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Wei S, Peng L, Yang J, Sang H, Jin D, Li X, Chen M, Zhang W, Dang Y, Zhang G. Exosomal transfer of miR-15b-3p enhances tumorigenesis and malignant transformation through the DYNLT1/Caspase-3/Caspase-9 signaling pathway in gastric cancer. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2020; 39:32. [PMID: 32039741 PMCID: PMC7011526 DOI: 10.1186/s13046-019-1511-6] [Citation(s) in RCA: 81] [Impact Index Per Article: 16.2] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/30/2019] [Accepted: 12/17/2019] [Indexed: 02/10/2023]
Abstract
Background Exosomes are essential for tumor growth, metastasis, and are used as novel signaling molecules in targeted therapies. Therefore, exosomal miRNAs can be used in new diagnostic and therapeutic approaches due to their involvement in the development of cancers. However, the detailed biological function, potential molecular mechanism and clinical application of exo-miR-15b-3p in gastric cancer (GC) remains unclear. Methods miR-15b-3p mRNA levels in tissues, serum, cells and exosomes were analyzed using qRT-PCR assays. qRT-PCR, immunohistochemical and western blotting analyses were utilized for the determination of DYNLT1 expression. The interrelationship connecting miR-15b-3p with DYNLT1 was verified using Dual-luciferase report, western blotting and qRT-PCR assays. Fluorescent PKH-26 or GFP-Lv-CD63 labeled exosomes, as well as Cy3-miR-15b-3p, were utilized to determine the efficacy of the transfer of exo-miR-15b-3p between BGC-823 and recipient cells. Several in vitro assays and xenograft tumor models were conducted to determine exo-miR-15b-3p impact on GC progression. Results This is the first study to confirm high miR-15b-3p expression in GC cell lines, tissues and serum. Exosomes obtained from 108 GC patient serum samples and GC cell-conditioned medium were found to show upregulation of exo-miR-15b-3p, with the area under the ROC curve (AUC) being 0.820 [0.763–0.876], which is superior to the AUC of tissues and serum miR-15b-3p (0.674 [0.600–0.748] and 0.642 [0.499–0.786], respectively). In addition, high exo-miR-15b-3p expression in serum was found to accurately predict worse overall survival. SGC-7901 and GES-1 cells are capable of internalizing BGC-823 cell-derived exosomes, allowing the transfer of miR-15b-3p. Migration, invasion, proliferation and inhibition of apoptosis in vitro and in vivo were enhanced by exo-miR-15b-3p, by restraining DYNLT1, Cleaved Caspase-9 and Caspase-3 expression. Conclusions This study identified a previously unknown regulatory pathway, exo-miR-15b-3p/DYNLT1/Caspase-3/Caspase-9, which promotes GC development and GES-1 cell malignant transformation. Therefore, serum exo-miR-15b-3p may be a potential GC diagnosis and prognosis biomarker, which can be used in precise targeted GC therapy.
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Affiliation(s)
- Shuchun Wei
- Department of Gastroenterology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China
| | - Lei Peng
- Department of Gastroenterology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China
| | - Jiajia Yang
- Department of Gastroenterology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China
| | - Huaiming Sang
- Department of Gastroenterology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China
| | - Duochen Jin
- Department of Gastroenterology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China
| | - Xuan Li
- Department of Gastroenterology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China
| | - Meihong Chen
- Department of Gastroenterology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China
| | - Weifeng Zhang
- Department of Gastroenterology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China
| | - Yini Dang
- Department of Gastroenterology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China.
| | - Guoxin Zhang
- Department of Gastroenterology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China.
