Department of BiologyFaculty of SciencesUniversity of Mohaghegh ArdabiliArdabilIran
| | - Saber Zahri
- Department of BiologyFaculty of SciencesUniversity of Mohaghegh ArdabiliArdabilIran
| | - Abbas Yazdanbod
- Digestive Diseases Research CenterArdabil University of Medical SciencesArdabilIran
| | - Farhad Pourfarzi
- Digestive Diseases Research CenterArdabil University of Medical SciencesArdabilIran
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The Hippo signaling effector WWTR1 is a metastatic biomarker of gastric cardia adenocarcinoma. Cancer Cell Int 2019; 19:74. [PMID: 30976198 PMCID: PMC6439973 DOI: 10.1186/s12935-019-0796-z] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2018] [Accepted: 03/21/2019] [Indexed: 01/26/2023] Open
Abstract
Background Gastric cardia adenocarcinoma (GCA) is an aggressive subtype of gastric cancer with a high metastatic rate. However, the metastatic biomarker of GCA has not been established. Methods To search for the biomarker for GCA metastasis, we here examined expression of the Hippo signaling effector WWTR1 (WW domain containing transcription regulator 1, commonly listed as TAZ) in tumor tissue samples from 214 GCA cases using the tissue microarray assay (TMA), and statistically analyzed association of the WWTR1 expression with metastasis-related pathological outcomes and cumulative survival of the GCA patients. Furthermore, shRNA knockdown was used to determine the role of WWTR1 in promoting cell migration in gastric cancer cells. Results The results have shown that WWTR1 is overexpressed in 66.4% of the GCA tumor samples. Expression of WWTR1 has a significant inverse correlation with cumulative survival of GCA patients (p < 0.01). WWTR1 positive patients had a mean survival of 56.9 ± 4.4 months, comparing to WWTR1 negative mean survival of 77.3 ± 5.9 months. More importantly, expression of WWTR1 significantly associated with tumor invasion and metastasis (in T stage, p = 0.031; N stage, p < 0.01; and TNM stage, p < 0.001). Furthermore, knockdown of WWTR1 impaired migration of gastric cancer AGS cells. Conclusions Our studies have identified WWTR1 as a metastatic biomarker of GCA for poor prognosis, defined a role of WWTR1 in driving metastasis of gastric cancer, and suggested WWTR1 as a potential target for anti-metastatic therapy of GCA.
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10
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Yesilkanal AE, Rosner MR. Targeting Raf Kinase Inhibitory Protein Regulation and Function. Cancers (Basel) 2018; 10:cancers10090306. [PMID: 30181452 PMCID: PMC6162369 DOI: 10.3390/cancers10090306] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2018] [Revised: 08/24/2018] [Accepted: 08/30/2018] [Indexed: 12/22/2022] Open
Abstract
Raf Kinase Inhibitory Protein (RKIP) is a highly conserved kinase inhibitor that functions as a metastasis suppressor in a variety of cancers. Since RKIP can reprogram tumor cells to a non-metastatic state by rewiring kinase networks, elucidating the mechanism by which RKIP acts not only reveals molecular mechanisms that regulate metastasis, but also represents an opportunity to target these signaling networks therapeutically. Although RKIP is often lost during metastatic progression, the mechanism by which this occurs in tumor cells is complex and not well understood. In this review, we summarize our current understanding of RKIP regulation in tumors and consider experimental and computational strategies for recovering or mimicking its function by targeting mediators of metastasis.
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Affiliation(s)
- Ali Ekrem Yesilkanal
- Ben May Department for Cancer Research, University of Chicago, Chicago, IL 60637, USA.
- Committee on Cancer Biology, University of Chicago, Chicago, IL 60637, USA.
| | - Marsha Rich Rosner
- Ben May Department for Cancer Research, University of Chicago, Chicago, IL 60637, USA.
- Committee on Cancer Biology, University of Chicago, Chicago, IL 60637, USA.
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11
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Vedeld HM, Goel A, Lind GE. Epigenetic biomarkers in gastrointestinal cancers: The current state and clinical perspectives. Semin Cancer Biol 2018; 51:36-49. [PMID: 29253542 PMCID: PMC7286571 DOI: 10.1016/j.semcancer.2017.12.004] [Citation(s) in RCA: 49] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2017] [Revised: 11/17/2017] [Accepted: 12/12/2017] [Indexed: 02/07/2023]
Abstract
Each year, almost 4.1 million people are diagnosed with gastrointestinal (GI) cancers. Due to late detection of this disease, the mortality is high, causing approximately 3 million cancer-related deaths annually, worldwide. Although the incidence and survival differs according to organ site, earlier detection and improved prognostication have the potential to reduce overall mortality burden from these cancers. Epigenetic changes, including aberrant promoter DNA methylation, are common events in both cancer initiation and progression. Furthermore, such changes may be identified non-invasively with the use of PCR based methods, in bodily fluids of cancer patients. These features make aberrant DNA methylation a promising substrate for the development of disease biomarkers for early detection, prognosis and for predicting response to therapy. In this article, we will provide an update and current clinical perspectives for DNA methylation alterations in patients with colorectal, gastric, pancreatic, liver and esophageal cancers, and discuss their potential role as cancer biomarkers.
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Affiliation(s)
- Hege Marie Vedeld
- Department of Molecular Oncology, Institute for Cancer Research, Oslo University Hospital, Norwegian Radium Hospital, Oslo, Norway; K.G. Jebsen Colorectal Cancer Research Centre, Oslo University Hospital, Oslo, Norway; Centre for Cancer Biomedicine, Faculty of Medicine, University of Oslo, Oslo, Norway.
| | - Ajay Goel
- Center for Gastrointestinal Research, and Center for Translational Genomics and Oncology, Baylor Scott & White Research Institute and Charles A. Sammons Cancer Center, Baylor University Medical Center, Dallas, TX, USA.
| | - Guro E Lind
- Department of Molecular Oncology, Institute for Cancer Research, Oslo University Hospital, Norwegian Radium Hospital, Oslo, Norway; K.G. Jebsen Colorectal Cancer Research Centre, Oslo University Hospital, Oslo, Norway; Centre for Cancer Biomedicine, Faculty of Medicine, University of Oslo, Oslo, Norway.
