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Yamagishi H, Kuroda H, Imai Y, Hiraishi H. Molecular pathogenesis of sporadic colorectal cancers. CHINESE JOURNAL OF CANCER 2016; 35:4. [PMID: 26738600 PMCID: PMC4704376 DOI: 10.1186/s40880-015-0066-y] [Citation(s) in RCA: 111] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/24/2015] [Accepted: 09/01/2015] [Indexed: 02/07/2023]
Abstract
Colorectal cancer (CRC) results from the progressive accumulation of genetic and epigenetic alterations that lead to the transformation of normal colonic mucosa to adenocarcinoma. Approximately 75% of CRCs are sporadic and occur in people without genetic predisposition or family history of CRC. During the past two decades, sporadic CRCs were classified into three major groups according to frequently altered/mutated genes. These genes have been identified by linkage analyses of cancer-prone families and by individual mutation analyses of candidate genes selected on the basis of functional data. In the first half of this review, we describe the genetic pathways of sporadic CRCs and their clinicopathologic features. Recently, large-scale genome analyses have detected many infrequently mutated genes as well as a small number of frequently mutated genes. These infrequently mutated genes are likely described in a limited number of pathways. Gene-oriented models of CRC progression are being replaced by pathway-oriented models. In the second half of this review, we summarize the present knowledge of this research field and discuss its prospects.
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Affiliation(s)
- Hidetsugu Yamagishi
- Department of Diagnostic Pathology, Dokkyo Medical University, 880 Kita-Kobayashi, Mibu, Shimotsuga, Tochigi, 321-0293, Japan.
| | - Hajime Kuroda
- Department of Pathology, International University of Health and Welfare Hospital, 537-3 Iguchi, Nasushiobara, Tochigi, 329-2763, Japan.
| | - Yasuo Imai
- Department of Diagnostic Pathology, Dokkyo Medical University, 880 Kita-Kobayashi, Mibu, Shimotsuga, Tochigi, 321-0293, Japan.
- Department of Diagnostic Pathology, Ota Memorial Hospital, Fuji Heavy Industries Health Insurance Society, 455-1 Oshima, Ota, Gunma, 373-8585, Japan.
| | - Hideyuki Hiraishi
- Department of Gastroenterology, Dokkyo Medical University, 880 Kita-Kobayashi, Mibu, Shimotsuga, Tochigi, 321-0293, Japan.
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Chiurillo MA. Role of the Wnt/β-catenin pathway in gastric cancer: An in-depth literature review. World J Exp Med 2015; 5:84-102. [PMID: 25992323 PMCID: PMC4436943 DOI: 10.5493/wjem.v5.i2.84] [Citation(s) in RCA: 244] [Impact Index Per Article: 24.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/04/2014] [Revised: 12/05/2014] [Accepted: 03/20/2015] [Indexed: 02/06/2023] Open
Abstract
Gastric cancer remains one of the most common cancers worldwide and one of the leading cause for cancer-related deaths. Gastric adenocarcinoma is a multifactorial disease that is genetically, cytologically and architecturally more heterogeneous than other gastrointestinal carcinomas. The aberrant activation of the Wnt/β-catenin signaling pathway is involved in the development and progression of a significant proportion of gastric cancer cases. This review focuses on the participation of the Wnt/β-catenin pathway in gastric cancer by offering an analysis of the relevant literature published in this field. Indeed, it is discussed the role of key factors in Wnt/β-catenin signaling and their downstream effectors regulating processes involved in tumor initiation, tumor growth, metastasis and resistance to therapy. Available data indicate that constitutive Wnt signalling resulting from Helicobacter pylori infection and inactivation of Wnt inhibitors (mainly by inactivating mutations and promoter hypermethylation) play an important role in gastric cancer. Moreover, a number of recent studies confirmed CTNNB1 and APC as driver genes in gastric cancer. The identification of specific membrane, intracellular, and extracellular components of the Wnt pathway has revealed potential targets for gastric cancer therapy. High-throughput “omics” approaches will help in the search for Wnt pathway antagonist in the near future.
