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1
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Algarra I, Garrido F, Garcia-Lora AM. MHC heterogeneity and response of metastases to immunotherapy. Cancer Metastasis Rev 2021; 40:501-517. [PMID: 33860434 DOI: 10.1007/s10555-021-09964-4] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/14/2020] [Accepted: 04/06/2021] [Indexed: 01/05/2023]
Abstract
In recent years, immunotherapy has proven to be an effective treatment against cancer. Cytotoxic T lymphocytes perform an important role in this anti-tumor immune response, recognizing cancer cells as foreign, through the presentation of tumor antigens by MHC class I molecules. However, tumors and metastases develop escape mechanisms for evading this immunosurveillance and may lose the expression of these polymorphic molecules to become invisible to cytotoxic T lymphocytes. In other situations, they may maintain MHC class I expression and promote immunosuppression of cytotoxic T lymphocytes. Therefore, the analysis of the expression of MHC class I molecules in tumors and metastases is important to elucidate these escape mechanisms. Moreover, it is necessary to determine the molecular mechanisms involved in these alterations to reverse them and recover the expression of MHC class I molecules on tumor cells. This review discusses the role and regulation of MHC class I expression in tumor progression. We focus on altered MHC class I phenotypes present in tumors and metastases, as well as the molecular mechanisms responsible for MHC-I alterations, emphasizing the mechanisms of recovery of the MHC class I molecules expression on cancer cells. The individualized study of the HLA class I phenotype of the tumor and the metastases of each patient will allow choosing the most appropriate immunotherapy treatment based on a personalized medicine.
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Affiliation(s)
- Ignacio Algarra
- Departamento de Ciencias de la Salud, Universidad de Jaén, Jaén, Spain
| | - Federico Garrido
- Servicio de Análisis Clínicos e Inmunología, UGC Laboratorio Clínico, Hospital Universitario Virgen de las Nieves, Av. de las Fuerzas Armadas 2, 18014, Granada, Spain.,Instituto de Investigación Biosanitaria ibs.Granada, Granada, Spain.,Departamento de Bioquímica, Biología Molecular e Inmunología III, Universidad de Granada, Granada, Spain
| | - Angel M Garcia-Lora
- Servicio de Análisis Clínicos e Inmunología, UGC Laboratorio Clínico, Hospital Universitario Virgen de las Nieves, Av. de las Fuerzas Armadas 2, 18014, Granada, Spain. .,Instituto de Investigación Biosanitaria ibs.Granada, Granada, Spain. .,Unidad de Biobanco, Hospital Universitario Virgen de las Nieves, Granada, Spain.
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2
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Pulido M, Chamorro V, Romero I, Algarra I, S-Montalvo A, Collado A, Garrido F, Garcia-Lora AM. Restoration of MHC-I on Tumor Cells by Fhit Transfection Promotes Immune Rejection and Acts as an Individualized Immunotherapeutic Vaccine. Cancers (Basel) 2020; 12:E1563. [PMID: 32545680 PMCID: PMC7352176 DOI: 10.3390/cancers12061563] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2020] [Revised: 06/04/2020] [Accepted: 06/08/2020] [Indexed: 12/15/2022] Open
Abstract
The capacity of cytotoxic-T lymphocytes to recognize and destroy tumor cells depends on the surface expression by tumor cells of MHC class I molecules loaded with tumor antigen peptides. Loss of MHC-I expression is the most frequent mechanism by which tumor cells evade the immune response. The restoration of MHC-I expression in cancer cells is crucial to enhance their immune destruction, especially in response to cancer immunotherapy. Using mouse models, we recovered MHC-I expression in the MHC-I negative tumor cell lines and analyzed their oncological and immunological profile. Fhit gene transfection induces the restoration of MHC-I expression in highly oncogenic MHC-I-negative murine tumor cell lines and genes of the IFN-γ transduction signal pathway are involved. Fhit-transfected tumor cells proved highly immunogenic, being rejected by a T lymphocyte-mediated immune response. Strikingly, this immune rejection was more frequent in females than in males. The immune response generated protected hosts against the tumor growth of non-transfected cells and against other tumor cells in our murine tumor model. Finally, we also observed a direct correlation between FHIT expression and HLA-I surface expression in human breast tumors. Recovery of Fhit expression on MHC class I negative tumor cells may be a useful immunotherapeutic strategy and may even act as an individualized immunotherapeutic vaccine.
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Grants
- 15-1166 Worldwide Cancer Research
- PI12/02031, PI14/01978, PI15/00528, PI17/00197, PI19/01179, PT13/0010/0039 and PT17/0015/0041 Instituto de Salud Carlos III
- Group CTS-143, CTS-3952, CVI-4740 grants Consejería de Economía, Innovación, Ciencia y Empleo, Junta de Andalucía
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Affiliation(s)
- María Pulido
- Servicio de Análisis Clínicos e Inmunología, UGC Laboratorio Clínico, Hospital Universitario Virgen de las Nieves, Av. de las Fuerzas Armadas 2, 18014 Granada, Spain; (M.P.); (V.C.); (A.S.-M.); (F.G.)