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12
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Wong CC, Li W, Chan B, Yu J. Epigenomic biomarkers for prognostication and diagnosis of gastrointestinal cancers. Semin Cancer Biol 2018; 55:90-105. [PMID: 29665409 DOI: 10.1016/j.semcancer.2018.04.002] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2017] [Revised: 04/04/2018] [Accepted: 04/10/2018] [Indexed: 12/12/2022]
Abstract
Altered epigenetic regulation is central to many human diseases, including cancer. Over the past two decade, major advances have been made in our understanding of the role of epigenetic alterations in carcinogenesis, particularly for DNA methylation, histone modifications and non-coding RNAs. Aberrant hypermethylation of DNA at CpG islands is a well-established phenomenon that mediates transcriptional silencing of tumor suppressor genes, and it is an early event integral to gastrointestinal cancer development. As such, detection of aberrant DNA methylation is being developed as biomarkers for prognostic and diagnostic purposes in gastrointestinal cancers. Diverse tissue types are suitable for the analyses of methylated DNA, such as tumor tissues, blood, plasma, and stool, and some of these markers are already utilized in the clinical setting. Recent advances in the genome-wide epigenomic approaches are enabling the comprehensive mapping of the cancer methylome, thus providing new avenues for mining novel biomarkers for disease prognosis and diagnosis. Here, we review the current knowledge on DNA methylation biomarkers for the prognostication and non-invasive diagnosis of gastrointestinal cancers and highlight their clinical application.
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Affiliation(s)
- Chi Chun Wong
- Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong.
| | - Weilin Li
- Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong; Department of Surgery, The Chinese University of Hong Kong, Hong Kong
| | - Bertina Chan
- Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong
| | - Jun Yu
- Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong.
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13
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Reduced RKIP Expression is Associated With Breast Neoplastic Progression and is Correlated With Poor Outcomes and Aberrant Methylation in Breast Carcinoma. Appl Immunohistochem Mol Morphol 2018; 25:467-474. [PMID: 26894644 DOI: 10.1097/pai.0000000000000323] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
Raf kinase inhibitor protein's (RKIP) downregulation can predict poor outcome in patients with various types of malignancy. In this study, we aimed to assess the potential involvement of RKIP in breast carcinogenesis and to evaluate its association with outcome variables and aberrant promoter methylation in breast carcinoma (BC). Tissue microarray sections were immunostained for RKIP in 26 normal breasts, 25 usual ductal hyperplasia, 76 ductal carcinoma in situ, and 198 BC specimens. The methylation status of RKIP was also determined in BC. In addition, the mRNA and protein level of RKIP was analyzed in 8 pairs of BC tissues and surrounding normal tissues by quantitative real-time polymerase chain reaction and Western blot analysis, respectively. RKIP mRNA and protein expression was significantly downregulated in BC tissues compared with the surrounding normal tissues (P<0.05 and P<0.01, respectively). Reduced RKIP expression seemed to increase progressively from normal breast to BC (P<0.001). Reduced RKIP expression was significantly associated with metastatic relapse (P<0.001) and was identified as an independent adverse prognostic indicator for disease-free survival (P=0.003). Reduced RKIP expression in BC was significantly correlated with its aberrant promoter methylation (P<0.05). In conclusion, downregulation of RKIP plays an important role in the breast neoplastic progression and correlates with poor prognosis in patients with BC. Aberrant RKIP methylation is one of the mechanisms that lead to downregulation of RKIP in BC.
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14
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Wei J, Yu G, Shao G, Sun A, Chen M, Yang W, Lin Q. CYR61 (CCN1) is a metastatic biomarker of gastric cardia adenocarcinoma. Oncotarget 2018; 7:31067-78. [PMID: 27105510 PMCID: PMC5058739 DOI: 10.18632/oncotarget.8845] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2016] [Accepted: 03/31/2016] [Indexed: 12/14/2022] Open
Abstract
Gastric cardia adenocarcinoma (GCA) is the most aggressive subtype of gastric cancer with a high metastatic rate. In this report, we collected tumor tissue samples from 214 GCA cases and examined expression of CYR61, a target gene product of the Hippo-YAP/TAZ pathway, in the GCA tumors by immunohistochemical (IHC) staining using the tissue microarray assay (TMA). The results have shown that CYR61 is overexpressed in 44% of the GCA tumor samples. Expression of CYR61 is inversely correlated with cumulative survival of GCA patients (p<0.001) and significantly associated only with metastatic pathological categories (with N category, p=0.052; with TNM stage, p=0.001). Furthermore, knockdown of CYR61 in gastric cancer AGS cells impairs the cancer cell migration and invasion, suggesting a driver role of CYR61 in metastasis. Thus, our studies have established CYR61 as a metastatic biomarker for prediction of poor prognosis of GCA and provided a potential molecular target for anti-metastatic therapy of GCA.
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Affiliation(s)
- Jing Wei
- School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, China
| | | | - Genbao Shao
- School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, China
| | - Aiqin Sun
- School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, China
| | - Miao Chen
- School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, China.,The Affiliated Hospital, Jiangsu University, Zhenjiang, Jiangsu, China
| | - Wannian Yang
- School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, China
| | - Qiong Lin
- School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, China
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15
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Wang Z, Bu J, Yao X, Liu C, Shen H, Li X, Li H, Chen G. Phosphorylation at S153 as a Functional Switch of Phosphatidylethanolamine Binding Protein 1 in Cerebral Ischemia-Reperfusion Injury in Rats. Front Mol Neurosci 2017; 10:358. [PMID: 29163033 PMCID: PMC5671526 DOI: 10.3389/fnmol.2017.00358] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2017] [Accepted: 10/19/2017] [Indexed: 01/07/2023] Open
Abstract
This study aimed to estimate the role of phosphatidylethanolamine binding protein 1 (PEBP1) in cerebral ischemia-reperfusion (I/R) injury and the underlying mechanisms. Middle cerebral artery occlusion/reperfusion (MCAO/R) model in adult male Sprague Dawley rats (250-280 g) were established and cultured neurons were exposed to oxygen-glucose deprivation/reoxygenation (OGD/R) to mimic I/R injury in vitro. Expression vectors encoding wild-type PEBP1 and PEBP1 with Ser153Ala mutation (S153A), PEBP1 specific siRNAs, and human recombinant PEBP1 (rhPEBP1) were administered intracerebroventricularly. Endogenous PEBP1 level and its phosphorylation at Ser153 were increased within penumbra tissue and cultured neurons after I/R, accompanied by decreased interaction between PEBP1 and Raf-1. There was a trend toward increased Raf-1/MEK/ERK/NF-κB signaling pathway and phosphatidylcholine-phospholipase C (PC-PLC) activity after I/R, which was enhanced by wild-type PEBP1overexpression and rhPEBP1 treatment and inhibited by PEBP1 (S153A) overexpression. And PEBP1 (S153A) overexpression increased its interaction with Raf-1, reduced infarct size, neuronal death and inflammation, and improved neurological function after I/R, while wild-type PEBP1overexpression exerted opposite effects, suggesting that phosphorylation at Ser153 may exert as a functional switch of PEBP1 by switching PEBP1 from Raf-1 inhibition to PC-PLC activation following I/R. Compared with PEBP1 knockdown, PEBP1 (S153A) overexpression exerted a better rescue effect on I/R injury, which further proved that PEBP1 may be a good protein gone bad with phosphorylation at S153 as a functional switch following I/R. Collectively, our findings suggest that PEBP1 contributed to neuronal death and inflammation after I/R. Selective inhibition of PEBP1 phosphorylation may be a novel approach to ameliorate I/R injury.
