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Pichiri G, Piludu M, Congiu T, Grandi N, Coni P, Piras M, Jaremko M, Lachowicz JI. Kojic Acid Derivative as an Antimitotic Agent That Selectively Kills Tumour Cells. Pharmaceuticals (Basel) 2024; 18:11. [PMID: 39861074 PMCID: PMC11768441 DOI: 10.3390/ph18010011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2024] [Revised: 12/17/2024] [Accepted: 12/19/2024] [Indexed: 01/27/2025] Open
Abstract
Background/Objectives: The primary method used to pharmacologically arrest cancer development and its metastasis is to disrupt the cell division process. There are a few approaches that may be used to meet this objective, mainly through inhibiting DNA replication or mitosis. Despite intensive studies on new chemotherapeutics, the biggest problem remains the side effects associated with the inhibition of cell division in non-tumoural host cells. Methods: The efficacy and selectivity of the kojic acid derivative (L1) was studied in vitro with the use of tumoural (Caco2, SW480, HT29, T98G) and non- tumoural (HEK293T, RAW) cell lines. Light and electron microscopy observations were supported by the next generation sequencing (NGS), cytoflow, and spectroscopy analysis of mRNA and biomolecules, respectively. Results: The light and electron microscopy observations showed that L1 treatment leads to significant morphological changes in Caco2 cells, which are characteristic of mitosis arrest. Moreover, the fluorescent tubulin staining revealed the formation of tubulin ring structure associated with the apoptotic stage. Mitotic exit into apoptosis was further conformed by the cytoflow of early/late apoptosis stages and caspase-3 analysis. NGS investigation showed differentiated expressions of genes involved in mitosis and apoptosis processes. The observed IC50 in tumoural cell lines were as follows: Caco2 (IC50 = 68.2 mM), SW480 (IC50 = 15.5 mM), and HT29 (IC50 = 4.7 mM). Conclusions: The findings presented here suggest that L1 could be a valid candidate for oral prevention and/or chemotherapy in colorectal cancer. Considering high selectivity of L1 versus tumoural cell lines, more in-depth mechanistic studies could reveal unknown stages in carcinogenesis.
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Affiliation(s)
- Giuseppina Pichiri
- Department of Medical Sciences and Public Health, University of Cagliari, Cittadella Universitaria, 09042 Monserrato, Italy; (G.P.); (T.C.); (P.C.); (M.P.)
| | - Marco Piludu
- Department of Biomedical Sciences, University of Cagliari, Cittadella Universitaria, 09042 Monserrato, Italy;
| | - Terenzio Congiu
- Department of Medical Sciences and Public Health, University of Cagliari, Cittadella Universitaria, 09042 Monserrato, Italy; (G.P.); (T.C.); (P.C.); (M.P.)
| | - Nicole Grandi
- Department of Life and Environmental Sciences, University of Cagliari, Cittadella Universitaria, 09042 Monserrato, Italy;
| | - Pierpaolo Coni
- Department of Medical Sciences and Public Health, University of Cagliari, Cittadella Universitaria, 09042 Monserrato, Italy; (G.P.); (T.C.); (P.C.); (M.P.)
| | - Monica Piras
- Department of Medical Sciences and Public Health, University of Cagliari, Cittadella Universitaria, 09042 Monserrato, Italy; (G.P.); (T.C.); (P.C.); (M.P.)
| | - Mariusz Jaremko
- Smart-Health Initiative (SHI) and Red Sea Research Center (RSRC), Division of Biological and Environmental Sciences and Engineering (BESE), King Abdullah University of Science and Technology (KAUST), Thuwal 23955-6900, Saudi Arabia;
| | - Joanna Izabela Lachowicz
- Department of Medical Sciences and Public Health, University of Cagliari, Cittadella Universitaria, 09042 Monserrato, Italy; (G.P.); (T.C.); (P.C.); (M.P.)
- Department of Population Health, Division of Environmental Health, Occupational Medicine and Epidemiology, Wroclaw Medical University, Mikulicza-Radeckiego 7, 50-368 Wroclaw, Poland
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He H, Dong K, Chen M, Wang Y, Li Y, Wang D, Jia M, Meng X, Sun W, Fu S, Yu J. TOB1 inhibits the gastric cancer progression by focal adhesion pathway and ERK pathway based on transcriptional and metabolic sequencing. BMC Cancer 2024; 24:1130. [PMID: 39261761 PMCID: PMC11389266 DOI: 10.1186/s12885-024-12894-3] [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: 04/01/2024] [Accepted: 09/03/2024] [Indexed: 09/13/2024] Open
Abstract
Gastric cancer is one of the most malignant digestive tract tumors worldwide and its progression is associated with gene expression and metabolic alteration. We revealed that the gastric cancer patients with lower expression level of TOB1 exhibited poorer overall survivals according to the data in Kaplan-Meier Plotter. The unphosphorylated TOB1 protein which is effective expressed lower in gastric cancer cells. The gastric cancer cells with TOB1 gene depletion performed higher abilities of proliferation, migration and invasion and lower ability of apoptosis in vitro. The TOB1 gene depletion also promoted the tumorigenesis of gastric cancer cells in vivo. The gastric cancer cells with TOB1 gene overexpression had the converse behaviors. The transcriptional and metabolic sequencing was performed. The analyzation results showed that genes correlate-expressed with TOB1 gene were enriched in the pathways related to ERK pathway, including focal adhesion pathway, which was verified using real-time quantitative PCR. After inhibiting ERK pathway, the proliferation, colony formation and migration abilities were reduced in gastric cancer cells with low phosphorylated TOB1 protein expression level. Moreover, Pearson correlation analysis was adopted to further analyze the correlation of enriched metabolic products and differentially expressed genes. The expression of Choline, UDP-N-acetylglucosamine, Adenosine and GMP were related to the function of TOB1. This study demonstrates the genes and metabolites related to focal adhesion pathway and ERK pathway are the potential diagnosis and therapeutic targets to gastric cancer with TOB1 depletion.