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Martin ES, Tonon G, Sinha R, Xiao Y, Feng B, Kimmelman AC, Protopopov A, Ivanova E, Brennan C, Montgomery K, Kucherlapati R, Bailey G, Redston M, Chin L, DePinho RA. Common and distinct genomic events in sporadic colorectal cancer and diverse cancer types. Cancer Res 2007; 67:10736-43. [PMID: 18006816 DOI: 10.1158/0008-5472.can-07-2742] [Citation(s) in RCA: 58] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Colorectal cancer (CRC) is a major cause of cancer morbidity and mortality, and elucidation of its underlying genetics has advanced diagnostic screening, early detection, and treatment. Because CRC genomes are characterized by numerous non-random chromosomal structural alterations, we sought to delimit regions of recurrent amplifications and deletions in a collection of 42 primary specimens and 37 tumor cell lines derived from chromosomal instability neoplasia and microsatellite instability neoplasia CRC subtypes and to compare the pattern of genomic aberrations in CRC with those in other cancers. Application of oligomer-based array-comparative genome hybridization and custom analytic tools identified 50 minimal common regions (MCRs) of copy number alterations, 28 amplifications, and 22 deletions. Fifteen were highly recurrent and focal (<12 genes) MCRs, five of them harboring known CRC genes including EGFR and MYC with the remaining 10 containing a total of 65 resident genes with established links to cancer. Furthermore, comparisons of these delimited genomic profiles revealed that 22 of the 50 CRC MCRs are also present in lung cancer, glioblastoma, and/or multiple myeloma. Among 22 shared MCRs, nine do not contain genes previously shown genetically altered in cancer, whereas the remaining 13 harbor 35 known cancer genes, of which only 14 have been linked to CRC pathogenesis. Together, these observations point to the existence of many yet-to-be discovered cancer genes driving CRC development, as well as other human cancers, and show the utility of high-resolution copy number analysis in the identification of genetic events common and specific to the development of various tumor types.
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Affiliation(s)
- Eric S Martin
- Department of Medical Oncology, Belfer Institute for Innovative Cancer Science, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA
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Meng WJ, Wang L, Tian C, Yu YY, Zhou B, Gu J, Xia QJ, Sun XF, Li Y, Wang R, Zheng XL, Zhou ZG. Novel mutations and sequence variants in exons 3-9 of human T Cell Factor-4 gene in sporadic rectal cancer patients stratified by microsatellite instability. World J Gastroenterol 2007; 13:3747-51. [PMID: 17659738 PMCID: PMC4250650 DOI: 10.3748/wjg.v13.i27.3747] [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 establish the role of human T Cell Factor-4 (hTCF-4) gene exons 3-9 mutation status in association with sporadic rectal cancer with microsatellite instability (MSI).
METHODS: Microsatellite markers were genotyped in 93 sporadic rectal cancer patients. Eleven cases were found to be high-frequency MSI (MSI-H). Sequence analysis of the coding region of the exons 3-9 of hTCF-4 gene was carried out for the 11 MSI-H cases and 10 controls (5 microsatellite stability (MSS) cases and 5 cases with normal mucosa). The sequencing and MSI identification were used.
RESULTS: Several novel mutations and variants were revealed. In exon 4, one is a 4-position continuous alteration which caused amino acid change from Q131T and S132I (391insA, 392 G > A, 393 A > G and 395delC) and another nucleotide deletion (395delC) is present in MSI-H cases (5/10 and 4/10, respectively) but completely absent in the controls.
CONCLUSION: Novel mutations in exon 4 of hTCF-4 gene were revealed in this study, which might be of importance in the pathogenesis of sporadic rectal cancer patients with MSI-H.