- Instituto de Investigación Biosanitaria ibs.GRANADA, 18012 Granada, Spain
| | - Virginia Chamorro
- Servicio de Análisis Clínicos e Inmunología, UGC Laboratorio Clínico, Hospital Universitario Virgen de las Nieves, Av. de las Fuerzas Armadas 2, 18014 Granada, Spain; (M.P.); (V.C.); (A.S.-M.); (F.G.)
- Instituto de Investigación Biosanitaria ibs.GRANADA, 18012 Granada, Spain
| | - Irene Romero
- UGC Laboratorios, Complejo Hospitalario de Jaén, 23007 Jaén, Spain;
| | - Ignacio Algarra
- Departamento de Ciencias de la Salud, Universidad de Jaén, 23071 Jaén, Spain;
| | - Alba S-Montalvo
- Servicio de Análisis Clínicos e Inmunología, UGC Laboratorio Clínico, Hospital Universitario Virgen de las Nieves, Av. de las Fuerzas Armadas 2, 18014 Granada, Spain; (M.P.); (V.C.); (A.S.-M.); (F.G.)
- Instituto de Investigación Biosanitaria ibs.GRANADA, 18012 Granada, Spain
| | - Antonia Collado
- Unidad de Biobanco, Hospital Universitario Virgen de las Nieves, 18014 Granada, Spain;
| | - Federico Garrido
- Servicio de Análisis Clínicos e Inmunología, UGC Laboratorio Clínico, Hospital Universitario Virgen de las Nieves, Av. de las Fuerzas Armadas 2, 18014 Granada, Spain; (M.P.); (V.C.); (A.S.-M.); (F.G.)
- Instituto de Investigación Biosanitaria ibs.GRANADA, 18012 Granada, Spain
- Departamento de Bioquímica, Biología Molecular e Inmunología III, Universidad de Granada, 18071 Granada, Spain
| | - Angel M. Garcia-Lora
- Servicio de Análisis Clínicos e Inmunología, UGC Laboratorio Clínico, Hospital Universitario Virgen de las Nieves, Av. de las Fuerzas Armadas 2, 18014 Granada, Spain; (M.P.); (V.C.); (A.S.-M.); (F.G.)
- Instituto de Investigación Biosanitaria ibs.GRANADA, 18012 Granada, Spain
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Hashimoto Y, Shiina M, Dasgupta P, Kulkarni P, Kato T, Wong RK, Tanaka Y, Shahryari V, Maekawa S, Yamamura S, Saini S, Deng G, Tabatabai ZL, Majid S, Dahiya R. Upregulation of miR-130b Contributes to Risk of Poor Prognosis and Racial Disparity in African-American Prostate Cancer. Cancer Prev Res (Phila) 2019; 12:585-598. [PMID: 31266828 DOI: 10.1158/1940-6207.capr-18-0509] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2018] [Revised: 05/23/2019] [Accepted: 06/24/2019] [Indexed: 12/18/2022]
Abstract
Prostate cancer incidence and mortality rates are higher in African-American (AA) than in European-American (EA) men. The main objective of this study was to elucidate the role of miR-130b as a contributor to prostate cancer health disparity in AA patients. We also determined whether miR-130b is a prognostic biomarker and a new therapeutic candidate for AA prostate cancer. A comprehensive approach of using cell lines, tissue samples, and the TCGA database was employed. We performed a series of functional assays such as cell proliferation, migration, invasion, RT2-PCR array, qRT-PCR, cell cycle, luciferase reporter, immunoblot, and IHC. Various statistical approaches such as Kaplan-Meier, uni-, and multivariate analyses were utilized to determine the clinical significance of miR-130b. Our results showed that elevated levels of miR-130b correlated with race disparity and PSA levels/failure and acted as an independent prognostic biomarker for AA patients. Two tumor suppressor genes, CDKN1B and FHIT, were validated as direct functional targets of miR-130b. We also found race-specific cell-cycle pathway activation in AA patients with prostate cancer. Functionally, miR-130b inhibition reduced cell proliferation, colony formation, migration/invasion, and induced cell-cycle arrest. Inhibition of miR-130b modulated critical prostate cancer-related biological pathways in AA compared with EA prostate cancer patients. In conclusion, attenuation of miR-130b expression has tumor suppressor effects in AA prostate cancer. miR-130b is a significant contributor to prostate cancer racial disparity as its overexpression is a risk factor for poor prognosis in AA patients with prostate cancer. Thus, regulation of miR-130b may provide a novel therapeutic approach for the management of prostate cancer in AA patients.