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Affiliation(s)
- Hongjie He
- Scientific Research Centre, the Second Affiliated Hospital of Harbin Medical University, Harbin, 150081, China
| | - Kexian Dong
- Key Laboratory of Preservation of Human Genetic Resources and Disease Control in China, Ministry of Education, Harbin Medical University, Harbin, 150081, China
- Laboratory of Medical Genetics, Harbin Medical University, Harbin, 150081, China
| | - Mingming Chen
- Scientific Research Centre, the Second Affiliated Hospital of Harbin Medical University, Harbin, 150081, China
| | - Yuanyuan Wang
- Scientific Research Centre, the Second Affiliated Hospital of Harbin Medical University, Harbin, 150081, China
| | - Yawen Li
- Scientific Research Centre, the Second Affiliated Hospital of Harbin Medical University, Harbin, 150081, China
| | - Dong Wang
- Scientific Research Centre, the Second Affiliated Hospital of Harbin Medical University, Harbin, 150081, China
| | - Mansha Jia
- Scientific Research Centre, the Second Affiliated Hospital of Harbin Medical University, Harbin, 150081, China
| | - Xiangning Meng
- Key Laboratory of Preservation of Human Genetic Resources and Disease Control in China, Ministry of Education, Harbin Medical University, Harbin, 150081, China
- Laboratory of Medical Genetics, Harbin Medical University, Harbin, 150081, China
| | - Wenjing Sun
- Key Laboratory of Preservation of Human Genetic Resources and Disease Control in China, Ministry of Education, Harbin Medical University, Harbin, 150081, China
- Laboratory of Medical Genetics, Harbin Medical University, Harbin, 150081, China
| | - Songbin Fu
- Key Laboratory of Preservation of Human Genetic Resources and Disease Control in China, Ministry of Education, Harbin Medical University, Harbin, 150081, China
- Laboratory of Medical Genetics, Harbin Medical University, Harbin, 150081, China
| | - Jingcui Yu
- Scientific Research Centre, the Second Affiliated Hospital of Harbin Medical University, Harbin, 150081, China.
- Key Laboratory of Preservation of Human Genetic Resources and Disease Control in China, Ministry of Education, Harbin Medical University, Harbin, 150081, China.
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Zhang J, Li Y, Chen J, Huang T, Lin J, Pi Y, Hao H, Wang D, Liang X, Fu S, Yu J. TOB1 modulates neutrophil phenotypes to influence gastric cancer progression and immunotherapy efficacy. Front Immunol 2024; 15:1369087. [PMID: 38617839 PMCID: PMC11010640 DOI: 10.3389/fimmu.2024.1369087] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2024] [Accepted: 03/15/2024] [Indexed: 04/16/2024] Open
Abstract
Introduction The ErbB-2.1(TOB1) signaling transducer protein is a tumor-suppressive protein that actively suppresses the malignant phenotype of gastric cancer cells. Yet, TOB1 negatively regulates the activation and growth of different immune cells. Understanding the expression and role of TOB1 in the gastric cancer immune environment is crucial to maximize its potential in targeted immunotherapy. Methods This study employed multiplex immunofluorescence analysis to precisely delineate and quantify the expression of TOB1 in immune cells within gastric cancer tissue microarrays. Univariate and multivariate Cox analyses were performed to assess the influence of clinical-pathological parameters, immune cells, TOB1, and double-positive cells on the prognosis of gastric cancer patients. Subsequent experiments included co-culture assays of si-TOB1-transfected neutrophils with AGS or HGC-27 cells, along with EdU, invasion, migration assays, and bioinformatics analyses, aimed at elucidating the mechanisms through which TOB1 in neutrophils impacts the prognosis of gastric cancer patients. Results We remarkably revealed that TOB1 exhibits varying expression levels in both the nucleus (nTOB1) and cytoplasm (cTOB1) of diverse immune cell populations, including CD8+ T cells, CD66b+ neutrophils, FOXP3+ Tregs, CD20+ B cells, CD4+ T cells, and CD68+ macrophages within gastric cancer and paracancerous tissues. Significantly, TOB1 was notably concentrated in CD66b+ neutrophils. Survival analysis showed that a higher density of cTOB1/nTOB1+CD66b+ neutrophils was linked to a better prognosis. Subsequent experiments revealed that, following stimulation with the supernatant of tumor tissue culture, the levels of TOB1 protein and mRNA in neutrophils decreased, accompanied by enhanced apoptosis. HL-60 cells were successfully induced to neutrophil-like cells by DMSO. Neutrophils-like cells with attenuated TOB1 gene expression by si-TOB1 demonstrated heightened apoptosis, consequently fostering a malignant phenotype in AGS and HCG-27 cells upon co-cultivation. The subsequent analysis of the datasets from TCGA and TIMER2 revealed that patients with high levels of TOB1 combined neutrophils showed better immunotherapy response. Discussion This study significantly advances our comprehension of TOB1's role within the immune microenvironment of gastric cancer, offering promising therapeutic targets for immunotherapy in this context.
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Affiliation(s)
- Jinfeng Zhang
- Scientific Research Center, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
| | - Yunlong Li
- Department of General Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
| | - Jing Chen
- Department of Gastroenterology, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
| | - Tongtong Huang
- Scientific Research Center, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
| | - Jing Lin
- Scientific Research Center, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
| | - Yilin Pi
- Department of Gastroenterology, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
| | - Huiting Hao
- Department of Clinical Laboratory, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang, China
| | - Dong Wang
- Scientific Research Center, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
| | - Xiao Liang
- Key Laboratory of Preservation of Human Genetic Resources and Disease Control in China, Harbin Medical University, Ministry of Education, Harbin, China
| | - Songbin Fu
- Key Laboratory of Preservation of Human Genetic Resources and Disease Control in China, Harbin Medical University, Ministry of Education, Harbin, China
| | - Jingcui Yu
- Scientific Research Center, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
- Key Laboratory of Preservation of Human Genetic Resources and Disease Control in China, Harbin Medical University, Ministry of Education, Harbin, China
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The promoter methylation drives down-regulation mode of HIC1 in gastric cancer, its molecular characteristics and downstream functional pathways. Gene 2022; 824:146380. [PMID: 35276239 DOI: 10.1016/j.gene.2022.146380] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2021] [Revised: 02/10/2022] [Accepted: 02/24/2022] [Indexed: 01/09/2023]
Abstract
Gastric cancer is a common malignant tumor of the gastrointestinal tract with a high incidence and mortality rate. Previous results have suggested that the HIC1 gene might be a tumor suppressor candidate in gastric cancer. However, several critical points need to be elucidated: (1) The correlation of HIC1 promoter methylation with its specific expression level in gastric cancer; (2) The molecular characterization of HIC1 promoter methylation; (3) The possible mechanism by which HIC1 performs its inhibitory role in gastric cancer. To address these questions, we retrieved data from TCGA database to analyze HIC1 promoter methylation levels and transcript expression data, and performed targeted region bisulfite sequencing on three stable HIC1 down-regulated cell lines and normal control cell lines, and performed whole transcriptome and metabolite assays in HIC1 knockout cell lines by CRISPR-Cas9 technique. Results demonstrated that HIC1 promoter hypermethylation might be a crucial driving force leading to its down-regulation in HIC1 expression in gastric cancer. This implicated that promoter CG methylation of HIC1 might play a major role in the development of gastric carcinogenesis. Besides, HIC1 may suppress gastric cancer progression by maintaining the normal cellular metabolism, and inhibiting the mTOR signaling pathway activity.