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Affiliation(s)
- Wen-Jian Meng
- Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, 37 Guo Xue Xiang, Chengdu 610041, Sichuan Province, China
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Chang HR, Cheng TL, Liu TZ, Hu HS, Hsu LS, Tseng WC, Chen CH, Tsao DA. Genetic and cellular characterizations of human TCF4 with microsatellite instability in colon cancer and leukemia cell lines. Cancer Lett 2006; 233:165-71. [PMID: 15905022 DOI: 10.1016/j.canlet.2005.03.011] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2005] [Revised: 03/05/2005] [Accepted: 03/07/2005] [Indexed: 12/29/2022]
Abstract
It has been reported that the mutational inactivation of the adenomatous polyposis coli (APC) and beta-catenin genes play important roles in colorectal carcinogenesis. However, alteration of the components in the Wnt signaling pathway in colorectal cancer (CRC) with microsatellite instability (MSI) has been elucidated. To define the precise role of the Wnt signaling components in CRC and leukemia cell lines with MSI, mutational analyses of the T cell factor 4 (TCF4) genes were performed. Here we describe for the first time a TCF4 MSI+ phenotype in leukemia cell lines except in colon cancer cell lines. Moreover, we found that these cell lines exhibited deletion and insertion of 1-2A in an (A)9 repeat so as to result in (A)7, (A)8, (A)10 and (A)11 repeat, respectively. To characterize the cellular function of these special TCF4 mutant clones, transient transfection and fluorescent microscopy were analyzed and the results revealed that the TCF4 frameshift gene products all localized in nuclei. Surprisingly, these TCF4 frameshift mutants lost transcriptional activity with beta-catenin and down-regulate the target gene expression. These results delineate a novel role for MSI+TCF4 in leukemia and colon cancer progression.
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Affiliation(s)
- Huoy-Rou Chang
- Department of Biomedical Engineering, I-Shou University, Kaohsiung Hsien 840, Taiwan, ROC
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Abstract
Adenovirus continues to be an important model system for investigating basic aspects of cell biology. Interactions of several cellular proteins with E1A conserved regions (CR) 1 and 2, and inhibition of apoptosis by E1B proteins are required for oncogenic transformation. CR2 binds RB family members, de-repressing E2F transcription factors, thus activating genes required for cell cycling. E1B-19K is a BCL2 homolog that binds and inactivates proapoptotic BAK and BAX. E1B-55K binds p53, inhibiting its transcriptional activation function. In productively infected cells, E1B-55K and E4orf6 assemble a ubiquitin ligase with cellular proteins Elongins B and C, Cullin 5 and RBX1 that polyubiquitinates p53 and one or more subunits of the MRN complex involved in DNA double-strand break repair, directing them to proteosomal degradation. E1A CR3 activates viral transcription by interacting with the MED23 Mediator subunit, stimulating preinitiation complex assembly on early viral promoters and probably also the rate at which they initiate transcription. The viral E1B-55K/E4orf6 ubiquitin ligase is also required for efficient viral late protein synthesis in many cell types, but the mechanism is not understood. E1A CR1 binds several chromatin-modifying complexes, but how this contributes to stimulation of cellular DNA synthesis and transformation is not clear. E1A CR4 binds the CtBP corepressor, but the mechanism by which this modulates the frequency of transformation remains to be determined. Clearly, adenovirus has much left to teach us about fundamental cellular processes.
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Affiliation(s)
- Arnold J Berk
- Department of Microbiology, Immunology and Molecular Genetics, Molecular Biology Institute, University of California, Los Angeles (UCLA), 90095-1570, USA.
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Narayan S, Roy D. Role of APC and DNA mismatch repair genes in the development of colorectal cancers. Mol Cancer 2003; 2:41. [PMID: 14672538 PMCID: PMC317355 DOI: 10.1186/1476-4598-2-41] [Citation(s) in RCA: 131] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2003] [Accepted: 12/12/2003] [Indexed: 02/06/2023] Open
Abstract
Colorectal cancer is the third most common cause of cancer-related death in both men and women in the western hemisphere. According to the American Cancer Society, an estimated 105,500 new cases of colon cancer with 57,100 deaths will occur in the U.S. in 2003, accounting for about 10% of cancer deaths. Among the colon cancer patients, hereditary risk contributes approximately 20%. The main inherited colorectal cancers are the familial adenomatous polyposis (FAP) and the hereditary nonpolyposis colorectal cancers (HNPCC). The FAP and HNPCC are caused due to mutations in the adenomatous polyposis coli (APC) and DNA mismatch repair (MMR) genes. The focus of this review is to summarize the functions of APC and MMR gene products in the development of colorectal cancers.
