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Butler LM, Perone Y, Dehairs J, Lupien LE, de Laat V, Talebi A, Loda M, Kinlaw WB, Swinnen JV. Lipids and cancer: Emerging roles in pathogenesis, diagnosis and therapeutic intervention. Adv Drug Deliv Rev 2020; 159:245-293. [PMID: 32711004 PMCID: PMC7736102 DOI: 10.1016/j.addr.2020.07.013] [Citation(s) in RCA: 365] [Impact Index Per Article: 73.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2020] [Revised: 07/02/2020] [Accepted: 07/16/2020] [Indexed: 02/06/2023]
Abstract
With the advent of effective tools to study lipids, including mass spectrometry-based lipidomics, lipids are emerging as central players in cancer biology. Lipids function as essential building blocks for membranes, serve as fuel to drive energy-demanding processes and play a key role as signaling molecules and as regulators of numerous cellular functions. Not unexpectedly, cancer cells, as well as other cell types in the tumor microenvironment, exploit various ways to acquire lipids and extensively rewire their metabolism as part of a plastic and context-dependent metabolic reprogramming that is driven by both oncogenic and environmental cues. The resulting changes in the fate and composition of lipids help cancer cells to thrive in a changing microenvironment by supporting key oncogenic functions and cancer hallmarks, including cellular energetics, promoting feedforward oncogenic signaling, resisting oxidative and other stresses, regulating intercellular communication and immune responses. Supported by the close connection between altered lipid metabolism and the pathogenic process, specific lipid profiles are emerging as unique disease biomarkers, with diagnostic, prognostic and predictive potential. Multiple preclinical studies illustrate the translational promise of exploiting lipid metabolism in cancer, and critically, have shown context dependent actionable vulnerabilities that can be rationally targeted, particularly in combinatorial approaches. Moreover, lipids themselves can be used as membrane disrupting agents or as key components of nanocarriers of various therapeutics. With a number of preclinical compounds and strategies that are approaching clinical trials, we are at the doorstep of exploiting a hitherto underappreciated hallmark of cancer and promising target in the oncologist's strategy to combat cancer.
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Affiliation(s)
- Lisa M Butler
- Adelaide Medical School and Freemasons Foundation Centre for Men's Health, University of Adelaide, Adelaide, SA 5005, Australia; South Australian Health and Medical Research Institute, Adelaide, SA 5000, Australia
| | - Ylenia Perone
- Department of Surgery and Cancer, Imperial College London, Imperial Centre for Translational and Experimental Medicine, London, UK
| | - Jonas Dehairs
- Laboratory of Lipid Metabolism and Cancer, KU Leuven Cancer Institute, 3000 Leuven, Belgium
| | - Leslie E Lupien
- Program in Experimental and Molecular Medicine, Geisel School of Medicine at Dartmouth, 1 Medical Center Drive, Lebanon, NH 037560, USA
| | - Vincent de Laat
- Laboratory of Lipid Metabolism and Cancer, KU Leuven Cancer Institute, 3000 Leuven, Belgium
| | - Ali Talebi
- Laboratory of Lipid Metabolism and Cancer, KU Leuven Cancer Institute, 3000 Leuven, Belgium
| | - Massimo Loda
- Pathology and Laboratory Medicine, Weill Cornell Medical College, Cornell University, New York, NY 10065, USA
| | - William B Kinlaw
- The Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, 1 Medical Center Drive, Lebanon, NH 03756, USA
| | - Johannes V Swinnen
- Laboratory of Lipid Metabolism and Cancer, KU Leuven Cancer Institute, 3000 Leuven, Belgium.