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Affiliation(s)
- Zhong Wang
- Nerve Research Laboratory, Department of Neurosurgery and Brain, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Jiyuan Bu
- Nerve Research Laboratory, Department of Neurosurgery and Brain, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Xiyang Yao
- Nerve Research Laboratory, Department of Neurosurgery and Brain, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Chenglin Liu
- Nerve Research Laboratory, Department of Neurosurgery and Brain, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Haitao Shen
- Nerve Research Laboratory, Department of Neurosurgery and Brain, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Xiang Li
- Nerve Research Laboratory, Department of Neurosurgery and Brain, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Haiying Li
- Nerve Research Laboratory, Department of Neurosurgery and Brain, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Gang Chen
- Nerve Research Laboratory, Department of Neurosurgery and Brain, The First Affiliated Hospital of Soochow University, Suzhou, China
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16
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Lee S, Wottrich S, Bonavida B. Crosstalks between Raf-kinase inhibitor protein and cancer stem cell transcription factors (Oct4, KLF4, Sox2, Nanog). Tumour Biol 2017; 39:1010428317692253. [PMID: 28378634 DOI: 10.1177/1010428317692253] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023] Open
Abstract
Raf-kinase inhibitor protein has been reported to inhibit both the Raf/mitogen extracellular signal-regulated kinase/extracellular signal-regulated kinase and nuclear factor kappa-light-chain of activated B cells pathways. It has also been reported in cancers that Raf-kinase inhibitor protein behaves as a metastatic suppressor as well as a chemo-immunosensitizing factor to drug/immune-mediated apoptosis. The majority of cancers exhibit low or no levels of Raf-kinase inhibitor protein. Hence, the activities of Raf-kinase inhibitor protein contrast, in part, to those mediated by several cancer stem cell transcription factors for their roles in resistance and metastasis. In this review, the existence of crosstalks in the signaling pathways between Raf-kinase inhibitor protein and several cancer stem cell transcription factors (Oct4, KLF4, Sox2 and Nanog) was assembled. Oct4 is induced by Lin28, and Raf-kinase inhibitor protein inhibits the microRNA binding protein Lin28. The expression of Raf-kinase inhibitor protein inversely correlates with the expression of Oct4. KLF4 does not interact directly with Raf-kinase inhibitor protein, but rather interacts indirectly via Raf-kinase inhibitor protein's regulation of the Oct4/Sox2/KLF4 complex through the mitogen-activated protein kinase pathway. The mechanism by which Raf-kinase inhibitor protein inhibits Sox2 is via the inhibition of the mitogen-activated protein kinase pathway by Raf-kinase inhibitor protein. Thus, Raf-kinase inhibitor protein's relationship with Sox2 is via its regulation of Oct4. Inhibition of extracellular signal-regulated kinase by Raf-kinase inhibitor protein results in the upregulation of Nanog. The inhibition of Oct4 by Raf-kinase inhibitor protein results in the failure of the heterodimer formation of Oct4 and Sox2 that is necessary to bind to the Nanog promoter for the transcription of Nanog. The findings revealed that there exists a direct correlation between the expression of Raf-kinase inhibitor protein and the expression of each of the above transcription factors. Based on these analyses, we suggest that the expression level of Raf-kinase inhibitor protein may be involved in the regulation of the cancer stem cell phenotype.
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Affiliation(s)
- SoHyun Lee
- Department of Microbiology, Immunology & Molecular Genetics, David Geffen School of Medicine, Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, CA, USA
| | - Stephanie Wottrich
- Department of Microbiology, Immunology & Molecular Genetics, David Geffen School of Medicine, Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, CA, USA
| | - Benjamin Bonavida
- Department of Microbiology, Immunology & Molecular Genetics, David Geffen School of Medicine, Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, CA, USA
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17
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Sonohara F, Inokawa Y, Hayashi M, Kodera Y, Nomoto S. Epigenetic modulation associated with carcinogenesis and prognosis of human gastric cancer. Oncol Lett 2017; 13:3363-3368. [PMID: 28529571 DOI: 10.3892/ol.2017.5912] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2015] [Accepted: 02/14/2017] [Indexed: 12/17/2022] Open
Abstract
Gastric cancer (GC) is a leading cause of cancer-related death, particularly in Asia. Epidemiological and other clinical studies have identified an association between a number of risk factors, including Helicobacter pylori, and GC. A number of studies have also examined genetic changes associated with the development and progression of GC. When considering the clinical significance of the expression of a specific gene, its epigenetic modulation should be considered. Epigenetic modulation appears to be a primary driver of changes in gastric tissue that promotes carcinogenesis and progression of GC and other neoplasms. The role of epigenetic modulation in GC carcinogenesis and progression has been widely studied in recent years. In the present review, recent results of epigenetic modulation associated with GC and their effects on clinical outcome are examined, with particular respect to DNA methylation, histone modulation and non-coding RNA. A number of studies indicate that epigenetic changes in the expression of specific genes critically affect their clinical significance and further study may reveal epigenetic changes as the basis for targeted molecular therapy or novel biomarkers that predict GC prognosis or extension of this often fatal disease.