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Affiliation(s)
- Yutaka Hashimoto
- Department of Urology, San Francisco VA Medical Center, San Francisco, California.,University of California San Francisco, San Francisco, California
| | - Marisa Shiina
- Department of Urology, San Francisco VA Medical Center, San Francisco, California.,University of California San Francisco, San Francisco, California
| | - Pritha Dasgupta
- Department of Urology, San Francisco VA Medical Center, San Francisco, California.,University of California San Francisco, San Francisco, California
| | - Priyanka Kulkarni
- Department of Urology, San Francisco VA Medical Center, San Francisco, California.,University of California San Francisco, San Francisco, California
| | - Taku Kato
- Department of Urology, San Francisco VA Medical Center, San Francisco, California.,University of California San Francisco, San Francisco, California
| | - Ryan K Wong
- Department of Urology, San Francisco VA Medical Center, San Francisco, California.,University of California San Francisco, San Francisco, California
| | - Yuichiro Tanaka
- Department of Urology, San Francisco VA Medical Center, San Francisco, California.,University of California San Francisco, San Francisco, California
| | - Varahram Shahryari
- Department of Urology, San Francisco VA Medical Center, San Francisco, California.,University of California San Francisco, San Francisco, California
| | - Shigekatsu Maekawa
- Department of Urology, San Francisco VA Medical Center, San Francisco, California.,University of California San Francisco, San Francisco, California
| | - Soichiro Yamamura
- Department of Urology, San Francisco VA Medical Center, San Francisco, California.,University of California San Francisco, San Francisco, California
| | - Sharanjot Saini
- Department of Urology, San Francisco VA Medical Center, San Francisco, California.,University of California San Francisco, San Francisco, California
| | - Guoren Deng
- Department of Urology, San Francisco VA Medical Center, San Francisco, California.,University of California San Francisco, San Francisco, California
| | - Z Laura Tabatabai
- Department of Pathology, San Francisco VA Medical Center, California.,University of California San Francisco, San Francisco, California
| | - Shahana Majid
- Department of Urology, San Francisco VA Medical Center, San Francisco, California. .,University of California San Francisco, San Francisco, California
| | - Rajvir Dahiya
- Department of Urology, San Francisco VA Medical Center, San Francisco, California. .,University of California San Francisco, San Francisco, California
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Abstract
We detected loss of heterozygosity (LOH) and microsatellite instabilities (MSI), as well as extron expression of the fragile histidine triad (FHIT) gene in gastric carcinoma (GC), in order to evaluate their association with clinicopathological processes in gastric carcinogenesis. LOH and MSI of the FHIT were detected by using PCR at 4 microsatellite loci: D3S 1300, D3S 4103, D3S 1481, D3S 1234 in cancer tissues from 50 patients with primary GC, with normal mucosa acting as matched controls. FHIT transcripts were detected by nested RT-PCR in 30 cases of GC and their products were sequenced. Results show that the average frequencies of LOH and MSI of the FHIT gene in GC were 32.4% and 26.4%, respectively. There was no correlation between LOH and MSI of the FHIT gene in GC and the histological characteristics of gastric carcinoma (Bormann's or Lauren's classification). LOH of the FHIT gene in GC was related to depth invasiveness, and its frequency in GC where serosa was penetrated was significantly higher than that in GC without serosa penetration (73.5% vs 37.5%, P < 0.05). The frequency of MSI in GC without lymph node metastasis was significantly higher than that in GC with lymph node metastasis (66.7% vs 34.3%, P < 0.05). Aberrant transcripts were found in 11/30 GC tissues. Sequencing analysis of the aberrant fragments found a RT-PCR product missing exons 5-7 in one case of GC, and another product missing exons 4-7. Four of 10 (40.0%) cases of primary GC showed absent or decreased expression of the FHIT protein as compared to their matched normal tissues. The findings in this study suggest that LOH and MSI of FHIT gene may induce aberrant extron expression, which might play a role in gastric carcinogenesis.
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5
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Gordiyuk VV. Genetic and epigenetic changes of genes on chromosome 3 in human urogenital tumors. ACTA ACUST UNITED AC 2011. [DOI: 10.7124/bc.00007e] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Affiliation(s)
- V. V. Gordiyuk
- Institute of Molecular Biology and Genetics, National Academy of Sciences of Ukraine
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6
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Hassan MI, Naiyer A, Ahmad F. Fragile histidine triad protein: structure, function, and its association with tumorogenesis. J Cancer Res Clin Oncol 2010; 136:333-50. [PMID: 20033706 DOI: 10.1007/s00432-009-0751-9] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2009] [Accepted: 12/09/2009] [Indexed: 01/31/2023]
Abstract
BACKGROUND The human fragile histidine triad (FHIT) gene is a putative tumor suppressor gene, which is located at chromosome region 3p14.2. It was suggested that the loss of heterozygosity (LOH), homozygous deletions, and abnormal expression of the FHIT gene were involved in several types of human malignancies. MATERIALS AND METHODS To determine the role of FHIT in various cancers, we have performed structural and functional analysis of FHIT in detail. RESULTS AND DISCUSSION The protein FHIT catalyzes the Mg(2+) dependent hydrolysis of P1-5 cent-O-adenosine-P3-5 cent-O-adenosine triphosphate, Ap3A, to AMP, and ADP. The reaction is thought to follow a two-step mechanism. Histidine triad proteins, named for a motif related to the sequence H-cent-H-cent-H-cent-cent- (cent, a hydrophobic amino acid), belong to superfamily of nucleotide hydrolases and transferases. This enzyme acts on the R-phosphate of ribonucleotides, and contain a approximately 30-kDa domain that is typically a homodimer of approximately 15 kDa polypeptides with catalytic site. CONCLUSION Here we have gathered information is known about biological activities of FHIT, the structural and biochemical bases for their functions. Our approach may provide a comparative framework for further investigation of FHIT.