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2
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Matsuda Y, Tanaka M, Sawabe M, Mori S, Muramatsu M, Mieno MN, Furukawa T, Arai T. Relationship between pancreatic intraepithelial neoplasias, pancreatic ductal adenocarcinomas, and single nucleotide polymorphisms in autopsied elderly patients. Genes Chromosomes Cancer 2017. [DOI: 10.1002/gcc.22479] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Affiliation(s)
- Yoko Matsuda
- Department of Pathology; Tokyo Metropolitan Geriatric Hospital; Tokyo Japan
| | - Masashi Tanaka
- Department of Genomics for Longevity and Health; Tokyo Metropolitan Institute of Gerontology; Tokyo Japan
| | - Motoji Sawabe
- Molecular Pathophysiology, Graduate School of Health Care Science, Tokyo Medical and Dental University; Tokyo Japan
| | - Seijiro Mori
- Center for Promotion of Clinical Investigation, Tokyo Metropolitan Geriatric Hospital; Tokyo Japan
| | - Masaaki Muramatsu
- Department of Molecular Epidemiology; Medical Research Institute, Tokyo Medical and Dental University; Tokyo Japan
| | - Makiko Naka Mieno
- Department of Medical Informatics; Center for Information, Jichi Medical University; Tochigi Japan
| | - Toru Furukawa
- Institute for Integrated Medical Sciences, Tokyo Women's Medical University; Tokyo Japan
| | - Tomio Arai
- Department of Pathology; Tokyo Metropolitan Geriatric Hospital; Tokyo Japan
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3
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Bucay N, Sekhon K, Yang T, Majid S, Shahryari V, Hsieh C, Mitsui Y, Deng G, Tabatabai ZL, Yamamura S, Calin GA, Dahiya R, Tanaka Y, Saini S. MicroRNA-383 located in frequently deleted chromosomal locus 8p22 regulates CD44 in prostate cancer. Oncogene 2016; 36:2667-2679. [PMID: 27893706 PMCID: PMC5426972 DOI: 10.1038/onc.2016.419] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2016] [Revised: 08/30/2016] [Accepted: 09/30/2016] [Indexed: 12/13/2022]
Abstract
A major genomic alteration in prostate cancer (PCa) is frequent loss of chromosome (chr) 8p with a common region of loss of heterozygosity (LOH) at chr8p22 locus. Genomic studies implicate this locus in the initiation of clinically significant PCa and with progression to metastatic disease. However, the genes within this region have not been fully characterized to date. Here we demonstrate for the first time that a microRNA component of this region –miR-383- is frequently downregulated in prostate cancer, plays a critical role in determining tumor initiating potential and is involved in prostate cancer metastasis via direct regulation of CD44, a ubiquitous marker of PCa tumor initiating cells (TICs)/ stem cells. Expression analyses of miR-383 in PCa clinical tissues established that low miR-383 expression is associated with poor prognosis. Functional data suggests that miR-383 regulates PCa tumor initiating/ stem-like cells via CD44 regulation. Ectopic expression of miR-383 inhibited tumor initiating capacity of CD44+ PCa cells. Also, ‘anti-metastatic’ effects of ectopic miR-383 expression were observed in a PCa experimental metastasis model. In view of our results, we propose that frequent loss of miR-383 at chr8p22 region leads to tumor initiation and prostate cancer metastasis. Thus, we have identified a novel finding that associates a long observed genomic alteration to PCa stemness and metastasis. Our data suggests that restoration of miR-383 expression may be an effective therapeutic modality against PCa. Importantly, we identified miR-383 as a novel PCa tissue diagnostic biomarker with a potential that outperforms that of serum PSA.