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The Overexpression of TOB1 Induces Autophagy in Gastric Cancer Cells by Secreting Exosomes. DISEASE MARKERS 2022; 2022:7925097. [PMID: 35465266 PMCID: PMC9019440 DOI: 10.1155/2022/7925097] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/17/2022] [Revised: 03/25/2022] [Accepted: 03/29/2022] [Indexed: 12/17/2022]
Abstract
We previously confirmed that transducer of ERBB2, 1 (TOB1) gene, can induce autophagy in gastric cancer cells. Studies have shown the biogenesis of exosomes overlaps with different autophagy processes, which helps to maintain the self-renewal and homeostasis of body cells. This study is aimed at verifying whether overexpressing TOB1 induces autophagy by secreting exosomes in gastric cancer cells and its underlying mechanisms. Differential ultracentrifugation was used to extracted the exosomes from the culture medium of gastric cancer cell line AGS-TOB1 ectopically overexpressing TOB1 (exo-AGS-TOB1, experimental group) and AGS-empty-vector cell line with low expression of endogenous TOB1 (exo-AGS-Vector, control group). Exosomal markers CD9 and TSG101 were determined in both the cell supernatants of exo-AGS-TOB1 and exo-AGS-Vector by Western blot. Under the transmission electron microscope (TEM), the exosomes were round and saucer-like vesicles with double-layer membrane structure, and the vesicles showed different translucency due to different contents. The peak size of exosomes detected by nanoparticle tracking analysis (NTA) was about 100 nm. When the exosomes of exo-AGS-TOB1 and exo-AGS-Vector were cocultured with TOB1 knockdown gastric cancer cell line HGC-27-TOB1-6E12 for 48 hours, the conversion of autophagy-related protein LC3-I to LC3-II in HGC-27-TOB1-6E12 gastric cancer cells cocultured with exo-AGS-TOB1 was significantly higher than that in the control group, and the ratio of LC3-II/LC3-I was statistically different (P < 0.05). More autophagosomes in HGC-27-TOB1-6E12 cells cocultured with exo-AGS-TOB1 for 48 hours were observed under TEM, while fewer autophagosomes were found in the control group. Lastly, miRNAs were differentially expressed by cell supernatant-exosomal whole transcriptome sequencing. Thus, our results provide new insights into TOB1-induced autophagy in gastric cancer.
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Wang D, Li Y, Sui S, Cai M, Dong K, Wang P, Liang X, Fu S, Yu J. Involvement of TOB1 on autophagy in gastric cancer AGS cells via decreasing the activation of AKT/mTOR signaling pathway. PeerJ 2022; 10:e12904. [PMID: 35186488 PMCID: PMC8820212 DOI: 10.7717/peerj.12904] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2021] [Accepted: 01/17/2022] [Indexed: 01/11/2023] Open
Abstract
BACKGROUND We previously identified the tumor suppressor gene TOB1 as related to gastric cancer. The purpose of this study was to explore whether TOB1 induces autophagy through the AKT/mTOR signaling pathway in gastric cancer. METHODS Western blotting was used to detect the protein levels of TOB1, LC3, AKT, mTOR, phosphorylated (p) AKT, and p-mTOR. A double fluorescent GFP-RFP-LC3 fusion protein was used to trace autophagy by laser confocal microscopy. Autophagosomes were observed by transmission electron microscopy. RESULTS The conversion of LC3-I to LC3-II and the LC3-II/LC3-I ratio were significantly increased in AGS cells overexpressing TOB1 compared with control cells. Fluorescence imaging showed LC3 puncta at 48 h, and these puncta increased significantly at 72 h after TOB1 transfection compared with control tumor cells. The presence of autophagosomes in AGS cells was observed at 72 h after TOB1 transfection by transmission electron microscopy, and no autophagosomes were found in the control cells. Moreover, the levels of p-AKT and p -mTOR were lower in AGS cells than in control cancer cells. CONCLUSION Our results provide novel insight that TOB1 might suppress gastric cancer by inducing autophagy, possibly through decreasing phosphorylation and the subsequent activation of the AKT/mTOR signaling pathway.
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Affiliation(s)
- Dong Wang
- Scientific Research Centre, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Yunlong Li
- Department of General Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Shuning Sui
- Scientific Research Centre, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Mengdi Cai
- Key Laboratory of Preservation of Human Genetic Resources and Disease Control in China, Ministry of Education, Harbin Medical University, Harbin, China
| | - Kexian Dong
- Key Laboratory of Preservation of Human Genetic Resources and Disease Control in China, Ministry of Education, Harbin Medical University, Harbin, China
| | - Ping Wang
- Key Laboratory of Preservation of Human Genetic Resources and Disease Control in China, Ministry of Education, Harbin Medical University, Harbin, China
| | - Xiao Liang
- Key Laboratory of Preservation of Human Genetic Resources and Disease Control in China, Ministry of Education, Harbin Medical University, Harbin, China
| | - Songbin Fu
- Key Laboratory of Preservation of Human Genetic Resources and Disease Control in China, Ministry of Education, Harbin Medical University, Harbin, China
| | - Jingcui Yu
- Scientific Research Centre, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
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Yu L, Li Y, Wang H, Wang D, Hao H, Zhang D, Liang X, Cai M, Guan R, Bai J, Yu J. The functional variant in promoter of OVCA1 was associated with the risk of gastric cancer in the northeast Chinese Han population. Pathol Res Pract 2021; 230:153755. [PMID: 34990869 DOI: 10.1016/j.prp.2021.153755] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/03/2021] [Revised: 12/25/2021] [Accepted: 12/28/2021] [Indexed: 11/24/2022]
Abstract
We previously found allelic deletions on chromosomes 17 in primary gastric cancers (GC) using microsatellite markers for loss of heterozygosity (LOH). OVCA1 lies in one of these regions (17q21.33). The association between single nucleotide polymorphism (SNP) of OVCA1 gene and risk of gastric cancer is not yet clear. In this study, the peripheral blood of 505 gastric cancer patients and 544 healthy controls were genotyped for six SNPs (rs2273981, rs1131600, rs3752963, rs3803806, rs2236375, and rs1051322) of OVCA1, to evaluate the association of these SNPs with the risk of gastric cancer in the Han population in northeast China. The effect of rs2273981 located in the promoter region of OVCA1 on the transcription activity was determined using dual luciferase reporter assay. We found that the association between the AA + AG genotype of rs2273981 and the risk of gastric cancer was significant in smokers (AA + AG vs. GG, OR = 2.47, 95% CI = 1.04 - 5.87, P < 0.05). Stratified analysis of the clinicopathological parameters revealed that rs1131600 AG + GG genotype were significantly associated with increased gastric tumor volume (AG + GG vs. AA, OR = 1.81, 95% CI = 1.00 - 3.29, P < 0.05). The rs2236375 CT + TT genotype was also significantly associated with increased gastric tumor volume (CT + TT vs. CC, OR = 2.65, 95% CI = 1.38 - 5.10, P < 0.05). Additionally, by interacting with the transcription factor AP2A, the GG genotype the rs2273981 increased the transcription activity of OVCA1 compared with AA genotype, thus involved in gastric cancer development.