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Affiliation(s)
- Fuminori Sonohara
- Department of Gastroenterological Surgery, Nagoya University Graduate School of Medicine, Nagoya, Aichi 466-8550, Japan.,Department of Surgery, Aichi-Gakuin University School of Dentistry, Nagoya, Aichi 464-8651, Japan
| | - Yoshikuni Inokawa
- Department of Gastroenterological Surgery, Nagoya University Graduate School of Medicine, Nagoya, Aichi 466-8550, Japan.,Department of Surgery, Aichi-Gakuin University School of Dentistry, Nagoya, Aichi 464-8651, Japan
| | - Masamichi Hayashi
- Department of Gastroenterological Surgery, Nagoya University Graduate School of Medicine, Nagoya, Aichi 466-8550, Japan
| | - Yasuhiro Kodera
- Department of Gastroenterological Surgery, Nagoya University Graduate School of Medicine, Nagoya, Aichi 466-8550, Japan
| | - Shuji Nomoto
- Department of Gastroenterological Surgery, Nagoya University Graduate School of Medicine, Nagoya, Aichi 466-8550, Japan.,Department of Surgery, Aichi-Gakuin University School of Dentistry, Nagoya, Aichi 464-8651, Japan
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18
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Wei H, Liu Z, She H, Liu B, Gu J, Wei D, Zhang X, Wang J, Qi S, Ping F. Promoter methylation and expression of Raf kinase inhibitory protein in esophageal squamous cell carcinoma. Oncol Lett 2017; 13:1866-1872. [PMID: 28454336 DOI: 10.3892/ol.2017.5617] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2015] [Accepted: 11/23/2016] [Indexed: 02/06/2023] Open
Abstract
Raf kinase inhibitory protein (RKIP) regulates multiple cellular processes, and its downregulation is associated with distinct human cancers. In the present study, the status of RKIP promoter methylation, as well as its expression and clinical significance in esophageal squamous cell carcinoma (ESCC), were examined. The promoter methylation status in the 5'-CpG island of the RKIP gene and the expression level of the RKIP protein were examined using a modified methylation-specific polymerase chain reaction (MSP) method and immunohistochemical staining, respectively, in 77 ESCC samples and matched paratumor normal tissues. The incidence of RKIP promoter methylation was significantly higher in tumor samples (75.3%) than in the matched normal tissues (27.3%; P<0.001). A higher incidence of promoter methylation was also detected in poorly differentiated cancers (93.5%) compared with well-differentiated cancers (50.0%; P<0.001), as well as in tumor samples with positive lymph node metastasis (86.7%) compared with those with negative lymph node metastasis (59.4%; P<0.001). Consistent with the promoter methylation status, the expression level of RKIP was significantly reduced in cancer tissues (36.4%) compared with matched normal tissues (76.6%; P<0.01), as well as in cancers with positive lymph node metastasis (24.4%) compared with those with negative lymph node metastasis (53.1%; P=0.01). Promoter methylation-induced gene silencing significantly correlated with the down regulation of RKIP and the development of ESCC. The results of the present study suggested that the methylation status of the RKIP promoter, when combined with its expression level, may serve as a biomarker for predicting the biological behaviors of ESCC.
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Affiliation(s)
- Hong Wei
- Department of Pathology, The Affiliated Hospital of Hebei University of Engineering, Handan, Hebei 056000, P.R. China
| | - Zhijun Liu
- Department of Pathology, The Affiliated Hospital of Hebei University of Engineering, Handan, Hebei 056000, P.R. China
| | - Hongyan She
- Department of Pathology, The Affiliated Hospital of Hebei University of Engineering, Handan, Hebei 056000, P.R. China
| | - Baoguo Liu
- Department of Pathology, The Affiliated Hospital of Hebei University of Engineering, Handan, Hebei 056000, P.R. China
| | - Junxia Gu
- Department of Pathology, The Affiliated Hospital of Hebei University of Engineering, Handan, Hebei 056000, P.R. China
| | - Dongmin Wei
- Department of Pathology, The Affiliated Hospital of Hebei University of Engineering, Handan, Hebei 056000, P.R. China
| | - Xiangyang Zhang
- Department of Pathology, The Affiliated Hospital of Hebei University of Engineering, Handan, Hebei 056000, P.R. China
| | - Jiufeng Wang
- Department of Pathology, The Affiliated Hospital of Hebei University of Engineering, Handan, Hebei 056000, P.R. China
| | - Shujing Qi
- Department of Pathology, The Affiliated Hospital of Hebei University of Engineering, Handan, Hebei 056000, P.R. China
| | - Fumin Ping
- Department of Pathology, The Affiliated Hospital of Hebei University of Engineering, Handan, Hebei 056000, P.R. China
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19
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Rajkumar K, Nichita A, Anoor PK, Raju S, Singh SS, Burgula S. Understanding perspectives of signalling mechanisms regulating PEBP1 function. Cell Biochem Funct 2016; 34:394-403. [PMID: 27385268 DOI: 10.1002/cbf.3198] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2015] [Revised: 05/13/2016] [Accepted: 05/19/2016] [Indexed: 12/21/2022]
Abstract
UNLABELLED Phosphatidylethanolamine-binding protein 1 (PEBP1), also known as Raf kinase inhibitor protein, belongs to PEBP family of proteins. It is known to interact with many proteins that are mainly involved in pathways that monitor cell proliferation and differentiation. PEBP1 in many cells interacts with several pathways, namely MAPK, GRK2, NF-кB, etc. that keeps the cell proliferation and differentiation in check. This protein is expressed by many cells in humans, including neurons where it is predominantly involved in production of choline acetyltransferase. Deregulated PEBP1 is known to cause cancer, diabetic nephropathy and neurodegenerative diseases like Alzheimer's and dementia. Recent research led to the discovery of many drugs that mainly target the interaction of PEBP1 with its partners. These compounds are known to bind PEBP1 in its conserved domain which abrogate its association with interacting partners in several different pathways. We outline here the latest developments in understanding of PEBP1 function in maintaining cell integrity. Copyright © 2016 John Wiley & Sons, Ltd. SIGNIFICANCE OF THE STUDY Phosphatidylethanolamine-binding protein is crucial in regulation of MAPK and PKC pathways. Its diverse roles, including regulating these pathways keep cell differentiation and proliferation in check. This review outlines some latest findings which greatly add to our current knowledge of phosphatidylethanolamine-binding protein.