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Affiliation(s)
- Md Imtaiyaz Hassan
- Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, Jamia Nagar, New Delhi, 110025, India
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Priya TP, Kapoor VK, Krishnani N, Agrawal V, Agarwal S. Fragile histidine triad (FHIT) gene and its association with p53 protein expression in the progression of gall bladder cancer. Cancer Invest 2009; 27:764-73. [PMID: 19452299 DOI: 10.1080/07357900802711304] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
OBJECTIVE Present study deals with LOH and MSI in FHIT gene and p53 expression in GBC, CC, XGC, and normal GB to elucidate the role of FHIT gene in gall bladder cancer. METHODS Five microsatellite markers D3S1217, D3S1300, D3S1313, D3S1600, and D3S2757, were selected. RESULTS Among GBC cases the frequency of MSI-H and LOH was 17.5% and 27.5%, respectively. Significant difference was found between GBC and normal GB (p = .02), and GBC and CC groups (p= .002) when LOH was compared. CONCLUSIONS Our results suggested CC might act as a preinvasive stage in the pathogenesis of GBC.
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Affiliation(s)
- T Padma Priya
- Department of Medical Genetics, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, UP, India
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8
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Ding Y, Larson G, Rivas G, Lundberg C, Geller L, Ouyang C, Weitzel J, Archambeau J, Slater J, Daly MB, Benson AB, Kirkwood JM, O'Dwyer PJ, Sutphen R, Stewart JA, Johnson D, Nordborg M, Krontiris TG. Strong signature of natural selection within an FHIT intron implicated in prostate cancer risk. PLoS One 2008; 3:e3533. [PMID: 18953408 PMCID: PMC2568805 DOI: 10.1371/journal.pone.0003533] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2008] [Accepted: 10/02/2008] [Indexed: 11/19/2022] Open
Abstract
Previously, a candidate gene linkage approach on brother pairs affected with prostate cancer identified a locus of prostate cancer susceptibility at D3S1234 within the fragile histidine triad gene (FHIT), a tumor suppressor that induces apoptosis. Subsequent association tests on 16 SNPs spanning approximately 381 kb surrounding D3S1234 in Americans of European descent revealed significant evidence of association for a single SNP within intron 5 of FHIT. In the current study, re-sequencing and genotyping within a 28.5 kb region surrounding this SNP further delineated the association with prostate cancer risk to a 15 kb region. Multiple SNPs in sequences under evolutionary constraint within intron 5 of FHIT defined several related haplotypes with an increased risk of prostate cancer in European-Americans. Strong associations were detected for a risk haplotype defined by SNPs 138543, 142413, and 152494 in all cases (Pearson's chi(2) = 12.34, df 1, P = 0.00045) and for the homozygous risk haplotype defined by SNPs 144716, 142413, and 148444 in cases that shared 2 alleles identical by descent with their affected brothers (Pearson's chi(2) = 11.50, df 1, P = 0.00070). In addition to highly conserved sequences encompassing SNPs 148444 and 152413, population studies revealed strong signatures of natural selection for a 1 kb window covering the SNP 144716 in two human populations, the European American (pi = 0.0072, Tajima's D = 3.31, 14 SNPs) and the Japanese (pi = 0.0049, Fay & Wu's H = 8.05, 14 SNPs), as well as in chimpanzees (Fay & Wu's H = 8.62, 12 SNPs). These results strongly support the involvement of the FHIT intronic region in an increased risk of prostate cancer.