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Affiliation(s)
- Lina Yu
- Scientific Research Centre, The Second Affiliated Hospital of Harbin Medical University, Harbin 150081, China
| | - Yunlong Li
- Department of General Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin 150081, China
| | - Hui Wang
- Scientific Research Centre, The Second Affiliated Hospital of Harbin Medical University, Harbin 150081, China
| | - Dong Wang
- Scientific Research Centre, The Second Affiliated Hospital of Harbin Medical University, Harbin 150081, China
| | - Huiting Hao
- Scientific Research Centre, The Second Affiliated Hospital of Harbin Medical University, Harbin 150081, China; Clinical Laboratory, Harbin Medical University Cancer Hospital, Harbin 150081, China
| | - DongWei Zhang
- Scientific Research Centre, The Second Affiliated Hospital of Harbin Medical University, Harbin 150081, China; Clinical Laboratory, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, China
| | - Xiao Liang
- Key Laboratory of Preservation of Human Genetic Resources and Disease Control in China (Harbin Medical University), Ministry of Education, Harbin 150081, China
| | - Mengdi Cai
- Key Laboratory of Preservation of Human Genetic Resources and Disease Control in China (Harbin Medical University), Ministry of Education, Harbin 150081, China
| | - Rongwei Guan
- Key Laboratory of Preservation of Human Genetic Resources and Disease Control in China (Harbin Medical University), Ministry of Education, Harbin 150081, China
| | - Jing Bai
- Key Laboratory of Preservation of Human Genetic Resources and Disease Control in China (Harbin Medical University), Ministry of Education, Harbin 150081, China
| | - Jingcui Yu
- Scientific Research Centre, The Second Affiliated Hospital of Harbin Medical University, Harbin 150081, China; Key Laboratory of Preservation of Human Genetic Resources and Disease Control in China (Harbin Medical University), Ministry of Education, Harbin 150081, China.
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Díaz Del Arco C, Estrada Muñoz L, Ortega Medina L, Fernández Aceñero MJ. [Update on gastric cancer. New molecular classifications]. REVISTA ESPANOLA DE PATOLOGIA : PUBLICACION OFICIAL DE LA SOCIEDAD ESPANOLA DE ANATOMIA PATOLOGICA Y DE LA SOCIEDAD ESPANOLA DE CITOLOGIA 2021; 54:102-113. [PMID: 33726886 DOI: 10.1016/j.patol.2020.06.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/21/2020] [Revised: 05/17/2020] [Accepted: 06/01/2020] [Indexed: 06/12/2023]
Abstract
Gastric cancer (GC) is an aggressive tumor, which is usually diagnosed at an advanced stage and shows high mortality rates. Several GC classifications have been published, based on features such as tumor location, endoscopic features or microscopic architecture. However, TNM stage remains the mainstay of GC management and treatment. In the last years, technical advances have allowed us to investigate the biological heterogeneity of GC and develop new molecular classifications. This knowledge may enhance current classifications, and has the potential to refine GC management and aid in the identification of new molecular targets. In this literature review we have summarized the main findings in epidemiology, screening, classification systems and treatment of GC, focusing on the molecular alterations and new molecular classifications published in the last years.
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Affiliation(s)
- Cristina Díaz Del Arco
- Universidad Complutense de Madrid, España; Anatomía Patológica, Hospital Clínico San Carlos, Madrid, España.
| | | | - Luis Ortega Medina
- Universidad Complutense de Madrid, España; Anatomía Patológica, Hospital Clínico San Carlos, Madrid, España
| | - Ma Jesús Fernández Aceñero
- Universidad Complutense de Madrid, España; Anatomía Patológica, Hospital General Universitario Gregorio Marañón, Madrid, España
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Zhao T, Afrifa J, Wang D, Yu J. Association between HIC1 promoter methylation and solid tumor: A meta-analysis. EXCLI JOURNAL 2020; 19:476-489. [PMID: 32398971 PMCID: PMC7214777 DOI: 10.17179/excli2020-1102] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/03/2020] [Accepted: 03/27/2020] [Indexed: 01/11/2023]
Abstract
The epigenetic silencing of tumor suppressor genes by promoter methylation plays an increasingly important role in cancer research. A number of studies have reported the contribution of HIC1 promoter methylation towards the occurrence and development of solid tumors, even though HIC1 promoter methylation has also been found in normal and benign tissue samples. We sought to perform a more accurate and comprehensive meta-analysis to assess the association between HIC1 promoter methylation and cancer risk. We searched and retrieved all published studies on HIC1 promoter methylation in PubMed, Google Scholar, Embase, Cochrane Library, and Web of Science databases. After two reviewers checked the studies and extracted the necessary data independently, the meta-analysis was performed using STATA 12.0 software. A total of 14 case-control studies (949 cancer patients, 282 benign, and 371 normal controls) were included in our study. We report a significantly elevated HIC1 promoter methylation in tumor samples compared to normal (OR = 7.02, 95 % CI 3.12-15.78, P < 0.001) and benign controls (OR = 2.69, 95 % CI 1.13-6.42, P = 0.025). Subgroup analysis stratified by ethnicity showed a significantly reduced heterogeneity among North American (I2 = 0.0 %, P = 0.502) and European (I2 = 33.7 %, P = 0.183) samples. In addition, heterogeneity was significantly reduced among MSP based detection method (I2 = 36.4 %, P = 0.139) when samples were stratified based on the methylation detection methods. The overall outcome demonstrated that HIC1 promoter methylation may be involved in the occurrence and development of solid tumors and has the potential to serve as an epigenetic maker in various specific tumors.