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Affiliation(s)
- Karthik Rajkumar
- Department of Microbiology, Osmania University, Hyderabad, India
| | - Aare Nichita
- Department of Microbiology, Osmania University, Hyderabad, India
| | | | - Swathi Raju
- Department of Microbiology, Osmania University, Hyderabad, India
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20
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Hu F, Chen X, Liu X, Wang C, Lv L, Xie N, Wang T, Huang H. Clinicopathological features and prognostic implications of Raf kinase inhibitor protein downregulation in tongue squamous cell carcinoma. Oncol Lett 2015; 10:1303-1308. [PMID: 26622668 DOI: 10.3892/ol.2015.3496] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2014] [Accepted: 04/24/2015] [Indexed: 01/30/2023] Open
Abstract
Raf kinase inhibitor protein (RKIP) is recognized as a suppressor of metastasis, and the downregulation of RKIP is associated with aggressive events and a poor outcome in a variety of solid tumors. However, the clinical relevance of RKIP expression in tongue squamous cell carcinoma (TSCC) remains unclear. In the present study, the expression of RKIP in 85 pairs of TSCC and corresponding adjacent non-cancerous tissues, 30 matched metastatic lesions from the cervical lymph nodes and 32 oral leukoplakia samples were assessed using immunohistochemical methods. The association between RKIP expression and clinicopathological features was then evaluated. Kaplan-Meier survival analysis and Cox proportional hazards model were used to estimate the effect of RKIP expression on the survival time of patients with TSCC. The results revealed that RKIP expression was dramatically downregulated in TSCC, and to an even greater extent in metastatic lesions. RKIP downregulation was significantly associated with the presence of lymphatic metastasis and the clinical stage of TSCC. Furthermore, patients with low RKIP expression demonstrated a significantly shorter overall survival time. Multivariate analysis indicated that RKIP expression may be an independent prognostic factor in TSCC. In conclusion, the present findings indicate that the lack of RKIP expression is of clinical significance and may serve as a prognostic biomarker in TSCC.
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Affiliation(s)
- Fengchun Hu
- Department of Oral Maxillofacial-Head and Neck Oncology, The Affiliated Hospital of Stomatology, Sun Yat-Sen University, Guangzhou, Guangdong 510055, P.R. China ; Guangdong Provincial Key Laboratory of Stomatology, Guangzhou, Guangdong 510080, P.R. China
| | - Xiaohua Chen
- Guangdong Provincial Key Laboratory of Stomatology, Guangzhou, Guangdong 510080, P.R. China ; Department of Oral Pathology, The Affiliated Hospital of Stomatology, Sun Yat-Sen University, Guangzhou, Guangdong 510055, P.R. China
| | - Xiqiang Liu
- Department of Oral Maxillofacial-Head and Neck Oncology, The Affiliated Hospital of Stomatology, Sun Yat-Sen University, Guangzhou, Guangdong 510055, P.R. China ; Guangdong Provincial Key Laboratory of Stomatology, Guangzhou, Guangdong 510080, P.R. China
| | - Cheng Wang
- Department of Oral Maxillofacial-Head and Neck Oncology, The Affiliated Hospital of Stomatology, Sun Yat-Sen University, Guangzhou, Guangdong 510055, P.R. China ; Guangdong Provincial Key Laboratory of Stomatology, Guangzhou, Guangdong 510080, P.R. China
| | - Lanhai Lv
- Guangdong Provincial Key Laboratory of Stomatology, Guangzhou, Guangdong 510080, P.R. China
| | - Nan Xie
- Guangdong Provincial Key Laboratory of Stomatology, Guangzhou, Guangdong 510080, P.R. China ; Department of Oral Pathology, The Affiliated Hospital of Stomatology, Sun Yat-Sen University, Guangzhou, Guangdong 510055, P.R. China
| | - Tianyi Wang
- Center for Immunology and Infectious Diseases, SRI International, Harrisonburg, VA 22802, USA
| | - Hongzhang Huang
- Department of Oral Maxillofacial-Head and Neck Oncology, The Affiliated Hospital of Stomatology, Sun Yat-Sen University, Guangzhou, Guangdong 510055, P.R. China ; Guangdong Provincial Key Laboratory of Stomatology, Guangzhou, Guangdong 510080, P.R. China
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21
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Jin Z, Jiang W, Wang L. Biomarkers for gastric cancer: Progression in early diagnosis and prognosis (Review). Oncol Lett 2015; 9:1502-1508. [PMID: 25788990 PMCID: PMC4356326 DOI: 10.3892/ol.2015.2959] [Citation(s) in RCA: 78] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2014] [Accepted: 01/08/2015] [Indexed: 12/12/2022] Open
Abstract
Gastric cancer is one of leading causes of cancer-related mortality worldwide and is a notable disease due to its heterogeneity. Recently, numerous studies have investigated the molecular basis of gastric cancer, involving the alteration of pathogenesis, and invasion and metastasis. With the development of modern technologies, various novel biomarkers had been identified that appear to possess diagnostic and prognostic value; therefore, the present review describes our current knowledge of biomarkers for the early diagnosis and prognosis of gastric cancer. Classic biomarkers for gastric cancer diagnosis include carcinoembryonic antigen and cancer antigen 19-9, while microRNA and DNA hypomethylation are proposed as novel biomarkers. Excluding classical biomarkers, biomarkers for determining the progression and prognosis of gastric cancer focus on targeting microRNAs, epigenetic alterations and genetic polymorphisms.