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Zhao Z, Herman JG, Brock MV, Sheng J, Zhang M, Liu B, Guo M. Methylation of DACT2 promotes papillary thyroid cancer metastasis by activating Wnt signaling. PLoS One 2014; 9:e112336. [PMID: 25375359 PMCID: PMC4223043 DOI: 10.1371/journal.pone.0112336] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2014] [Accepted: 10/08/2014] [Indexed: 01/26/2023] Open
Abstract
Thyroid cancer is the most common endocrine malignant disease and the incidence is increasing. DACT2 was found frequently methylated in human lung cancer and hepatocellular carcinoma. To explore the epigenetic change and the role of DACT2 in thyroid cancer, 7 thyroid cancer cell lines, 10 cases of non-cancerous thyroid tissue samples and 99 cases of primary thyroid cancer samples were involved in this study. DACT2 was expressed and unmethylated in K1, SW579, FTC-133, TT, W3 and 8505C cell lines. Loss of expression and complete methylation was found in TPC-1 cells. Restoration of DACT2 expression was induced by 5-aza-2′deoxycytidine treatment. It demonstrates that the expression of DACT2 was regulated by promoter region methylation. In human primary papillary thyroid cancer, 64.6% (64/99) was methylated and methylation of DACT2 was related to lymph node metastasis (p<0.01). Re-expression of DACT2 suppresses cell proliferation, invasion and migration in TPC-1 cells. The activity of TCF/LEF was inhibited by DACT2 in wild-type or mutant β-catenin cells. The activity of TCF/LEF was increased by co-transfecting DACT2 and Dvl2 in wild-type or mutant β-catenin cells. Overexpression of wild-type β-catenin promotes cell migration and invasion in DACT2 stably expressed cells. The expression of β-catenin, c-myc, cyclinD1 and MMP-9 were decreased and the level of phosphorylated β-catenin (p-β-catenin) was increased after restoration of DACT2 expression in TPC-1 cells. The expression of β-catenin, c-myc, cyclinD1 and MMP-9 were increased and the level of p-β-catenin was reduced after knockdown of DACT2 in W3 and SW579 cells. These results suggest that DACT2 suppresses human papillary thyroid cancer growth and metastasis by inhibiting Wnt signaling. In conclusion, DACT2 is frequently methylated in papillary thyroid cancer. DACT2 expression was regulated by promoter region methylation. DACT2 suppresses papillary thyroid cancer proliferation and metastasis by inhibiting Wnt signaling.
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Affiliation(s)
- Zhiyan Zhao
- The Department of Head & Neck Surgery, Peking University Cancer Hospital and Institute, #52 Fucheng Road, Beijing 100036, China
- The Department of Gastroenterology & Hepatology, Chinese PLA General Hospital, #28 Fuxing Road, Beijing 100853, China
| | - James G. Herman
- The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, The Bunting-Blaustein Cancer Research Building, Room 543, 1650 Orleans Street, Baltimore, Maryland 21231, United States of America
| | - Malcolm V. Brock
- The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, The Bunting-Blaustein Cancer Research Building, Room 543, 1650 Orleans Street, Baltimore, Maryland 21231, United States of America
| | - Jindong Sheng
- The Department of Head & Neck Surgery, Peking University Cancer Hospital and Institute, #52 Fucheng Road, Beijing 100036, China
| | - Meiying Zhang
- The Department of Gastroenterology & Hepatology, Chinese PLA General Hospital, #28 Fuxing Road, Beijing 100853, China
- The Medical College of Nan Kai University, #94 Weijin Road, Tianjin 300071, China
| | - Baoguo Liu
- The Department of Head & Neck Surgery, Peking University Cancer Hospital and Institute, #52 Fucheng Road, Beijing 100036, China
- * E-mail: (MG); (BL)
| | - Mingzhou Guo
- The Department of Gastroenterology & Hepatology, Chinese PLA General Hospital, #28 Fuxing Road, Beijing 100853, China
- * E-mail: (MG); (BL)
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Zhang X, Yang Y, Liu X, Herman JG, Brock MV, Licchesi JDF, Yue W, Pei X, Guo M. Epigenetic regulation of the Wnt signaling inhibitor DACT2 in human hepatocellular carcinoma. Epigenetics 2013; 8:373-82. [PMID: 23449122 DOI: 10.4161/epi.24113] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
DACT2 (Dapper, Dishevelled-associated antagonist of β-catenin homolog 2) is a member of the DACT family involved in the regulation of embryonic development. Human DACT2 is localized on 6q27, a region of frequent loss of heterozygosity in human cancers. However, the regulation of DACT2 expression and function in hepatocellular carcinoma (HCC) remains unclear. In this study, genetic and epigenetic changes of DACT2 were analyzed in HCC cell lines and primary cancer. We found no single-nucleotide polymorphism (SNP) associated with HCC. Promoter region methylation was correlated with loss or reduction of DACT2 expression, and restoration of DACT2 expression was induced by 5-aza-2'-deoxycytidine (5-AZA) in HCC cell lines. Promoter region methylation was found in 54.84% of primary HCC. Reduction of DACT2 expression was associated with promoter hypermethylation, and expression of DACT2 was inversely related to β-catenin expression in primary HCC. DACT2 suppressed cell proliferation, induced G 2-M arrest in cell lines and inhibited tumor growth in xenograft nude mice. The transcriptional activity of TCF-4 and the expression of Wnt signaling downstream genes were suppressed by DACT2 re-expression and reactivated by depletion of DACT2. In conclusion, DACT2 is frequently methylated in HCC and its expression is regulated by promoter hypermethylation. DACT2 suppresses HCC by inhibiting Wnt signaling in human HCC.