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Affiliation(s)
- Yan Ding
- Division of Molecular Medicine, Beckman Research Institute of the City of Hope, Duarte, California, United States of America
| | - Garrett Larson
- Division of Molecular Medicine, Beckman Research Institute of the City of Hope, Duarte, California, United States of America
| | - Guillermo Rivas
- Division of Molecular Medicine, Beckman Research Institute of the City of Hope, Duarte, California, United States of America
| | - Cathryn Lundberg
- Division of Molecular Medicine, Beckman Research Institute of the City of Hope, Duarte, California, United States of America
| | - Louis Geller
- Division of Molecular Medicine, Beckman Research Institute of the City of Hope, Duarte, California, United States of America
| | - Ching Ouyang
- Division of Molecular Medicine, Beckman Research Institute of the City of Hope, Duarte, California, United States of America
| | - Jeffrey Weitzel
- Department of Cancer Genetics, City of Hope, Duarte, California, United States of America
| | - John Archambeau
- Department of Radiation Medicine, Loma Linda School of Medicine, Loma Linda, California, United States of America
| | - Jerry Slater
- Department of Radiation Medicine, Loma Linda School of Medicine, Loma Linda, California, United States of America
| | - Mary B. Daly
- Department of Population Science, Fox Chase Cancer Center, Philadelphia, Pennsylvania, United States of America
| | - Al B. Benson
- Division of Hematology/Oncology, Department of Medicine, Robert J. Lurie Comprehensive Cancer Center, Northwestern University School of Medicine, Chicago, Illinois, United States of America
| | - John M. Kirkwood
- Division of Hematology/Oncology, Department of Medicine, University of Pittsburgh Cancer Center, Pittsburgh, Pennsylvania, United States of America
| | - Peter J. O'Dwyer
- Division of Hematology/Oncology, Department of Medicine, University of Pennsylvania Cancer Center, Philadelphia, Pennsylvania, United States of America
| | - Rebecca Sutphen
- Interdisciplinary Oncology Program, H. Lee Moffitt Cancer Center and Research Institute, University of South Florida, Tampa, Florida, United States of America
| | - James A. Stewart
- University of Wisconsin Comprehensive Cancer Center, University of Wisconsin School of Medicine, Madison, Wisconsin, United States of America
| | - David Johnson
- Division of Hematology/Oncology, Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America
| | - Magnus Nordborg
- Department of Molecular and Computational Biology, Biological Sciences, University of Southern California, Los Angeles, California, United States of America
| | - Theodore G. Krontiris
- Division of Molecular Medicine, Beckman Research Institute of the City of Hope, Duarte, California, United States of America
- * E-mail:
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9
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Tutar E, Kiyici H. Role of fragile histidine triad protein expression in pathogenesis of malignant pleural mesothelioma. Pathology 2008; 40:42-5. [PMID: 18038314 DOI: 10.1080/00313020701716383] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
AIM To investigate the relationship of fragile histidine triad (FHIT) and Ki-67 expression with clinicopathological variables of patients with malignant pleural mesothelioma (MPM). METHODS Formalin-fixed, paraffin-embedded tissue sections of 30 asbestos induced MPM (epithelial and biphasic) patients were examined for FHIT and Ki-67 expression using immunohistochemical techniques and results were compared with clinicopathological variables. RESULTS Immunohistochemical study results were as follows: 12 (40%) cases showed low FHIT expression and 18 (60%) showed high expression. There was no significant relationship between FHIT and age, gender or histological subtypes (p > 0.05). Ki-67 expression was 'low' in 13 (43.3%) cases and 'high' in 17 (56.7%) cases. No correlation could be demonstrated between Ki-67 expression and age, gender or histological subtypes (p > 0.05). No significant association was observed between FHIT and Ki-67 expression in MPM. CONCLUSION The results support the role of FHIT as a tumour suppressor gene in asbestos induced MPM. There is no significant correlation between FHIT and cell proliferation marker expressions in malignant pleural mesothelioma. Therefore, it can be concluded that loss of FHIT does not interfere with tumour proliferation. This can be accepted as evidence for an early role of FHIT loss in carcinogenesis; however, it needs to be strengthened by further studies.
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Affiliation(s)
- Ediz Tutar
- Department of Pathology, Medical Faculty, Gaziantep University, Gaziantep, Turkey.
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10
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Levin AM, Ray AM, Zuhlke KA, Douglas JA, Cooney KA. Association between Germline Variation in the FHIT Gene and Prostate Cancer in Caucasians and African Americans. Cancer Epidemiol Biomarkers Prev 2007; 16:1294-7. [PMID: 17548701 DOI: 10.1158/1055-9965.epi-06-1054] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Many studies have established that loss of heterozygosity and/or altered expression of the fragile histidine triad (FHIT) gene is a common event in a number of tumor types including prostate carcinoma. Encompassing the most active fragile site in the human genome, FRA3B, FHIT has become the model fragile site-associated tumor suppressor gene. In a recent study, linkage and association between germline genetic variation in FHIT (specifically single nucleotide polymorphism rs760317) and prostate cancer were reported. We sought to confirm this finding in two independent samples: (a) a family-based sample of 817 men with (n = 434) and without (n = 383) prostate cancer from 323 Caucasian families, and (b) a community-based case-control sample of African American men with (n = 133) and without (n = 342) prostate cancer. Using a family-based association test, rs760317 was associated with prostate cancer in Caucasians (P = 0.031), with a reduction in the risk of prostate cancer among carriers of the minor allele (odds ratio, 0.66; 95% confidence interval, 0.42-1.04; P = 0.074). African American carriers experienced a similar risk reduction (odds ratio, 0.63; 95% confidence interval, 0.42-0.96; P = 0.032). These results are remarkably consistent across ethnic samples but are in opposition to results from the original study, which showed an association between the minor allele of rs760317 and an increased risk of prostate cancer. Taken together, the consistently significant but flipped association between single nucleotide polymorphism rs760317 and prostate cancer in three independent samples suggests that rs760317 may be in linkage disequilibrium with one or more prostate cancer susceptibility variants in or near FHIT.