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Affiliation(s)
- Ziliang Jin
- Department of Oncology, Shanghai Key Laboratory of Pancreatic Diseases, Shanghai Jiaotong University Affiliated First People's Hospital, Shanghai 200080, P.R. China
| | - Weihua Jiang
- Department of Oncology, Shanghai Key Laboratory of Pancreatic Diseases, Shanghai Jiaotong University Affiliated First People's Hospital, Shanghai 200080, P.R. China
| | - Liwei Wang
- Department of Oncology, Shanghai Key Laboratory of Pancreatic Diseases, Shanghai Jiaotong University Affiliated First People's Hospital, Shanghai 200080, P.R. China
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22
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Oh MG, Kim JH, Han MA, Park J, Ryu SY, Choi SW. Family history and survival of patients with gastric cancer: a meta-analysis. Asian Pac J Cancer Prev 2015; 15:3465-70. [PMID: 24870741 DOI: 10.7314/apjcp.2014.15.8.3465] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Previous studies have generated conflicting evidence regarding associations between family history and survival after gastric cancer surgery. In this study, we investigated this question using a meta-analysis. MATERIALS AND METHODS To identify relevant studies, PubMed and Embase databases were searched up to June 2013. Two reviewers independently assessed search results and data extraction of included studies. Hazard ratios (HRs) and 95% confidence intervals (CIs) for overall survival (OS) were calculated based on fixed- or random- effects models. Homogeneity of effects across studies was assessed using x2 test statistics and quantified by I2. RESULTS A total of five studies were selected according to the inclusion criteria. The total number of patients included was 2,030, which ranged from 145 to 598 per study. There was no significant difference in OS by family history of cancer (HR=0.83, 95%CIs=0.50-1.38), but subgroup analysis of patients with a first-degree family history of cancer (HR=0.74, 95%CIs=0.60-0.93) and gastric cancer family history (HR=0.56, 95%CIs=0.41-0.76) tended to show better OS in these patients. CONCLUSIONS This meta-analysis suggests that a first-degree family history of cancer or gastric cancer family history is associated with better survival of gastric cancer patients after surgery, after a systematic review of five previous studies. These results can be applied by clinicians when counselling patients regarding their risk of death from gastric cancer. Further study is needed to investigate the underlying mechanism between family history and survival in gastric cancer patients.
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Affiliation(s)
- Myueng Guen Oh
- Department of Internal Medicine, Chosun University Hospital, Chosun University, Gwangju, Korea E-mail :
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23
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Calcagno DQ, de Arruda Cardoso Smith M, Burbano RR. Cancer type-specific epigenetic changes: gastric cancer. Methods Mol Biol 2015; 1238:79-101. [PMID: 25421656 DOI: 10.1007/978-1-4939-1804-1_5] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Gastric cancer (GC) remains a major cause of mortality despite declining rate in the world. Epigenetic alterations contribute significantly to the development and progression of gastric tumors. Epigenetic refers to the number of modifications of the chromatin structure that affect gene expression without altering the primary sequence of DNA, and these changes lead to transcriptional activation or silencing of the gene. Over the years, the study of epigenetic processes has increased, and novel therapeutic approaches have emerged. This chapter summarizes the main epigenomic mechanisms described recently involved in gastric carcinogenesis, focusing on the roles that aberrant DNA methylation, histone modifications (histone acetylation and methylation), and miRNAs (oncogenic and tumor suppressor function of miRNA) play in the onset and progression of gastric tumors. Clinical implications of these epigenetic alterations in GC are also discussed.
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Affiliation(s)
- Danielle Queiroz Calcagno
- Núcleo de Pesquisas em Oncologia, Universidade Federal do Pará, Rua dos Mundurucus, 4487, Guamá, CEP 66073-000 Belém, PA, Brazil,
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Pinheiro DDR, Ferreira WAS, Barros MBL, Araújo MD, Rodrigues-Antunes S, Borges BDN. Perspectives on new biomarkers in gastric cancer: Diagnostic and prognostic applications. World J Gastroenterol 2014; 20:11574-11585. [PMID: 25206265 PMCID: PMC4155351 DOI: 10.3748/wjg.v20.i33.11574] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/22/2013] [Revised: 03/14/2014] [Accepted: 05/05/2014] [Indexed: 02/06/2023] Open
Abstract
Gastric cancer is considered one of the most deadly tumors worldwide. Even with the decline in its incidence, the mortality rate of this disease has remained high, mainly due to its late diagnosis and to the lack of precise prognostic markers. The main purpose of this review is to present genetic, epigenetic and proteomic molecular markers that may be used in a diagnostic and prognostic manner and to discuss the pros and cons of each type of marker for improving clinical practice. In this sense, we observed that the use of genetic markers, especially mutations and polymorphisms, should be carefully considered, as they are strongly affected by ethnicity. Proteomic-based markers show promise, but the higher costs of the associated techniques continue to make this approach expensive for routine use. Alternatively, epigenetic markers appear to be very promising, as they can be detected in bodily fluids as well as tissues. However, such markers must be used carefully because epigenetic changes may occur due to environmental factors and aging. Despite the advances in technology and its access, to date, there are few defined biomarkers of prognostic and diagnostic use for gastric tumors. Therefore, the use of a panel of several approaches (genetic, epigenetic and proteomic) should be considered the best alternative for clinical practice.
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25
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Li DX, Cai HY, Wang X, Feng YL, Cai SW. Promoter methylation of Raf kinase inhibitory protein: A significant prognostic indicator for patients with gastric adenocarcinoma. Exp Ther Med 2014; 8:844-850. [PMID: 25120612 PMCID: PMC4113522 DOI: 10.3892/etm.2014.1833] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2014] [Accepted: 06/20/2014] [Indexed: 12/23/2022] Open
Abstract
DNA methylation has an important role in the development of carcinomas. As a metastasis suppressor gene, Raf kinase inhibitory protein (RKIP) suppresses tumor cell invasion and metastasis. In the present study, the associations between RKIP protein expression and promoter methylation with clinicopathological parameters, prognosis and survival rates in gastric adenocarcinoma were investigated. RKIP protein expression and promoter methylation were measured in 135 cases of surgically resected gastric adenocarcinoma specimens and corresponding normal tissues using immunohistochemistry and methylation-specific polymerase chain reaction, respectively. Kaplan-Meier analyses were performed to analyze the patient survival rate. Prognostic factors were determined using multivariate Cox analysis. RKIP promoter methylation was detected in 48.9% of gastric carcinoma tissues and 5.17% of adjacent tissues (P<0.05). RKIP protein expression was detected in 43.0% of gastric carcinoma tissues and 91.1% of adjacent tissues (P<0.05). The protein expression levels and promoter methylation of RKIP were shown to correlate with pathological staging, Union for International Cancer Control-stage, tumor differentiation and lymph node metastasis (P<0.05). In addition, the protein expression of RKIP in gastric carcinomas was demonstrated to be associated with promoter methylation of RKIP. Survival analysis of gastric carcinoma patients revealed that promoter methylation in RKIP-positive tumors correlated with a significantly shorter survival time when compared with RKIP-negative tumors (P=0.0002, using the log-rank test). Using multivariate Cox analysis, promoter methylation of RKIP was shown to be an independent prognostic factor (P=0.033). These results indicated that abnormal promoter methylation of RKIP may be one cause of downregulated RKIP expression. Downregulation of RKIP expression was shown to correlate with the incidence and development of gastric carcinomas. Thus, abnormal promoter methylation of RKIP may be a valuable biomarker for estimating gastric carcinoma prognosis.