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Affiliation(s)
- Xiaomei Zhang
- Department of Gastroenterology & Hepatology; Chinese PLA General Hospital; Beijing, P.R. China
| | - Yunsheng Yang
- Department of Gastroenterology & Hepatology; Chinese PLA General Hospital; Beijing, P.R. China
| | - Xuefeng Liu
- Department of Gastroenterology & Hepatology; Chinese PLA General Hospital; Beijing, P.R. China
| | - James G Herman
- The Sidney Kimmel Comprehensive Cancer Institute at Johns Hopkins; Johns Hopkins University; Baltimore, MD USA
| | - Malcolm V Brock
- The Sidney Kimmel Comprehensive Cancer Institute at Johns Hopkins; Johns Hopkins University; Baltimore, MD USA
| | - Julien D F Licchesi
- The Sidney Kimmel Comprehensive Cancer Institute at Johns Hopkins; Johns Hopkins University; Baltimore, MD USA
| | - Wen Yue
- Stem Cells and Regenerative Medicine Lab; Beijing Institute of Transfusion Medicine; Beijing, P.R. China
| | - Xuetao Pei
- Stem Cells and Regenerative Medicine Lab; Beijing Institute of Transfusion Medicine; Beijing, P.R. China
| | - Mingzhou Guo
- Department of Gastroenterology & Hepatology; Chinese PLA General Hospital; Beijing, P.R. China
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Mehdi SJ, Ali A, Rizvi MMA. Parkin Gene Alterations in Ovarian Carcinoma from Northern Indian Population. Pathol Oncol Res 2011; 17:579-86. [DOI: 10.1007/s12253-010-9351-x] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/12/2010] [Accepted: 12/17/2010] [Indexed: 10/18/2022]
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Mehdi SJ, Alam MS, Batra S, Rizvi MMA. Allelic loss of 6q25-27, the PARKIN tumor suppressor gene locus, in cervical carcinoma. Med Oncol 2010; 28:1520-6. [PMID: 20652448 DOI: 10.1007/s12032-010-9633-x] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2010] [Accepted: 07/09/2010] [Indexed: 10/19/2022]
Abstract
Studies on loss of heterozygosity have been made for Parkin gene-specific microsatellite markers in malignancies like breast, ovary and lungs, and the results have shown a significant association. However, till date, there is no study with respect to Parkin gene-associated microsatellite markers in cervical cancer. The present study deals with the Parkin gene-associated microsatellite markers and the occurrence of its loss of heterozygosity in patients with human cervical cancer. DNA was isolated from the 105 cervical carcinoma samples and matched control specimens. Polymerase chain reaction was performed using primer specific for two intragenic markers D6S1599 and D6S305 present in Parkin introns 2 and 7, respectively, and one marker (D6S1008) at telomeric end and further electrophoresed on 8% denaturing polyacrylamide gel. Overall, 59 of 105 (56%) samples showed loss of heterozygosity in at least one locus in the region examined. The percentage of loss of heterozygosity for these markers ranged from 25% (D6S1008) to 48% (D6S305). Chi-square test was performed, and loss of heterozygosity was found significantly higher in both the intragenic markers (D6S1599 and D6S305) when compared with the locus at telomeric end (D6S1008) with P<0.05. These data argue that Parkin is a tumor suppressor gene whose inactivation may play an important role in the carcinoma of uterine cervix.