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Affiliation(s)
- N Bucay
- Department of Urology, Veterans Affairs Medical Center, San Francisco and University of California San Francisco, San Fransisco, CA, USA
| | - K Sekhon
- Department of Urology, Veterans Affairs Medical Center, San Francisco and University of California San Francisco, San Fransisco, CA, USA
| | - T Yang
- Department of Urology, Veterans Affairs Medical Center, San Francisco and University of California San Francisco, San Fransisco, CA, USA
| | - S Majid
- Department of Urology, Veterans Affairs Medical Center, San Francisco and University of California San Francisco, San Fransisco, CA, USA
| | - V Shahryari
- Department of Urology, Veterans Affairs Medical Center, San Francisco and University of California San Francisco, San Fransisco, CA, USA
| | - C Hsieh
- Department of Urology, Veterans Affairs Medical Center, San Francisco and University of California San Francisco, San Fransisco, CA, USA
| | - Y Mitsui
- Department of Urology, Veterans Affairs Medical Center, San Francisco and University of California San Francisco, San Fransisco, CA, USA
| | - G Deng
- Department of Urology, Veterans Affairs Medical Center, San Francisco and University of California San Francisco, San Fransisco, CA, USA
| | - Z L Tabatabai
- Department of Urology, Veterans Affairs Medical Center, San Francisco and University of California San Francisco, San Fransisco, CA, USA
| | - S Yamamura
- Department of Urology, Veterans Affairs Medical Center, San Francisco and University of California San Francisco, San Fransisco, CA, USA
| | - G A Calin
- Department of Experimental Therapeutics, Non-Coding RNA Center, MD Anderson Cancer Center, University of Texas, Houston, TX, USA
| | - R Dahiya
- Department of Urology, Veterans Affairs Medical Center, San Francisco and University of California San Francisco, San Fransisco, CA, USA
| | - Y Tanaka
- Department of Urology, Veterans Affairs Medical Center, San Francisco and University of California San Francisco, San Fransisco, CA, USA
| | - S Saini
- Department of Urology, Veterans Affairs Medical Center, San Francisco and University of California San Francisco, San Fransisco, CA, USA
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4
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Loo LWM, Tiirikainen M, Cheng I, Lum-Jones A, Seifried A, Church JM, Gryfe R, Weisenberger DJ, Lindor NM, Gallinger S, Haile RW, Duggan DJ, Thibodeau SN, Casey G, Le Marchand L. Integrated analysis of genome-wide copy number alterations and gene expression in microsatellite stable, CpG island methylator phenotype-negative colon cancer. Genes Chromosomes Cancer 2013; 52:450-66. [PMID: 23341073 DOI: 10.1002/gcc.22043] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2012] [Revised: 12/04/2012] [Accepted: 12/16/2012] [Indexed: 12/11/2022] Open
Abstract
Microsatellite stable (MSS), CpG island methylator phenotype (CIMP)-negative colorectal tumors, the most prevalent molecular subtype of colorectal cancer, are associated with extensive copy number alteration (CNA) events and aneuploidy. We report on the identification of characteristic recurrent CNA (with frequency >25%) events and associated gene expression profiles for a total of 40 paired tumor and adjacent normal colon tissues using genome-wide microarrays. We observed recurrent CNAs, namely gains at 1q, 7p, 7q, 8p12-11, 8q, 12p13, 13q, 20p, 20q, Xp, and Xq and losses at 1p36, 1p31, 1p21, 4p15-12, 4q12-35, 5q21-22, 6q26, 8p, 14q, 15q11-12, 17p, 18p, 18q, 21q21-22, and 22q. Within these genomic regions we identified 356 genes with significant differential expression (P < 0.0001 and ±1.5-fold change) in the tumor compared to adjacent normal tissue. Gene ontology and pathway analyses indicated that many of these genes were involved in functional mechanisms that regulate cell cycle, cell death, and metabolism. An amplicon present in >70% of the tumor samples at 20q11-20q13 contained several cancer-related genes (AHCY, POFUT1, RPN2, TH1L, and PRPF6) that were upregulated and demonstrated a significant linear correlation (P < 0.05) for gene dosage and gene expression. Copy number loss at 8p, a CNA associated with adenocarcinoma and poor prognosis, was observed in >50% of the tumor samples and demonstrated a significant linear correlation for gene dosage and gene expression for two potential tumor suppressor genes, MTUS1 (8p22) and PPP2CB (8p12). The results from our integration analysis illustrate the complex relationship between genomic alterations and gene expression in colon cancer.
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Affiliation(s)
- Lenora W M Loo
- Epidemiology Program, University of Hawaii Cancer Center, Honolulu, HI 96813, USA.