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Affiliation(s)
- Albert M Levin
- Departments of Human Genetics, University of Michigan Medical School, Ann Arbor, Michigan, USA
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11
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Xiao YP, Wu DY, Xu L, Xin Y. Loss of heterozygosity and microsatellite instabilities of fragile histidine triad gene in gastric carcinoma. World J Gastroenterol 2006; 12:3766-9. [PMID: 16773697 PMCID: PMC4087473 DOI: 10.3748/wjg.v12.i23.3766] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To detect the loss of heterozygosity (LOH) and microsatellite instabilities (MSI) of fragile histidine triad (FHIT) gene in gastric carcinoma and to study their association with the clinical pathological characteristics of gastric carcinoma.
METHODS: LOH and MSI of FHIT gene were detected at four microsatellite loci D3Sl3H, D3S4l03, D3Sl48l and D3S1234 using PCR in matched normal and cancerous tissues from 50 patients with primary gastric cancer.
RESULTS: The average frequency of LOH and MSI of FHIT gene in gastric cancer was 32.4% and 26.4% respectively. LOH and MSI of FHIT gene in gastric cancer had no association with histological, Borrmann, and Lauren’s classification. LOH of FHIT gene in gastric cancer was related to invasive depth. The frequency of FHIT LOH in gastric cancer with serosa-penetration was obviously higher than that in gastric cancer without serosa-penetration (73.5% vs 37.5%, P < 0.05). MSI of FHIT gene in gastric cancer was associated with the lymph node metastasis. The frequency of MSI in gastric cancer without lymph node metastasis was significantly higher than that in gastric cancer with lymph node metastasis (66.7% vs 34.3%, P < 0.05).
CONCLUSION: LOH of FHIT gene is correlated with invasive depth of gastric carcinoma. MSI of FHIT gene is correlated with lymph node metastases. LOH and MSI of FHIT gene play an important role in carcinogenesis of gastric cancer.
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Affiliation(s)
- Yu-Ping Xiao
- Cancer Insititute, No.1 Hospital of China Medical University, Shenyang, Liaoning Province
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12
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Xiao YP, Han CB, Mao XY, Li JY, Xu L, Ren CS, Xin Y. Relationship between abnormality of FHIT gene and EBV infection in gastric cancer. World J Gastroenterol 2005; 11:3212-6. [PMID: 15929169 PMCID: PMC4316050 DOI: 10.3748/wjg.v11.i21.3212] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To examine the aberrant expression of fragile histidine triad (FHIT) gene and protein in gastric cancer, and to evaluate the role of FHIT gene and the relationship between FHIT gene and EBV infection in gastric carcinogenesis.
METHODS: FHIT transcripts were detected by nested RT-PCR in 30 cases of gastric cancer and their products were sequenced. FHIT protein was detected by Western blot. EBV infection was detected by PCR method in 50 cases of gastric cancer.
RESULTS: The wild type transcripts were detected in all 30 matched normal tissues of gastric cancer. Aberrant transcripts were found in 11/30 (36.7%) gastric cancerous tissues. Sequencing analysis of the aberrant fragments found an RT-PCR product missing exons 5-7 in one case of gastric cancer, and another product missing exons 4-7. Four of ten (40.0%) cases of primary gastric cancer showed absent or decreased expression of FHIT protein as compared with their matched normal tissues. EBV was detected in 5/50 (10%) gastric cancers, among which 4/5 (80%) had aberrant transcripts of FHIT gene.
CONCLUSION: Loss of FHIT gene or FHIT protein plays an important role in carcinogenesis, development and progression of gastric cancer. EBV infection might influence carcinogenesis of gastric cancer by inducing the abnormality of FHIT gene.