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Affiliation(s)
- Tie Zhao
- Scientific Research Centre, The Second Affiliated Hospital of Harbin Medical University, Harbin 150081, China
| | - Justice Afrifa
- Scientific Research Centre, The Second Affiliated Hospital of Harbin Medical University, Harbin 150081, China.,Department of Medical Laboratory Science, University of Cape Coast, Cape Coast, Ghana
| | - Dong Wang
- Scientific Research Centre, The Second Affiliated Hospital of Harbin Medical University, Harbin 150081, China
| | - Jingcui Yu
- Scientific Research Centre, The Second Affiliated Hospital of Harbin Medical University, Harbin 150081, China
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10
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Wang D, Song H, Zhao T, Wang M, Wang Y, Yu L, Wang P, Yu J. Phosphorylation of TOB1 at T172 and S320 is critical for gastric cancer proliferation and progression. Am J Transl Res 2019; 11:5227-5239. [PMID: 31497236 PMCID: PMC6731426] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2019] [Accepted: 07/17/2019] [Indexed: 06/10/2023]
Abstract
We previously revealed that increased phosphorylation of TOB1, a tumor suppressor protein, may promote the progression of gastric cancer. However, the phosphorylated sites on TOB1 and their functional implication in gastric cancer remain to be clarified. Here, we addressed these questions using the gastric mucosal epithelial cell line GES-1 and three gastric cancer cell lines (HGC-27, AGS, and MKN-1). Compared with the control GES-1 cells, the gastric cancer cells showed decreased levels of TOB1 protein and increased levels of phosphorylated TOB1 (p-TOB1) by Western blotting. Then, TOB1 protein was enriched and purified by immunoprecipitation. Two novel phosphorylation sites at threonine 172 (T172) and serine 320 (S320) in TOB1 were identified in gastric cancer MKN-1 cells using LC-MS/MS. Furthermore, treatment with the serine/threonine kinase inhibitor staurosporine (STS; 2 nmol/L, 8 h) significantly decreased the levels of p-TOB1. As a result, the proliferation, migration, and invasion of gastric cancer cells were diminished, accompanied by an increased proportion of cells in G1 phase and a decreased proportion of cells in G2 phase. Taken together, these findings indicate for the first time that TOB1 is phosphorylated at T172 and S320 in gastric cancer cells, which are sensitive to STS. Downregulation of p-TOB1 levels by STS treatment can weaken the malignant phenotype of gastric cancer cells and block their progression through the cell cycle. Moreover, STS may exert its antiproliferative activity in gastric cancers by restoring TOB1 protein activity.
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Affiliation(s)
- Dong Wang
- Scientific Research Centre, The Second Affiliated Hospital of Harbin Medical UniversityHarbin 150081, Heilongjiang, P. R. China
| | - He Song
- Scientific Research Centre, The Second Affiliated Hospital of Harbin Medical UniversityHarbin 150081, Heilongjiang, P. R. China
| | - Tie Zhao
- Scientific Research Centre, The Second Affiliated Hospital of Harbin Medical UniversityHarbin 150081, Heilongjiang, P. R. China
| | - Mengxi Wang
- Scientific Research Centre, The Second Affiliated Hospital of Harbin Medical UniversityHarbin 150081, Heilongjiang, P. R. China
| | - Yanhong Wang
- Scientific Research Centre, The Second Affiliated Hospital of Harbin Medical UniversityHarbin 150081, Heilongjiang, P. R. China
| | - Lina Yu
- Scientific Research Centre, The Second Affiliated Hospital of Harbin Medical UniversityHarbin 150081, Heilongjiang, P. R. China
| | - Ping Wang
- Key Laboratory of Preservation of Human Genetic Resources and Disease Control in China (Harbin Medical University), Ministry of EducationHarbin 150081, Heilongjiang, P. R. China
| | - Jingcui Yu
- Scientific Research Centre, The Second Affiliated Hospital of Harbin Medical UniversityHarbin 150081, Heilongjiang, P. R. China
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Decreased expression levels of DAL-1 and TOB1 are associated with clinicopathological features and poor prognosis in gastric cancer. Pathol Res Pract 2019; 215:152403. [PMID: 30962003 DOI: 10.1016/j.prp.2019.03.031] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/07/2018] [Revised: 03/19/2019] [Accepted: 03/31/2019] [Indexed: 12/18/2022]
Abstract
PURPOSE We previously demonstrated that the functional inactivation of DAL-1 and TOB1 promotes an aggressive phenotype in gastric cancer cells, but the links between both genes and the survival of patients with gastric cancer are unknown. Here, we investigated the correlations of the expression levels of DAL-1 and TOB1 with the progression of gastric cancer. METHODS A total of 270 patients who underwent resectable gastrectomy were included. The expression of DAL-1 and TOB1 was detected by immunohistochemistry. RESULTS Low expression of DAL-1 in cancer tissue was significantly associated with tumor site (p < 0.05), histological grade (p < 0.01), depth of invasion (p < 0.05), lymph node metastasis status (p < 0.05), Lauren classification (p < 0.001), and clinical stage (p < 0.01). A lower level of TOB1 was observed in gastric cancer patients with diffuse type disease compared to patients with either intestinal or mixed type disease (p < 0.001). Additionally, Spearman's correlation analysis revealed that decreased expression of DAL-1 was positively correlated with low TOB1 expression (r=0.304, p < 0.001). The survival analysis showed that low levels of DAL-1 and TOB1 were significantly associated with poor survival of gastric cancer patients (p <0.001 and p < 0.05, respectively). CONCLUSION The downregulation of DAL-1 and TOB1 expression is associated with shorter survival of gastric cancer patients. Hence, DAL-1 and TOB1 may be considered potential novel markers for predicting the outcomes of patients with gastric cancer.
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12
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Guo H, Ji F, Zhao X, Yang X, He J, Huang L, Zhang Y. MicroRNA-371a-3p promotes progression of gastric cancer by targeting TOB1. Cancer Lett 2019; 443:179-188. [DOI: 10.1016/j.canlet.2018.11.021] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2018] [Revised: 11/19/2018] [Accepted: 11/21/2018] [Indexed: 02/07/2023]
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13
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Wang H, Hao H, Guo H, Wang Y, Zhang X, Xu L, Yu J. Association between the SNPs of the TOB1 gene and gastric cancer risk in the Chinese Han population of northeast China. J Cancer 2018; 9:1371-1378. [PMID: 29721046 PMCID: PMC5929081 DOI: 10.7150/jca.23805] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2017] [Accepted: 01/21/2018] [Indexed: 01/14/2023] Open
Abstract
The TOB1 (ErbB-2,1) gene is an anti-proliferative factor that has the potential to regulate cell growth and encodes a member of the transducer of erbB-2/B-cell translocation gene protein. The association between the polymorphisms of the TOB1 gene and gastric cancer (GC) risk is still unclear. In this study, 506 GC cases and 548 healthy controls (HCs) were collected to evaluate the association between the eleven SNPs (rs35220381, rs12950561, rs7221352, rs61482741, rs9303568, rs34700818, rs12949115, rs9903822, rs12601477, rs11656976 and rs4626) of the TOB1 gene and GC risk in the population of northeast China. The results showed that there were significant associations of haplotype GCCTTGC, haplotype ATCTTGG, and haplotype GCCACGC with GC risk (P < 0.05, P < 0.001, and P <0.001, respectively). The association between rs12601477 GA+AA genotypes and GC risk was significant among individuals older than 58 (adjusted OR=1.53, 95% CI=1.05-2.22, P< 0.05). The association between rs4626 AG+GG genotypes and GC risk was significant among individuals older than 58 (adjusted OR=1.54, 95% CI = 1.03-2.28, P<0.05). The rs34700818 CT+TT genotypes were associated with a significantly increased risk of T3-T4 (CT+TT vs CC, adjusted OR=1.71, 95% CI= 1.01-2.88, P<0.05) and TNM stage II (CT+TT vs CC, adjusted OR=2.40, 95% CI =1.27-4.52, P<0.01). The rs61482741 CG+GG genotypes were also associated with a significantly increased risk of T3-T4 (CG+GG vs CC, adjusted OR=1.71, 95% CI = 1.01-2.88, P<0.05) and TNM stage II (CG+GG vs CC, adjusted OR=2.40, 95% CI=1.27-4.52, P<0.01). The results suggest that four SNPs (rs12601477, rs4626, rs34700818 and rs61482741) of the TOB1 gene play an important role in the occurrence and development of GC in the Chinese Han population of northeast China.