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Zhang Y, Yan G, Zhai L, Xu S, Shen H, Yao J, Wu F, Xie L, Tang H, Yu H, Liu M, Yang P, Xu P, Zhang C, Li L, Chang C, Li N, Wu S, Zhu Y, Wang Q, Wen B, Lin L, Wang Y, Zheng G, Zhou L, Lu H, Liu S, He F, Zhong F. Proteome atlas of human chromosome 8 and its multiple 8p deficiencies in tumorigenesis of the stomach, colon, and liver. J Proteome Res 2013; 12:81-88. [PMID: 23256868 DOI: 10.1021/pr300834r] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
Chromosome 8, a medium-length euchromatic unit in humans that has an extraordinarily high mutation rate, can be detected not only in evolution but also in multiple mutant diseases, such as tumorigenesis, and further invasion/metastasis. The Chromosome-Centric Human Proteome Project of China systematically profiles the proteomes of three digestive organs (i.e., stomach, colon, and liver) and their corresponding carcinoma tissues/cell lines according to a chromosome organizational roadmap. By rigorous standards, we have identified 271 (38.7%), 330 (47.1%), and 325 (46.4%) of 701 chromosome 8-coded proteins from stomach, colon, and liver samples, respectively, in Swiss-Prot and observed a total coverage rate of up to 58.9% by 413 identified proteins. Using large-scale label-free proteome quantitation, we also found some 8p deficiencies, such as the presence of 8p21-p23 in tumorigenesis of the above-described digestive organs, which is in good agreement with previous reports. To our best knowledge, this is the first study to have verified these 8p deficiencies at the proteome level, complementing genome and transcriptome data.
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Affiliation(s)
- Yang Zhang
- Institutes of Biomedical Sciences and Department of Chemistry, Fudan University, Shanghai 200032, China
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Takasu S, Mutoh M, Takahashi M, Nakagama H. Lipoprotein lipase as a candidate target for cancer prevention/therapy. Biochem Res Int 2011; 2012:398697. [PMID: 22028972 PMCID: PMC3199119 DOI: 10.1155/2012/398697] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2011] [Accepted: 08/17/2011] [Indexed: 12/30/2022] Open
Abstract
Epidemiological studies have shown that serum triglyceride (TG) levels are linked with risk of development of cancer, including colorectal and pancreatic cancers, and their precancerous lesions. Thus, it is assumed that serum TG plays an important role in carcinogenesis, and the key enzyme lipoprotein lipase (LPL), which catalyzes the hydrolysis of plasma TG, may therefore be involved. Dysregulation of LPL has been reported to contribute to many human diseases, such as atherosclerosis, chylomicronaemia, obesity, and type 2 diabetes. Recently, it has been reported that LPL gene deficiency, such as due to chromosome 8p22 loss, LPL gene polymorphism, and epigenetic changes in its promoter region gene, increases cancer risk, especially in the prostate. In animal experiments, high serum TG levels seem to promote sporadic/carcinogen-induced genesis of colorectal and pancreatic cancers. Interestingly, tumor suppressive effects of LPL inducers, such as PPAR ligands, NO-1886, and indomethacin, have been demonstrated in animal models. Moreover, recent evidence that LPL plays important roles in inflammation and obesity implies that it is an appropriate general target for chemopreventive and chemotherapeutic agents.
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Affiliation(s)
- Shinji Takasu
- Division of Cancer Development System, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan
| | - Michihiro Mutoh
- Division of Cancer Development System, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan
| | - Mami Takahashi
- Division of Cancer Development System, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan
| | - Hitoshi Nakagama
- Division of Cancer Development System, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan
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Huang J, Zheng DL, Qin FS, Cheng N, Chen H, Wan BB, Wang YP, Xiao HS, Han ZG. Genetic and epigenetic silencing of SCARA5 may contribute to human hepatocellular carcinoma by activating FAK signaling. J Clin Invest 2009; 120:223-41. [PMID: 20038795 DOI: 10.1172/jci38012] [Citation(s) in RCA: 105] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2008] [Accepted: 10/14/2009] [Indexed: 01/16/2023] Open
Abstract
The epigenetic silencing of tumor suppressor genes is a crucial event during carcinogenesis and metastasis. Here, in a human genome-wide survey, we identified scavenger receptor class A, member 5 (SCARA5) as a candidate tumor suppressor gene located on chromosome 8p. We found that SCARA5 expression was frequently downregulated as a result of promoter hypermethylation and allelic imbalance and was associated with vascular invasion in human hepatocellular carcinoma (HCC). Furthermore, SCARA5 knockdown via RNAi markedly enhanced HCC cell growth in vitro, colony formation in soft agar, and invasiveness, tumorigenicity, and lung metastasis in vivo. By contrast, SCARA5 overexpression suppressed these malignant behaviors. Interestingly, SCARA5 was found to physically associate with focal adhesion kinase (FAK) and inhibit the tyrosine phosphorylation cascade of the FAK-Src-Cas signaling pathway. Conversely, silencing SCARA5 stimulated the signaling pathway via increased phosphorylation of certain tyrosine residues of FAK, Src, and p130Cas; it was also associated with activation of MMP9, a tumor metastasis-associated enzyme. Taken together, these data suggest that the plasma membrane protein SCARA5 can contribute to HCC tumorigenesis and metastasis via activation of the FAK signaling pathway.