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Affiliation(s)
- Dong-Xia Li
- School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, Henan 453003, P.R. China
| | - Hai-Yang Cai
- School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, Henan 453003, P.R. China
| | - Xia Wang
- The First Affiliated Hospital of Xinxiang Medical University, Weihui, Henan 453100, P.R. China
| | - Yan-Ling Feng
- Department of Pathology, Public Health Clinical Center of Fudan University, Shanghai 201508, P.R. China
| | - Song-Wang Cai
- Department of Cardiothoracic Surgery, Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510630, P.R. China
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26
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Al-Mulla F, Bitar MS, Taqi Z, Yeung KC. RKIP: much more than Raf kinase inhibitory protein. J Cell Physiol 2013; 228:1688-702. [PMID: 23359513 DOI: 10.1002/jcp.24335] [Citation(s) in RCA: 78] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2012] [Accepted: 01/16/2013] [Indexed: 12/11/2022]
Abstract
From its discovery as a phosphatidylethanolamine-binding protein in bovine brain to its designation as a physiological inhibitor of Raf kinase protein, RKIP has emerged as a critical molecule for maintaining subdued, well-orchestrated cellular responses to stimuli. The disruption of RKIP in a wide range of pathologies, including cancer, Alzheimer's disease, and pancreatitis, makes it an exciting target for individualized therapy and disease-specific interventions. This review attempts to highlight recent advances in the RKIP field underscoring its potential role as a master modulator of many pivotal intracellular signaling cascades that control cellular growth, motility, apoptosis, genomic integrity, and therapeutic resistance. Specific biological and functional niches are highlighted to focus future research towards an enhanced understanding of the multiple roles of RKIP in health and disease.
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Affiliation(s)
- Fahd Al-Mulla
- Faculty of Medicine, Department of Pathology, Kuwait University Health Sciences Centre, Safat, Kuwait.
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27
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Guo W, Dong Z, Guo Y, Chen Z, Kuang G, Yang Z. Methylation-mediated repression of GADD45A and GADD45G expression in gastric cardia adenocarcinoma. Int J Cancer 2013; 133:2043-53. [PMID: 23616123 DOI: 10.1002/ijc.28223] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2012] [Accepted: 04/11/2013] [Indexed: 01/28/2023]
Abstract
The growth arrest DNA damage-inducible gene (GADD45) family, which is composed of GADD45A, GADD45B, and GADD45G, may play similar but not identical roles in tumorigenesis. Genetic changes associated with or responsible for their dysregulation are in general uncommon. This study was to detect the role of GADD45 gene family in gastric cardia adenocarcinoma (GCA) and the relationship of GADD45A and GADD45G methylation to a series of pathological parameters in a large GCA sample, in order to elucidate more information on the role of GADD45 gene family with regard to the pathogenesis of GCA. Decreased mRNA and protein expression of GADD45A and GADD45G but not GADD45B were found in 138 GCA tumor tissues. The methylation frequency of 5' 4 CpG region located in distal promoter of GADD45A and proximal promoter of GADD45G in GCA tumor tissues was significantly higher than that in corresponding normal tissues. The expression levels of GADD45A and GADD45G were inversely correlated with methylation levels. GADD45B expression was not correlated with GCA patients survival, while GADD45A and GADD45G methylation status and protein expression were independently associated with GCA patients' survival. These results suggest that GADD45A and GADD45G gene may act as functional tumor suppressor but being frequently inactivated epigenetically in patients with GCA. Silencing of GADD45A and GADD45G, negative regulator of cell growth, is most likely responsible for conferring a selective growth advantage during GCA evolution and outgrowth.
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Affiliation(s)
- Wei Guo
- Department of Pathology, Hebei Cancer Institute, the Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
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Qu Y, Dang S, Hou P. Gene methylation in gastric cancer. Clin Chim Acta 2013; 424:53-65. [PMID: 23669186 DOI: 10.1016/j.cca.2013.05.002] [Citation(s) in RCA: 279] [Impact Index Per Article: 23.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2013] [Revised: 05/03/2013] [Accepted: 05/03/2013] [Indexed: 02/07/2023]
Abstract
Gastric cancer is one of the most common malignancies and remains the second leading cause of cancer-related death worldwide. Over 70% of new cases and deaths occur in developing countries. In the early years of the molecular biology revolution, cancer research mainly focuses on genetic alterations, including gastric cancer. Epigenetic mechanisms are essential for normal development and maintenance of tissue-specific gene expression patterns in mammals. Disruption of epigenetic processes can lead to altered gene function and malignant cellular transformation. Recent advancements in the rapidly evolving field of cancer epigenetics have shown extensive reprogramming of every component of the epigenetic machinery in cancer, including DNA methylation, histone modifications, nucleosome positioning, noncoding RNAs, and microRNAs. Aberrant DNA methylation in the promoter regions of gene, which leads to inactivation of tumor suppressor and other cancer-related genes in cancer cells, is the most well-defined epigenetic hallmark in gastric cancer. The advantages of gene methylation as a target for detection and diagnosis of cancer in biopsy specimens and non-invasive body fluids such as serum and gastric washes have led to many studies of application in gastric cancer. This review focuses on the most common and important phenomenon of epigenetics, DNA methylation, in gastric cancer and illustrates the impact epigenetics has had on this field.