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Affiliation(s)
- Yu-Ping Xiao
- Cancer Institute, the First Hospital, China Medical University, Shenyang 110001, Liaoning Province, China
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Larson GP, Ding Y, Cheng LSC, Lundberg C, Gagalang V, Rivas G, Geller L, Weitzel J, MacDonald D, Archambeau J, Slater J, Neuberg D, Daly MB, Angel I, Benson AB, Smith K, Kirkwood JM, O'Dwyer PJ, Raskay B, Sutphen R, Drew R, Stewart JA, Werndli J, Johnson D, Ruckdeschel JC, Elston RC, Krontiris TG. Genetic Linkage of Prostate Cancer Risk to the Chromosome 3 Region Bearing FHIT. Cancer Res 2005. [DOI: 10.1158/0008-5472.805.65.3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Abstract
We conducted linkage analysis of 80 candidate genes in 201 brother pairs affected with prostatic adenocarcinoma. Markers representing two adjacent candidate genes on chromosome 3p, CDC25A and FHIT, showed suggestive evidence for linkage with single-point identity-by-descent allele-sharing statistics. Fine-structure multipoint linkage analysis yielded a maximum LOD score of 3.17 (P = 0.00007) at D3S1234 within FHIT intron 5. For a subgroup of 38 families in which three or more affected brothers were reported, the LOD score was 3.83 (P = 0.00001). Further analysis reported herein suggested a recessive mode of inheritance. Association testing of 16 single nucleotide polymorphisms (SNP) spanning a 381-kb interval surrounding D3S1234 in 202 cases of European descent with 143 matched, unrelated controls revealed significant evidence for association between case status and the A allele of single nucleotide polymorphism rs760317, located within intron 5 of FHIT (Pearson's χ2 = 8.54, df = 1, P = 0.0035). Our results strongly suggest involvement of germline variations of FHIT in prostate cancer risk.
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Affiliation(s)
| | - Yan Ding
- 1Divisions of Molecular Medicine and
| | - Li S-C. Cheng
- 2Information Sciences, Beckman Research Institute and
| | | | | | | | | | - Jeffrey Weitzel
- 1Divisions of Molecular Medicine and
- 3Department of Cancer Genetics, City of Hope National Medical Center, Duarte, California
| | - Deborah MacDonald
- 3Department of Cancer Genetics, City of Hope National Medical Center, Duarte, California
| | - John Archambeau
- 4Department of Radiation Medicine, Loma Linda University Medical Center, Loma Linda, California
| | - Jerry Slater
- 4Department of Radiation Medicine, Loma Linda University Medical Center, Loma Linda, California
| | - Donna Neuberg
- 5Division of Biostatistics, Dana-Farber Cancer Institute, Harvard Medical School and Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts
| | - Mary B. Daly
- 6Department of Population Science, Fox Chase Cancer Center, Philadelphia, Pennsylvania
| | - Irene Angel
- 6Department of Population Science, Fox Chase Cancer Center, Philadelphia, Pennsylvania
| | - Al B. Benson
- 7Department of Medicine, Division of Hematology/Oncology and
| | - Kimberly Smith
- 8Clinical Research Office, Robert J. Lurie Comprehensive Cancer Center, Northwestern University School of Medicine, Chicago, Illinois
| | - John M. Kirkwood
- 9Department of Medicine, Division of Hematology/Oncology, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania
| | - Peter J. O'Dwyer
- 10Department of Medicine, Hematology-Oncology Division, University of Pennsylvania Cancer Center, Philadelphia, Pennsylvania
| | - Barbara Raskay
- 10Department of Medicine, Hematology-Oncology Division, University of Pennsylvania Cancer Center, Philadelphia, Pennsylvania
| | - Rebecca Sutphen
- 11Interdisciplinary Oncology Program, H. Lee Moffitt Cancer Center and Research Institute, University of South Florida, Tampa, Florida
| | - Rosalind Drew
- 11Interdisciplinary Oncology Program, H. Lee Moffitt Cancer Center and Research Institute, University of South Florida, Tampa, Florida
| | - James A. Stewart
- 12University of Wisconsin Comprehensive Cancer Center and University of Wisconsin School of Medicine, Madison, Wisconsin
| | - Jae Werndli
- 12University of Wisconsin Comprehensive Cancer Center and University of Wisconsin School of Medicine, Madison, Wisconsin
| | - David Johnson
- 13Division of Hematology & Oncology, Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee
| | | | - Robert C. Elston
- 15Department of Epidemiology and Biostatistics, Case Western Reserve University, Metro Health Medical Center, Cleveland, Ohio
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Nan KJ, Ruan ZP, Jing Z, Qin HX, Wang HY, Guo H, Xu R. Expression of fragile histidine triad in primary hepatocellular carcinoma and its relation with cell proliferation and apoptosis. World J Gastroenterol 2005; 11:228-31. [PMID: 15633221 PMCID: PMC4205407 DOI: 10.3748/wjg.v11.i2.228] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To evaluate the expression of fragile histidine triad (FHIT) gene protein, product of a candidate tumor suppressor, and to investigate the relationship between FHIT, cell apoptosis and proliferation, and pathological features of primary hepatocellular carcinoma (HCC).
METHODS: Forty-seven HCC and ten normal liver specimens were collected during surgical operation between 2001 and 2003. FHIT and proliferating cell nuclear antigen (PCNA) expression were detected by immunohistochemistry, and apoptotic level was evaluated by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay on the tissue sections.