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Affiliation(s)
- Jian Huang
- National Human Genome Center, Rui-Jin Hospital, Shanghai Jiaotong University School of Medicine, 351 Guo Shou-Jing Road, Shanghai, People's Republic of China
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8
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Anti-hepatitis B virus X protein in sera is one of the markers of development of liver cirrhosis and liver cancer mediated by HBV. J Biomed Biotechnol 2009; 2009:289068. [PMID: 19746176 PMCID: PMC2738860 DOI: 10.1155/2009/289068] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2009] [Accepted: 07/16/2009] [Indexed: 02/06/2023] Open
Abstract
Hepatitis B virus X protein (HBx) plays a crucial role in the development of hepatocellular carcinoma (HCC). However, the significance of circulating antibody to hepatitis B virus X antigen (anti-HBx) in sera remains unclear. In the present study, we examined the titers of anti-HBx (IgG) in the sera from 173 patients with chronic hepatitis B (CHB), 106 liver cirrhosis (LC), and 61 HCC by enzyme-linked immunosorbent assay (ELISA), respectively. Our data showed that the positive rates of anti-HBx were higher in sera of LC (40.6%) and HCC (34.4%) than those of CHB (10.4%), P < .05. In all 40 patients with anti-HBx+ out of 340 patients, 39 (97.5%) were HBsAg/HBeAg/anti-HBc+ and 1 (2.5%) was anti-HBs+ (P < .01), suggesting that anti-HBx in sera is a marker of HBV replication rather than a protective antibody. Thus, our findings reveal that circulating anti-HBx in sera is one of the markers of development of LC and HCC mediated by HBV.
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9
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Sunami E, Shinozaki M, Higano CS, Wollman R, Dorff TB, Tucker SJ, Martinez SR, Mizuno R, Singer FR, Hoon DSB. Multimarker circulating DNA assay for assessing blood of prostate cancer patients. Clin Chem 2009; 55:559-67. [PMID: 19131636 DOI: 10.1373/clinchem.2008.108498] [Citation(s) in RCA: 92] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
BACKGROUND Prostate cancer (PCa) detection using serum-based prostate specific antigen (PSA) is limited by frequent false-positive and -negative results. Genetic aberrations such as allelic imbalance (AI) and epigenetic changes such as promoter hypermethylation have been detected in circulating DNA of cancer patients. We hypothesized that circulating multimarker DNA assays detecting both genetic and epigenetic markers in serum would be useful in assessing PCa patients. METHODS We assayed blood from healthy male donors (n = 40) and 83 patients with American Joint Cancer Committee (AJCC) stage I-IV PCa. DNA was assayed for AI of 6 genome microsatellites. We assessed methylation of RASSF1, RARB2, and GSTP1 using a methylation-specific PCR assay and analyzed the sensitivity of each assay for the detection of genetic or epigenetic changes in circulating DNA. The relation between circulating tumor-related DNA detection and prognostic factors was investigated. RESULTS The proportion of patients demonstrating AI for > or =1 marker was 47% (38 of 81 patients). Methylation biomarkers were detected in 24 of 83 patients (28%). By combining 2 DNA assays, the number of PCa patients positive for > or =1 methylated or LOH marker increased (52 of 83; 63%). The combined assays detected PCa in 15 of 24 patients (63%) with normal PSA concentrations. The combination of the DNA assays detected the presence of PCa regardless of AJCC stage or PSA concentration. Combination of the DNA and PSA assays gave 89% sensitivity. CONCLUSIONS This pilot study demonstrates that the combined circulating DNA multimarker assay identifies patients with PCa and may yield information independent of AJCC stage or PSA concentration.