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Key Words
- 5-hmC
- 5-hydroxymethylcytosine
- 5-mC
- 5-methylcytosine
- ADAM metallopeptidase domain 23
- ADAM metallopeptidase with thrombospondin type 1 motif, 9
- ADAM23
- ADAMTS9
- AML
- APC
- ARID1A
- AT motif-binding factor 1
- AT rich interactive domain 1A (SWI-like)
- ATBF1
- Acute myelocytic leukemia
- Adenomatosis polyposis coli
- B-cell translocation gene 4
- BCL2/adenovirus E1B 19kDa interacting protein 3
- BMP-2
- BNIP3
- BS
- BTG4
- Biomarkers
- Bisulfite sequencing
- Bone morphogenetic protein 2
- C-MET
- CACNA1G
- CACNA2D3
- CD44
- CD44 molecule (Indian blood group)
- CDH1
- CDK4
- CDK6
- CDKN1C
- CDKN2A
- CDX2
- CGI
- CHD5
- CHFR
- CKLF-like MARVEL transmembrane domain containing 3
- CMTM3
- CNS
- CRBP1
- Cadherin 1 or E-cadherin
- Calcium channel, voltage-dependent, T type, alpha 1G subunit
- Calcium channel, voltage-dependent, alpha 2/delta subunit 3
- Caudal type homeobox 2
- Central nervous system
- Checkpoint with forkhead and ring finger domains, E3 ubiquitin protein ligase
- Chromodomain helicase DNA binding protein 5
- Chromosome 2 open reading frame 40
- Clinical outcomes
- CpG islands
- Cyclin-dependent kinase 4
- Cyclin-dependent kinase 6
- Cyclin-dependent kinase inhibitor 1A
- Cyclin-dependent kinase inhibitor 1B
- Cyclin-dependent kinase inhibitor 1C
- Cyclin-dependent kinase inhibitor 2A
- Cyclin-dependent kinase inhibitor 2B
- DAB2 interacting protein
- DACT1
- DAPK
- DNA
- DNA methylatransferases
- DNA mismatch repair
- DNMT
- Dapper, antagonist of beta-catenin, homolog 1 (Xenopus laevis)
- Death-associated protein kinase
- Deoxyribose Nucleic Acid
- Dickkopf 3 homolog (Xenopus laevis)
- Dkk-3
- EBV
- ECRG4
- EDNRB
- EGCG
- ERBB4
- Endothelin receptor type B
- Epigallocatechin gallate
- Epigenetics
- Epstein–Barr Virus
- FDA
- FLNc
- Filamin C
- Food and Drug Administration
- GC
- GDNF
- GI endoscopy
- GPX3
- GRIK2
- GSTP1
- Gastric cancer
- Gene methylation
- Glutamate receptor, ionotropic, kainate 2
- Glutathione S-transferase pi 1
- Glutathione peroxidase 3 (plasma)
- H. pylori
- HACE1
- HAI-2/SPINT2
- HECT domain and ankyrin repeat containing E3 ubiquitin protein ligase 1
- HGFA
- HLTF
- HOXA1
- HOXA10
- HRAS-like suppressor
- HRASLS
- Helicase-like transcription factor
- Helicobacter pylori
- Homeobox A1
- Homeobox A10
- Homeobox D10
- HoxD10
- IGF-1
- IGF-1R
- IGFBP3
- IL-1β
- ITGA4
- Insulin-like growth factor 1 (somatomedin C)
- Insulin-like growth factor I receptor
- Insulin-like growth factor binding protein 3
- Integrin, alpha 4 (antigen CD49D, alpha 4 subunit of VLA-4 receptor)
- Interleukin 1, beta
- KL
- KRAS
- Klotho
- LL3
- LMP2A
- LOX
- LRP1B
- Low density lipoprotein receptor-related protein 1B
- Lysyl oxidase
- MAPK
- MBPs
- MDS
- MGMT
- MINT25
- MLF1
- MLL
- MMR
- MSI
- MSP
- Matrix metallopeptidase 24 (membrane-inserted)
- Met proto-oncogene (hepatocyte growth factor receptor)
- Methyl-CpG binding proteins
- Methylation-specific PCR
- Microsatellite instability
- Myeloid leukemia factor 1
- Myeloid/lymphoid or mixed-lineage leukemia (trithorax homolog, Drosophila)
- Myeloid/lymphoid or mixed-lineage leukemia 3
- NDRG family member 2
- NDRG2
- NPR1
- NR3C1
- Natriuretic peptide receptor A/guanylate cyclase A
- Notch 1
- Nuclear receptor subfamily 3, group C, member 1 (glucocorticoid receptor)
- O-6-methylguanine-DNA methyltransferase
- PCDH10
- PCDH17
- PI3K/Akt
- PIK3CA
- PR domain containing 5
- PRDM5
- PTCH1
- Patched 1
- Phosphatidylethanolamine binding protein 1
- Protein tyrosine phosphatase, non-receptor type 6
- Protocadherin 10
- Protocadherin 17
- Q-MSP
- Quantitative methylation-specific PCR
- RAR-related orphan receptor A
- RARRES1
- RARß
- RAS/RAF/MEK/ERK
- RASSF1A
- RASSF2
- RBP1
- RKIP
- RORA
- ROS
- RUNX3
- Ras association (RalGDS/AF-6) domain family member 1
- Ras association (RalGDS/AF-6) domain family member 2
- Rb
- Retinoic acid receptor responder (tazarotene induced) 1
- Retinoic acid receptor, beta
- Retinol binding protein 1, cellular
- Runt-related transcription factor 3
- S-adenosylmethionine
- SAM
- SFRP2
- SFRP5
- SHP1
- SOCS-1
- STAT3
- SYK
- Secreted frizzled-related protein 2
- Secreted frizzled-related protein 5
- Serine peptidase inhibitor, Kunitz type, 2
- Spleen tyrosine kinase
- Suppressor of cytokine signaling 1
- TCF4
- TET
- TFPI2
- TGF-β
- TIMP metallopeptidase inhibitor 3
- TIMP3
- TNM
- TP73
- TSP1
- Thrombospondin 1
- Tissue factor pathway inhibitor 2
- Transcription factor 4
- Tumor Node Metastasis
- Tumor protein p73
- V-erb-a erythroblastic leukemia viral oncogene homolog 4
- ZFP82 zinc finger protein
- ZIC1
- ZNF545
- Zinc finger protein of the cerebellum 1
- gastrointestinal endoscopy
- glial cell derived neurotrophic factor
- hDAB2IP
- hMLH1
- hepatocyte growth factor activator
- latent membrane protein
- mutL homolog 1
- myelodysplastic syndromes
- p15
- p16
- p21
- p27
- p53
- p73
- phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha
- phosphoinositide 3-kinase (PI3K)/Akt
- reactive oxygen species
- retinoblastoma
- signal transducer and activator of transcription-3
- ten-eleven translocation
- transforming growth factor-β
- tumor protein p53
- tumor protein p73
- v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog
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Affiliation(s)
- Yiping Qu
- Department of Endocrinology, The First Affiliated Hospital of Xi'an Jiaotong University School of Medicine, Xi'an 710061, People's Republic of China
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