RESULTS: All normal liver tissues showed a strong expression of FHIT, whereas 28 of 47 (59.6%) carcinomas showed a significant loss or absence of FHIT expression (P = 0.001). The proportion of reduced FHIT expression in those carcinomas at stages III-IV (70.6%) and in those with extrahepatic metastasis (86.7%) showed an increasing trend compared with those at stages I-II (30.8%, P = 0.013) and those without metastasis (46.9%, P = 0.010) respectively. Apoptotic incidence in advanced TNM stage carcinoma and those with positive FHIT expression was higher than that in early stage carcinoma (P = 0.030) and in those with negative FHIT expression (P = 0.044) respectively. The proliferating potential of hepatocellular carcinoma was associated with FHIT expression (P = 0.016) and the aggressive feature (P = 0.019). Kaplan-Meier analysis demonstrated that the survival time of these 47 patients correlated with TNM stage, FHIT expression and metastasis.
CONCLUSION: There is marked loss or absence of FHIT expression, as well as abnormal apoptosis-proliferation balance in HCC. FHIT may play an important role in carcinogenesis and development of HCC.
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Affiliation(s)
- Ke-Jun Nan
- Department of Oncology, First Hospital of Xi'an Jiaotong University, Xi'an 710061, Shaanxi Province, China
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Ohali A, Avigad S, Zaizov R, Ophir R, Horn-Saban S, Cohen IJ, Meller I, Kollender Y, Issakov J, Yaniv I. Prediction of high risk Ewing's sarcoma by gene expression profiling. Oncogene 2004; 23:8997-9006. [PMID: 15467746 DOI: 10.1038/sj.onc.1208060] [Citation(s) in RCA: 84] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Ewing's sarcoma (ES) is the second most common primary malignant bone tumor in children and adolescents. Currently accepted clinical prognostic factors fail to classify ES patients' risk to relapse at diagnosis. We aimed to find a new strategy to distinguish between poor and good prognosis ES patients already at diagnosis. We analysed the gene expression profiles of 14 primary tumor specimens and six metastases from ES patients, using oligonucleotide microarray analysis. The over-expression of two genes was validated by quantitative PCR using the LightCycler system. We identified two distinct gene expression signatures distinguishing high-risk ES patients that are likely to progress from low-risk ES patients with a favorable prognosis of long-term progression-free survival. The microarray-based classification was superior to currently used prognostic parameters. Over-expressed genes in the poor prognosis patients included genes regulating the cell cycle and genes associated with invasion and metastasis, while among the downregulated genes were tumor suppressor genes and inducers of apoptosis. Our results indicate the existence of a specific gene expression signature of outcome in ES already at diagnosis, and provide a strategy to select patients who would benefit from risk-adapted improved therapy.
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Affiliation(s)
- Anat Ohali
- Molecular Oncology, Felsenstein Medical Research Center, Rabin Medical Campus, 39 Jabotinski Street, Petah Tikva 49100, Israel
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Zhao P, Liu W, Lu YL. Loss of fragile histidine triad protein expression and its clinicopathological significance in gastric cancer. Shijie Huaren Xiaohua Zazhi 2004; 12:516-519. [DOI: 10.11569/wcjd.v12.i3.516] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the expression of fragile histidine triad protein, Fhit and the possible relationship between its expression and clinicopathological indices in gastric carcinoma.
METHODS: Fhit protein expression was detected in 76 cases of gastric carcinoma, 58 dysplasia and 10 normal mucosae by immunohistochemical method to analyse its relationship to histological grade, clinical stage, metastatic status and prognosis.
RESULTS: The loss of Fhit protein expression was detected in 48/76 (63.2%) cases of cancer tissue, 36/58 (62.1%)cases of adjacent dysplastic tissue and 0/10 cases of normal gastric mucosa. There was a significant difference in the expression of Fhit protein between cancer or adjacent dysplastic tissue and normal gastric mucosa (P=0.000). It was also showed that loss of Fhit protein expression was found first in 35.7% (10/28) of grade I-II, and in 79.2% (38/48) of grade III (P = 0.000); second in 43.8% (14/32)of stage I-II, whereas in 77.3% (34/44) of stage III-IV (P = 0.004); and last in 36.4% (8/22) of tumors without metastasis but in 74.1% (40/54) of those with metastasis (P = 0.003). The significant difference in the loss of expression of Fhit was found between cancers on different histological grade, clinical stage and metastatic status, respectively. Follow-up data showed that there was a significant difference in median survival time between carcinomas with loss of Fhit (33 mos) and those without (71 mos) (Log rank = 20.78; P = 0.000).
CONCLUSION: Fhit protein is an important tumor suppressor protein. Loss of Fhit protein expression may be associated with carcinogenesis, invasion, metastasis and prognosis in gastric carcinoma.
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