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Affiliation(s)
- Eiji Sunami
- Department of Molecular Oncology and the Breast and Endocrine Program, John Wayne Cancer Institute, Saint John's Health Center, Santa Monica, CA 90404, USA
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Nakano M, Takahashi H, Shiraishi T, Lu T, Furusato M, Wakui S, Hano H. Prediction of clinically insignificant prostate cancer by detection of allelic imbalance at 6q, 8p and 13q. Pathol Int 2008; 58:415-20. [DOI: 10.1111/j.1440-1827.2008.02246.x] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
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Lu T, Hano H. Deletion at chromosome arms 6q16-22 and 10q22.3-23.1 associated with initiation of prostate cancer. Prostate Cancer Prostatic Dis 2008; 11:357-61. [PMID: 18227855 DOI: 10.1038/pcan.2008.4] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
Loss of heterozygosity (LOH) at 6q16-22 and 10q22.3-23.1 is common chromosomal alteration in advanced prostate cancer and suggests that one or more tumor suppressor genes may lie within these chromosome arms. However, the genetic changes in early stage prostate cancer and premalignant lesions remain to be investigated. We used 11 informative microsatellite markers at 6q16-22 and 10q22.3-23.1 in Japanese patients to compare the frequency of LOH in 53 lesions of high-grade prostatic intraepithelial neoplasia (HGPIN), 38 cases (38 lesions) of incidental prostate cancer (IPC) and 107 cases (168 lesions) of clinical prostate cancer (CPC). The frequency of LOH at 6q16-22 with at least one marker was 38 and 49% in IPC and CPC cases, respectively. Similarly, allelic loss at 10q22.3-23.1 was present in 35 and 39% of IPC and CPC, respectively. High-frequency LOH was detected in both the clinically insignificant and significant prostate cancers at 6q16-22 and 10q22.3-23.1 (P>0.05). However, no allelic loss was detected in any markers at the same regions in HGPIN (0%), which is usually considered a premalignant lesion to prostate cancer. Deletions of both the chromosome regions, 6q16-22 and 10q22.3-23.1, are more likely important events in the initiation and/or promotion of prostate cancer.
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Affiliation(s)
- T Lu
- Department of Pathology, The Jikei University School of Medicine, Tokyo, Japan.
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12
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Allelic imbalance at 13q14.2 approximately q14.3 in localized prostate cancer is associated with early biochemical relapse. ACTA ACUST UNITED AC 2008; 179:118-26. [PMID: 18036398 DOI: 10.1016/j.cancergencyto.2007.08.017] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2007] [Accepted: 08/30/2007] [Indexed: 11/17/2022]
Abstract
Allelic imbalance (AI), particularly at chromosomes 8p, 10q, and 13q, is the most frequently observed genetic change in sporadic prostate cancer. AI at these sites may inactivate tumor suppressor genes that regulate normal cell growth. To establish the relationship between AI and progression, we analyzed loci on 8p, 10q, and 13q14 in archival prostate tumors matched for Gleason grade, pre-operative prostate-specific antigen levels, and pathologic stage, and they were paired on the basis of relapse status after 3 years. AI was identified in 66% of patients without relapse and in 73% with relapse. There was no statistically significant difference for AI at 8p21.3 and 10q23.2 between the two groups of patients, but significant differences between relapsers and nonrelapsers in the frequency of AI at D13S165 at 13q14.2 (P=0.006) and D13S273 at 13q14.3 (P=0.03). There was also a significantly higher incidence of AI at both loci in the relapsers compared to the nonrelapsers (P=0.03). In three relapsers, AI occurred at all three loci between 13q14.2 and 13q14.3, with no nonrelapsers demonstrating AI at all three loci. These findings show that AI at 13q14.2 approximately q14.3 is an important event in the progression of localized prostate cancer, and suggest a possible role for microRNAs.