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Affiliation(s)
- Hui Wang
- Scientific Research Centre, the Second Affiliated Hospital of Harbin Medical University, Harbin 150081, China.,Department of Blood Transfusion, the Second Affiliated Hospital of Harbin Medical University, Harbin 150081, China
| | - Huiting Hao
- Scientific Research Centre, the Second Affiliated Hospital of Harbin Medical University, Harbin 150081, China.,The clinical laboratory, the Tumor Hospital Affiliated to Harbin Medical University, Harbin 150081, China
| | - Haonan Guo
- Scientific Research Centre, the Second Affiliated Hospital of Harbin Medical University, Harbin 150081, China
| | - Yuanyuan Wang
- Scientific Research Centre, the Second Affiliated Hospital of Harbin Medical University, Harbin 150081, China
| | - Xuelong Zhang
- Laboratory of Medical Genetics, Harbin Medical University, Harbin 150081, China
| | - Lidan Xu
- Laboratory of Medical Genetics, Harbin Medical University, Harbin 150081, China
| | - Jingcui Yu
- Scientific Research Centre, the Second Affiliated Hospital of Harbin Medical University, Harbin 150081, China
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14
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Decreased TOB1 expression and increased phosphorylation of nuclear TOB1 promotes gastric cancer. Oncotarget 2017; 8:75243-75253. [PMID: 29088861 PMCID: PMC5650416 DOI: 10.18632/oncotarget.20749] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2017] [Accepted: 08/01/2017] [Indexed: 01/08/2023] Open
Abstract
TOB1, a member of the BTG/TOB protein family, inhibits tumor cell proliferation. We previously observed down-regulation and phosphorylation of TOB1 in gastric cancer (GC). Here, we examined the subcellular distribution and clinical significance of TOB1 expression and phosphorylation in GC. Immunohistochemical analysis of 341 primary GC and corresponding normal gastric tissue samples demonstrated that nuclear TOB1 expression was lower in GC than normal tissue (80.4% vs. 92.4%), and decreased nuclear TOB1 expression correlated with high TNM stage. By contrast, phosphorylation of nuclear TOB1 was higher in GC than normal gastric tissue (66.0% vs. 36.4%), and was associated with poorly differentiated and high TNM stage tumors. Patients with intestinal type GC and increased nuclear TOB1 phosphorylation had poor overall survival. Multivariate survival analysis indicated the nuclear concentration of phosphorylated TOB1 was an independent prognostic factor for intestinal type GC. Overexpression of TOB1 containing mutations in its nuclear export signal inhibited GC cell proliferation, migration, and invasion compared to cells expressing TOB1 with the nuclear localization signal. Thus, decreased TOB1 expression and increased phosphorylation of nuclear TOB1 is associated with aggressive tumor behavior and poor prognosis in intestinal type GC. Additionally, TOB1 nuclear retention is critical for its anti-proliferative activity.
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15
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Lee HS, Kundu J, Kim RN, Shin YK. Transducer of ERBB2.1 (TOB1) as a Tumor Suppressor: A Mechanistic Perspective. Int J Mol Sci 2015; 16:29815-28. [PMID: 26694352 PMCID: PMC4691146 DOI: 10.3390/ijms161226203] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2015] [Revised: 11/22/2015] [Accepted: 12/08/2015] [Indexed: 01/06/2023] Open
Abstract
Transducer of ERBB2.1 (TOB1) is a tumor-suppressor protein, which functions as a negative regulator of the receptor tyrosine-kinase ERBB2. As most of the other tumor suppressor proteins, TOB1 is inactivated in many human cancers. Homozygous deletion of TOB1 in mice is reported to be responsible for cancer development in the lung, liver, and lymph node, whereas the ectopic overexpression of TOB1 shows anti-proliferation, and a decrease in the migration and invasion abilities on cancer cells. Biochemical studies revealed that the anti-proliferative activity of TOB1 involves mRNA deadenylation and is associated with the reduction of both cyclin D1 and cyclin-dependent kinase (CDK) expressions and the induction of CDK inhibitors. Moreover, TOB1 interacts with an oncogenic signaling mediator, β-catenin, and inhibits β-catenin-regulated gene transcription. TOB1 antagonizes the v-akt murine thymoma viral oncogene (AKT) signaling and induces cancer cell apoptosis by activating BCL2-associated X (BAX) protein and inhibiting the BCL-2 and BCL-XL expressions. The tumor-specific overexpression of TOB1 results in the activation of other tumor suppressor proteins, such as mothers against decapentaplegic homolog 4 (SMAD4) and phosphatase and tensin homolog-10 (PTEN), and blocks tumor progression. TOB1-overexpressing cancer cells have limited potential of growing as xenograft tumors in nude mice upon subcutaneous implantation. This review addresses the molecular basis of TOB1 tumor suppressor function with special emphasis on its regulation of intracellular signaling pathways.
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Affiliation(s)
- Hun Seok Lee
- Research Institute of Pharmaceutical Science, Department of Pharmacy, College of Pharmacy, Seoul National University, Seoul 08826, Korea.
| | - Juthika Kundu
- Research Institute of Pharmaceutical Science, Department of Pharmacy, College of Pharmacy, Seoul National University, Seoul 08826, Korea.
| | - Ryong Nam Kim
- Research Institute of Pharmaceutical Science, Department of Pharmacy, College of Pharmacy, Seoul National University, Seoul 08826, Korea.
- Tumor Microenvironment Global Core Research Center, Seoul National University, Seoul 08826, Korea.
| | - Young Kee Shin
- Research Institute of Pharmaceutical Science, Department of Pharmacy, College of Pharmacy, Seoul National University, Seoul 08826, Korea.
- Tumor Microenvironment Global Core Research Center, Seoul National University, Seoul 08826, Korea.
- The Center for Anti-cancer Companion Diagnostics, School of Biological Science, Institutes of Entrepreneurial BioConvergence, Seoul National University, Seoul 08826, Korea.