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Affiliation(s)
- S J Mehdi
- Genome Biology Lab., Department of Biosciences, Jamia Millia Islamia, New Delhi, 110025, India
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Inhibition of DNA methyltransferase activity upregulates Fyn tyrosine kinase expression in Hut-78 T-lymphoma cells. Biomed Pharmacother 2008; 62:672-6. [DOI: 10.1016/j.biopha.2008.01.011] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2008] [Accepted: 01/22/2008] [Indexed: 11/21/2022] Open
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Taube JM, Griffin CA, Yonescu R, Morsberger L, Argani P, Askin FB, Batista DAS. Pleuropulmonary blastoma: cytogenetic and spectral karyotype analysis. Pediatr Dev Pathol 2006; 9:453-61. [PMID: 17163790 DOI: 10.2350/06-02-0044.1] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/08/2006] [Accepted: 03/02/2006] [Indexed: 01/21/2023]
Abstract
Pleuropulmonary blastoma (PPB) is a rare neoplasm of the pleuropulmonary mesenchyme. The molecular mechanisms underlying the genesis of this tumor are of particular interest as a large number of affected patients as well as their relatives have concurrent disease including additional dysplasia or neoplasia. To date, detailed karyotypes have been published on a limited number of cases. We report clinical, pathologic, and cytogenetic data in 2 cases of PPB including spectral karyotyping in 1 of them. Additionally, we conducted a review of the literature and compiled 15 published karyotypes of this tumor. Gain of chromosome 8 material was a highly prevalent finding in PPB, most times occurring as trisomy, but tetrasomy of the long arm was also frequent. Other occurring abnormalities, in order of observed frequency, included loss of 17p, loss of chromosome 10 or 10q, rearrangement of 11p, loss of chromosome X or Xp, gain of chromosomes/arms 1q, 2, and 7q, and loss of 6q and 18p. Loss of 10q has not been previously emphasized in PPB. The significance of these chromosome findings is discussed in relation to tumorigenesis.
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Affiliation(s)
- Janis M Taube
- Department of Pathology, The Johns Hopkins Medical Institutions, Baltimore, MD, USA
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Zhang XM, Wang XY, Sheng SR, Wang JR, Li J. Expression of tumor related genes NGX6, NAG-7, BRD7 in gastric and colorectal cancer. World J Gastroenterol 2003; 9:1729-33. [PMID: 12918109 PMCID: PMC4611532 DOI: 10.3748/wjg.v9.i8.1729] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
AIM: NGX6, NAG-7 and BRD7 genes are tumor related genes, which have been newly cloned by positional candidate cloning strategy. This study was designed to investigate the expression levels of NGX6, NAG-7 and BRD7 genes in human gastric and colorectal cancer tissues, and their corresponding normal tissues, and to investigate whether these genes play a role in the pathogenesis of gastric and colorectal cancers.
METHODS: Reverse transcription-polymerase chain reaction (RT-PCR), dot hybridization and Northern blot analysis were used to compare the expression levels of NGX6, NAG-7 and BRD7 genes in 34 gastric cancer tissues and 34 colorectal cancer tissues with their corresponding normal tissues of the same patients, respectively.
RESULTS: Among the 34 colorectal cancer specimens and the 34 gastric cancer specimens, the expression of NGX6 in 25 colorectal cancer tissues was absent or very weak (73.5%) by RT-PCR analysis. The down-regulation rate of NGX6 in colorectal cancer tissues was significantly higher than that in corresponding normal tissues (26.5%,9/34) (P < 0.005). Moreover, the down-regulation of NGX6 was significantly correlated with lymph node and/or distance metastases. Patients with lymph node and/or distance metastasis had much higher down-regulation rate of NGX6 than patients without metastases (93.8% vs 55.6%, P < 0.05). However no correlation was found between the expression of NGX6 and pathologic type of colorectal cancer in this study, and also the expression of NGX6 did not display any difference between gastric cancer and corresponding normal tissues (58.8% vs 70.6%, P > 0.25). Dot hybridization and Northern blot analysis confirmed the results of RT-PCR. Furthermore, NAG-7 and BRD7 mRNA was not up- or down-regulated in gastric and colorectal cancers compared with their corresponding normal tissues in our study.
CONCLUSION: The down-regulation of NGX6 may be closely associated with tumorigenesis and metastasis of colorectal carcinoma. However, it may not contribute to the development and progression of gastric carcinoma. In addition, the expression levels of NAG-7, and BRD7 did not alter in gastric and colorectal cancers. This seems to suggest that NAG-7 and BRD7 genes may not play a role in gastric and colorectal carcinogenesis.