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13
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Lu T, Hano H. Identification of minimal regions of deletion at 8p23.1-22 associated with metastasis of hepatocellular carcinoma. Liver Int 2007; 27:782-90. [PMID: 17617121 DOI: 10.1111/j.1478-3231.2007.01504.x] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/13/2023]
Abstract
AIMS/BACKGROUND Loss of heterozygosity (LOH) at 8p is the most frequent chromosomal alteration in tumorigenesis of human cancers. However, the genetic change in metastasis of hepatocellular carcinoma (HCC) still has to be investigated. METHODS We used 16 microsatellite markers informative in Japanese patients, selected from among 61 published microsatellite markers at 8p23.2-21 to compare the frequency of LOH in primary tumours (Tps) and metastatic tumours (Tms) in a PCR-based analysis. Sixty-three informative cancerous lesions (26 were Tps, 37 were Tms) from 23 cases of HCC were used. RESULTS The frequency of LOH at 8p23.2-21 with at least one marker was 19% in Tps and 68% in Tms. Allelic loss at 8p23.2-21 was significantly more frequent in Tms than in Tps (P=0.0003). More specifically, the frequency of LOH at D8S262, D8S1819, D8S503, D8S1130, D8S552, D8S1109, and D8S261 in Tms was 36-60% respectively. CONCLUSIONS In contrast, allelic loss at the same markers in Tp was only detected in 0-17% of the tumour respectively. The significant difference in the frequency of LOH at 8p between primary cancer and metastatic cancer in individual cases of HCC suggests LOH at 8p to be involved in the enhancement of tumour aggressiveness, especially during metastasis.
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Affiliation(s)
- Tomoe Lu
- Department of Pathology, Jikei University School of Medicine, Tokyo, Japan.
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14
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Hosseini HA, Ahani A, Galehdari H, Froughmand AM, Hosseini M, Masjedizadeh A, Zali MR. Frequent loss of heterozygosity at 8p22 chromosomal region in diffuse type of gastric cancer. World J Gastroenterol 2007; 13:3354-8. [PMID: 17659675 PMCID: PMC4172716 DOI: 10.3748/wjg.v13.i24.3354] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [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 study the loss of heterozygosity (LOH) at 8p21-23 locus in diffuse gastric cancer.
METHODS: To evaluate the involvement of this region in gastric cancer, we used eight microsatellite markers covering two Mb of mentioned region, to perform a high-resolution analysis of allele loss in 42 cases of late diffuse gastric adenocarcinoma.
RESULTS: Six of these STS makers: D8S1149, D8S1645, D8S1643, D8S1508, D8S1591, and D8S1145 showed 36%, 28%, 37%, 41%, 44% and 53% LOH, respectively.
CONCLUSION: A critical region of loss, close to the NAT2 locus and relatively far from FEZ1 gene currently postulated as tumor suppressor gene in this region.
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15
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Lu T, Hano H, Meng C, Nagatsuma K, Chiba S, Ikegami M. Frequent loss of heterozygosity in two distinct regions, 8p23.1 and 8p22, in hepatocellular carcinoma. World J Gastroenterol 2007; 13:1090-7. [PMID: 17373745 PMCID: PMC4146873 DOI: 10.3748/wjg.v13.i7.1090] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.8] [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 identify the precise location of putative tumor suppressor genes (TSGs) on the short arm of chromosome 8 in patients with hepatocellular carcinoma (HCC).
METHODS: We used 16 microsatellite markers informative in Japanese patients, which were selected from 61 published markers, on 8p, to analyze the frequency of loss of heterozygosity (LOH) in each region in 33 cases (56 lesions) of HCC.
RESULTS: The frequency of LOH at 8p23.2-21 with at least one marker was 63% (20/32) in the informative cases. More specifically, the frequency of LOH at 8p23.2, 8p23.1, 8p22, and 8p21 was 6%, 52%, 47%, and 13% in HCC cases. The LOH was significantly more frequent at 8p23.1 and 8p22 than the average (52% vs 22%, P = 0.0008; and 47% vs 22%, P = 0.004, respectively) or others sites, such as 8p23.2 (52% vs 6%, P = 0.003; 47% vs 22%, P = 0.004) and 8p21 (52% vs 13%, P = 0.001; 47% vs 13%, P = 0.005) in liver cancer on the basis of cases. Notably, LOH frequency was significantly higher at D8S277, D8S503, D8S1130, D8S552, D8S254 and D8S258 than at the other sites. However, no allelic loss was detected at any marker on 8p in the lesions of nontumor liver tissues.
CONCLUSION: Deletion of 8p, especially the loss of 8p23.1-22, is an important event in the initiation or promotion of HCC. Our results should be useful in identifying critical genes that might lie at 8p23.1-22.
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Affiliation(s)
- Tomoe Lu
- Department of Pathology, The Jikei University School of Medicine, Tokyo 105-8461, Japan.
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