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16
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Zhou J, Zhou J, Wang W, Li W, Wu L, Li G, Shi J, Zhou S. The polymorphism in miR-25 attenuated the oncogenic function in gastric cancer. Tumour Biol 2015; 37:5515-20. [PMID: 26572149 DOI: 10.1007/s13277-015-4376-0] [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: 10/13/2015] [Accepted: 11/03/2015] [Indexed: 12/17/2022] Open
Abstract
miR-25 was identified as an essential oncogene by promoting the growth and metastasis through TOB1 in gastric cancer (GC). The function of the single nucleotide polymorphism (SNP) located in the mature region of miR-25 (rs41274221) has not been investigated. In this study, we aimed to explore the involvement of rs41274221 in miR-25 in gastric cancer. We found that SNP rs41274221 in miR-25 was participated in the occurrence of GC by acting as a tumor protective factor associating with the tumor growth and metastasis. Besides, further investigation found that upregulation of miR-25 with AA genotype could attenuate the proliferation and invasion of tumor cells caused by wild-type miR-25. The dual-luciferase reporter assay also confirmed that miR-25 harbored the A allele which caused an incapacitation of binding at the TOB1. In conclusion, rs41274221 in miR-25 was a subgroup which may protect the patients from further growth and metastasis of gastric cancer and might serve as a novel biomarker for the disease.
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Affiliation(s)
- Jianping Zhou
- Department of General Surgery, Yixing People's Hospital Affiliated to Jiangsu University, Yixing, 214200, Jiangsu, China
| | - Jiangang Zhou
- Department of General Surgery, Yixing People's Hospital Affiliated to Jiangsu University, Yixing, 214200, Jiangsu, China
| | - Weimin Wang
- Department of General Surgery, Yixing People's Hospital Affiliated to Jiangsu University, Yixing, 214200, Jiangsu, China
| | - Weiling Li
- Department of General Surgery, Yixing People's Hospital Affiliated to Jiangsu University, Yixing, 214200, Jiangsu, China
| | - Lulu Wu
- Department of General Surgery, Yixing People's Hospital Affiliated to Jiangsu University, Yixing, 214200, Jiangsu, China
| | - Gang Li
- Department of General Surgery, Yixing People's Hospital Affiliated to Jiangsu University, Yixing, 214200, Jiangsu, China
| | - Jun Shi
- Department of General Surgery, Yixing People's Hospital Affiliated to Jiangsu University, Yixing, 214200, Jiangsu, China
| | - Sujun Zhou
- Department of General Surgery, Yixing People's Hospital Affiliated to Jiangsu University, Yixing, 214200, Jiangsu, China. .,Yixing People's Hospital (The Affiliated Hospital of Jiangsu University), Yixing, 214200, Jiangsu, China.
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17
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Li BS, Zuo QF, Zhao YL, Xiao B, Zhuang Y, Mao XH, Wu C, Yang SM, Zeng H, Zou QM, Guo G. MicroRNA-25 promotes gastric cancer migration, invasion and proliferation by directly targeting transducer of ERBB2, 1 and correlates with poor survival. Oncogene 2014; 34:2556-65. [PMID: 25043310 DOI: 10.1038/onc.2014.214] [Citation(s) in RCA: 103] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2013] [Revised: 06/03/2014] [Accepted: 06/06/2014] [Indexed: 12/14/2022]
Abstract
Gastric cancer (GC) is one of the most common tumors and the molecular mechanism underlying its metastasis is still largely unclear. Here, we show that miR-25 was overexpressed in plasma and primary tumor tissues of GC patients with tumor node metastasis stage (III or IV) or lymph node metastasis. MiR-25 inhibition significantly decreased the metastasis, invasion and proliferation of GC cells in vitro, and reduced their capacity to develop distal pulmonary metastases and peritoneal dissemination in vivo. Furthermore, miR-25 repressed transducer of ERBB2, 1 (TOB1) expression by directly binding to TOB1-3'-UTR, and the inverse correlation was observed between the expressions of miR-25 and TOB1 mRNA in primary GC tissues. Moreover, the loss of TOB1 increased the metastasis, invasion and proliferation of GC cells, and the restoration of TOB1 led to suppressed metastasis, invasion and proliferation. The receiver operating characteristics analysis yielded an area under the curve value of 0.7325 in distinguishing the GC patients with death from those with survival. The analysis of optimal cutoff value revealed poor survival in GC patients with high plasma concentrations of miR-25 (>0.2333 amol/μl). Taken together, miR-25 promotes GC progression by directly downregulating TOB1 expression, and may be a noninvasive biomarker for the prognosis of GC patients.
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Affiliation(s)
- B-S Li
- National Engineering Research Center of Immunological Products, Department of Microbiology and Biochemical Pharmacy, College of Pharmacy, Third Military Medical University, Chongqing, PR China
| | - Q-F Zuo
- National Engineering Research Center of Immunological Products, Department of Microbiology and Biochemical Pharmacy, College of Pharmacy, Third Military Medical University, Chongqing, PR China
| | - Y-L Zhao
- General Surgery and Center of Minimally Invasive Gastrointestinal Surgery, Southwest Hospital, Third Military Medical University, Chongqing, PR China
| | - B Xiao
- National Engineering Research Center of Immunological Products, Department of Microbiology and Biochemical Pharmacy, College of Pharmacy, Third Military Medical University, Chongqing, PR China
| | - Y Zhuang
- National Engineering Research Center of Immunological Products, Department of Microbiology and Biochemical Pharmacy, College of Pharmacy, Third Military Medical University, Chongqing, PR China
| | - X-H Mao
- National Engineering Research Center of Immunological Products, Department of Microbiology and Biochemical Pharmacy, College of Pharmacy, Third Military Medical University, Chongqing, PR China
| | - C Wu
- National Engineering Research Center of Immunological Products, Department of Microbiology and Biochemical Pharmacy, College of Pharmacy, Third Military Medical University, Chongqing, PR China
| | - S-M Yang
- Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing, PR China
| | - H Zeng
- National Engineering Research Center of Immunological Products, Department of Microbiology and Biochemical Pharmacy, College of Pharmacy, Third Military Medical University, Chongqing, PR China
| | - Q-M Zou
- National Engineering Research Center of Immunological Products, Department of Microbiology and Biochemical Pharmacy, College of Pharmacy, Third Military Medical University, Chongqing, PR China
| | - G Guo
- National Engineering Research Center of Immunological Products, Department of Microbiology and Biochemical Pharmacy, College of Pharmacy, Third Military Medical University, Chongqing, PR China
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18
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Inactivation of tumor suppressor gene HIC1 in gastric cancer is reversed via small activating RNAs. Gene 2013; 527:102-8. [DOI: 10.1016/j.gene.2013.05.034] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2012] [Revised: 04/23/2013] [Accepted: 05/20/2013] [Indexed: 11/19/2022]
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Rood BR, Leprince D. Deciphering HIC1 control pathways to reveal new avenues in cancer therapeutics. Expert Opin Ther Targets 2013; 17:811-27. [PMID: 23566242 DOI: 10.1517/14728222.2013.788152] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
INTRODUCTION The tumor suppressor gene HIC1 (Hypermethylated in Cancer 1), which encodes a transcriptional repressor with multiple partners and multiple targets, is epigenetically silenced but not mutated in tumors. HIC1 has broad biological roles during normal development and is implicated in many canonical processes of cancer such as control of cell growth, cell survival upon genotoxic stress, cell migration, and motility. AREAS COVERED The HIC1 literature herein discussed includes its discovery as a candidate tumor suppressor gene hypermethylated or deleted in many human tumors, animal models establishing it as tumor suppressor gene, its role as a sequence-specific transcriptional repressor recruiting several chromatin regulatory complexes, its cognate target genes, and its functional roles in normal tissues. Finally, this review discusses how its loss of function contributes to the early steps in tumorigenesis. EXPERT OPINION Given HIC1's ability to direct repressive complexes to sequence-specific binding sites associated with its target genes, its loss results in specific changes in the transcriptional program of the cell. An understanding of this program through identification of HIC1's target genes and their involvement in feedback loops and cell process regulation will yield the ability to leverage this knowledge for therapeutic translation.