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Affiliation(s)
- Xiao-Mei Zhang
- Department of Digestion Medicine, The Third Xiangya Hospital, Central South University, Changsha 410013, Hunan Province, China
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Prochazkova M, Chevret E, Beylot-Barry M, Sobotka J, Vergier B, Delaunay M, Turmo M, Ferrer J, Kuglik P, Merlio JP. Chromosomal imbalances: a hallmark of tumour relapse in primary cutaneous CD30+ T-cell lymphoma. J Pathol 2003; 201:421-9. [PMID: 14595754 DOI: 10.1002/path.1469] [Citation(s) in RCA: 19] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
Abstract
Primary cutaneous CD30+ large T-cell lymphoma (CD30+ CTCL) is a subset of non-epidermotropic primary cutaneous T-cell lymphoma. Although frequent spontaneous regression may be observed, skin relapses occur frequently. Cytogenetic abnormalities that could play a role in CD30+ CTCL tumour pathogenesis and relapses remain unknown. The identification of recurrent cytogenetic abnormalities is hampered by difficulty in culturing tumours and the lack of CD30+ CTCL serial studies comparing genetic changes both at diagnosis and at relapse. The purpose of this study was to investigate the cytogenetic abnormalities present in a series of 13 CD30+ CTCL samples obtained from nine patients fulfilling both EORTC and WHO diagnostic criteria, by the use of comparative genomic hybridization (CGH). CGH analysis revealed a non-random distribution of genetic imbalances between relapsing and non-relapsing disease. In relapsing disease, chromosomal abnormalities were detected both in the primary tumour and in relapses. The mean number of changes in non-relapsing disease was 0.33 (range 0-1), compared with 6.29 (range 1-16) in relapsing disease. The recurrent chromosomes involved in relapsing disease were chromosomes 6 (86%), 9 (86%), and 18 (43%). While chromosome 9 was mostly affected by gain, chromosomes 6 and 18 mainly contained regions of loss, exclusively on 6q and 18p. The common regions of deletion were 6q21 and 18p11.3. In one patient, we successfully cultured tumour cells from a skin biopsy from a second relapse. The G-banded karyotype was concordant with both CGH and fluorescence in situ hybridization (FISH) results. Although further studies are required to strengthen these data, this CGH analysis demonstrates chromosomal imbalances that may be involved in the pathogenesis of relapsing CD30+ CTCL.
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MESH Headings
- Adult
- Aged
- Chromosome Aberrations
- Chromosomes, Human, Pair 18/genetics
- Chromosomes, Human, Pair 6/genetics
- Chromosomes, Human, Pair 9/genetics
- DNA, Neoplasm/analysis
- Gene Deletion
- Gene Rearrangement
- Humans
- Hybridization, Genetic/genetics
- In Situ Hybridization, Fluorescence/methods
- Karyotyping/methods
- Ki-1 Antigen/genetics
- Lymphoma, Large B-Cell, Diffuse/genetics
- Lymphoma, T-Cell, Cutaneous/genetics
- Middle Aged
- Neoplasm Recurrence, Local/genetics
- Skin Neoplasms/genetics
- Tumor Cells, Cultured
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Affiliation(s)
- Martina Prochazkova
- Histology and Molecular Pathology Laboratory, EA2406, V Segalen University, Bordeaux, France
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Carvalho R, Kayademir T, Soares P, Canedo P, Sousa S, Oliveira C, Leistenschneider P, Seruca R, Gött P, Blin N, Carneiro F, Machado JC. Loss of heterozygosity and promoter methylation, but not mutation, may underlie loss of TFF1 in gastric carcinoma. J Transl Med 2002; 82:1319-26. [PMID: 12379766 DOI: 10.1097/01.lab.0000029205.76632.a8] [Citation(s) in RCA: 70] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open
Abstract
It has been advanced that the trefoil factor (TFF) 1 gene is a candidate tumor-suppressor gene and may be involved in the development and/or progression of human gastric cancer. We aimed to clarify the putative role of TFF1 in gastric carcinogenesis. Ninety gastric carcinomas and eight gastric carcinoma-derived cell lines were screened for TFF1 mutations; subsets of the primary tumors and of the cell lines were subjected to loss of heterozygosity (LOH), immunohistochemistry, and promoter methylation analyses. TFF1 mutations were not detected in any of 90 gastric carcinomas. Eight (28%) of 28 informative cases displayed LOH at the TFF1 locus and absence of TFF1 staining by immunohistochemistry. These results indicate a frequent loss of TFF1 expression in gastric carcinomas through a mutation-independent mechanism. Extensive TFF1 promoter methylation was observed in nonexpressing gastric carcinoma-derived cell lines and tissues. Expressing cell lines, as well as normal gastric mucosa, presented little or no methylation of the promoter. Gastric carcinoma DNA presented de novo methylation of the promoter. These results point to the involvement of promoter methylation in the shutting down of TFF1. We conclude that TFF1 point mutations seem to be a rare event in gastric carcinogenesis. The loss of expression of TFF1 in a proportion of gastric carcinomas may be explained by LOH and methylation of the TFF1 promoter region. Our results further support the role of TFF1 inactivation in gastric carcinogenesis, in agreement with the results obtained in the Tff1-knockout mice model.
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Affiliation(s)
- Ralph Carvalho
- Institute of Molecular Pathology and Immunology, University of Porto, Porto, Portugal
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