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Affiliation(s)
- Brian R Rood
- Center for Cancer and Blood Disorders, Children's National Medical Center, Division of Oncology, 111 Michigan Ave. NW, Washington, DC 20010, USA
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20
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Qie S, Liang D, Yin C, Gu W, Meng M, Wang C, Sang N. Glutamine depletion and glucose depletion trigger growth inhibition via distinctive gene expression reprogramming. Cell Cycle 2012; 11:3679-90. [PMID: 22935705 DOI: 10.4161/cc.21944] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Glutamine (Gln) and glucose (Glc) represent two important nutrients for proliferating cells, consistent with the observations that oncogenic processes are associated with enhanced glycolysis and glutaminolysis. Gln depletion and Glc depletion have been shown to trigger growth arrest and eventually cell death. Solid tumors often outgrow the blood supply, resulting in ischemia, which is associated with hypoxia and nutrient insufficiency. Whereas oxygen-sensing and adaptive mechanisms to hypoxia have been well-studied, how cells directly sense and respond to Gln and Glc insufficiency remains unclear. Using mRNA profiling techniques, we compared the gene expression profiles of acute Gln-depleted cells, Glc-depleted cells and cells adapted to Gln depletion. Here we report the global changes of the gene expression in those cells cultured under the defined nutrient conditions. Analysis of mRNA profiling data revealed that Gln and Glc depletion triggered dramatic gene expression reprogramming. Either Gln or Glc deletion leads to changes of the expression of cell cycle genes, but these conditions have distinctive effects on transcription regulators and gene expression profiles. Moreover, Gln and Glc depletion triggered distinguishable ER-stress responses. The gene expression patterns support that Gln and Glc have distinctive metabolic roles in supporting cell survival and proliferation, and cells use different mechanisms to sense and respond to Gln and Glc insufficiency. Our mRNA profiling database provides a resource for further investigating the nutrient-sensing mechanisms and potential effects of Glc and Gln abundance on the biological behaviors of cells.
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Affiliation(s)
- Shuo Qie
- Department of Biology, College of Arts and Sciences, Drexel University, Philadelphia, PA, USA
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Kundu J, Wahab SMR, Kundu JK, Choi YL, Erkin OC, Lee HS, Park SG, Shin YK. Tob1 induces apoptosis and inhibits proliferation, migration and invasion of gastric cancer cells by activating Smad4 and inhibiting β‑catenin signaling. Int J Oncol 2012; 41:839-48. [PMID: 22710759 PMCID: PMC3582759 DOI: 10.3892/ijo.2012.1517] [Citation(s) in RCA: 50] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2012] [Accepted: 05/08/2012] [Indexed: 01/24/2023] Open
Abstract
Transducer of ErbB-2.1 (Tob1), a tumor suppressor protein, is inactivated in a variety of cancers including stomach cancer. However, the role of Tob1 in gastric carcinogenesis remains elusive. The present study aimed to investigate whether Tob1 could inhibit gastric cancer progression in vitro, and to elucidate its underlying molecular mechanisms. We found differential expression of Tob1 in human gastric cancer (MKN28, AGS and MKN1) cells. The overexpression of Tob1 induced apoptosis in MKN28 and AGS cells, which was associated with sub-G1 arrest, activation of caspase-3, induction of Bax, inhibition of Bcl-2 and cleavage of poly (ADP-ribose) polymerase (PARP). In addition, Tob1 inhibited proliferation, migration and invasion, which were reversed in MKN1 and AGS cells transfected with Tob1 siRNA. Overexpression of Tob1 in MKN28 and AGS cells induced the expression of Smad4, leading to the increased expression and the promoter activity of p15, which was diminished by silencing of Tob1 using specific siRNA. Tob1 decreased the phosphorylation of Akt and glycogen synthase kinase-3β (GSK3β) in MKN28 and AGS cells, resulting in the reduced protein expression and the transcriptional activity of β‑catenin, which in turn decreased the expression of cyclin D1, cyclin-dependent kinase-4 (CDK4), urokinase plasminogen activator receptor (uPAR) and peroxisome proliferator and activator receptor-δ (PPARδ). Conversely, silencing of Tob1 induced the phosphorylation of Akt and GSK-3β, and increased the expression of β‑catenin and its target genes. Collectively, our study demonstrates that the overexpression of Tob1 inhibits gastric cancer progression by activating Smad4- and inhibiting β‑catenin-mediated signaling pathways.
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Affiliation(s)
- Juthika Kundu
- Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, Republic of Korea
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Li XQ, Guo YY, De W. DNA methylation and microRNAs in cancer. World J Gastroenterol 2012; 18:882-8. [PMID: 22408346 PMCID: PMC3297046 DOI: 10.3748/wjg.v18.i9.882] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/14/2011] [Revised: 09/09/2011] [Accepted: 01/18/2012] [Indexed: 02/06/2023] Open
Abstract
DNA methylation is a type of epigenetic modification in the human genome, which means that gene expression is regulated without altering the DNA sequence. Methylation and the relationship between methylation and cancer have been the focus of molecular biology researches. Methylation represses gene expression and can influence embryogenesis and tumorigenesis. In different tissues and at different stages of life, the level of methylation of DNA varies, implying a fundamental but distinct role for methylation. When genes are repressed by abnormal methylation, the resulting effects can include instability of that gene and inactivation of a tumor suppressor gene. MicroRNAs have some aspects in common with this regulation of gene expression. Here we reviewed the influence of gene methylation on cancer and analyzed the methods used to profile methylation. We also assessed the correlation between methylation and other epigenetic modifications and microRNAs. About 55 845 research papers have been published about methylation, and one-fifth of these are about the appearance of methylation in cancer. We conclude that methylation does play a role in some cancer types.
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Kasamatsu A, Uzawa K, Usukura K, Koike K, Nakashima D, Ishigami T, Fushimi K, Ogawara K, Shiiba M, Tanzawa H. Loss of heterozygosity in oral cancer. ACTA ACUST UNITED AC 2011. [DOI: 10.1016/s1348-8643(11)00027-9] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
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