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Affiliation(s)
- Satya Narayan
- Department of Anatomy and Cell Biology and UF Shands Cancer Center, College of Medicine, Academic Research Building, Room R4-216, 1600 SW Archer Road, University of Florida, Gainesville, FL 32610, USA
| | - Deodutta Roy
- Environmental Health Sciences, University of Alabama at Birmingham, 317 Ryals Building, 1665 University Boulevard, Birmingham, AL 35294-0022, USA
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Jiang Y, Zhou XD, Liu YK, Wu X, Huang XW. Association of hTcf-4 gene expression and mutation with clinicopathological characteristics of hepatocellular carcinoma. World J Gastroenterol 2002; 8:804-7. [PMID: 12378619 PMCID: PMC4656565 DOI: 10.3748/wjg.v8.i5.804] [Citation(s) in RCA: 19] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: Hepatocellular carcinoma (HCC) is a significant health problem in China. But the molecular mechanisms of HCC remains unclear. APC/β-Catenin/Tcf signaling pathway, also known as Wnt pathway, plays a critical role in the development and oncogenesis. As little is known about the alteration of human T-cell transcription factor-4 (hTcf-4) gene in HCC, it is of interest to study the expression and mutation of hTcf-4 gene in HCC and the relationship between hTcf-4 gene and progression of HCC.
METHODS: Reverse transcription-polymerase chain reaction (RT-PCR) method was used to detect the expression of hTcf-4 mRNA in 32 HCC and para-cancerous tissues and 5 normal liver tissues. PCR-single strand conformation polymorphism (PCR-SSCP) method was used to detect the mutation of hTcf-4 exons 1, 4, 9 and 15 in HCC. The correlation of expression and mutation of the hTcf-4 gene with clinicopathological characteristics of HCC was also analyzed.
RESULTS: RT-PCR showed that the expression rate of hTcf-4 mRNA in HCC, para-cancerous tissues and normal liver tissues was 90.6%, 71.9% and 80%, respectively. The gene expression level in tumor was 0.71 ± 0.13, much higher than that in para-cancerous liver 0.29 ± 005 and normal liver 0.26 ± 0.05 (P < 0.001), although there was no significant difference in gene expression level between para-cancerous tissues and normal liver (P > 0.05). Furthermore, hTcf-4 gene expression was closely associated with tumor capsule status and intrahepatic metastasis of HCC. On SSCP, 2 of 32 cases of HCC (6.25%) displayed characteristic mutational mobility shifts in exon 15 of the hTcf-4 gene. No abnormal shifting bands were observed in para-cancerous tissues.
CONCLUSION: The high expression level of hTcf-4 in HCC, especially in tumors with metastasis, suggests that the over-expression of hTcf-4 gene may be closely associated with development and progression of HCC, but the mutation of this gene seemed to play less important role in this respect.
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Affiliation(s)
- Ying Jiang
- Liver Cancer Institute, Zhong Shan Hospital, Fudan University, Shanghai 200032, China
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Czopek J, Bialas M, Rudzki Z, Zazula M, Pituch-Noworolska A, Zembala M, Popiela T, Kulig J, Kolodziejczyk P, Stachura J. The relationship between gastric cancer cells circulating in the blood and microsatellite instability positive gastric carcinomas. Aliment Pharmacol Ther 2002; 16 Suppl 2:128-36. [PMID: 11966533 DOI: 10.1046/j.1365-2036.16.s2.5.x] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND Cancers characterized by microsatellite instability may be biologically different from their counterparts with stable microsatellite sequences. Circulating cancers cell present in blood prior to surgery may constitute an adverse prognostic finding. AIM To correlate these two phenomena with morphological features and survival in advanced gastric cancer. METHODS We examined 76 cases of resected sporadic, advanced gastric cancer by means of routine morphology and a panel of microsatellite markers. Sixty-six cases were screened for presence of cancer cells circulating in blood prior to the surgery using combined morphological and immunocytochemical approach. RESULTS Twenty-one (27.6%) cases demonstrated microsatellite instability in at least one locus. Among them 11 (14.5%) showed microsatellite instability in more than 30% (4/12) examined loci, and they were therefore designated as replication error positive (RER+). Circulating cancer cells were detected in 2/19 microsatellite instability and in 11/47 remaining cases (difference not significant). The survival of the microsatellite instability cases was significantly better. The presence of circulating cancer cells did not correlate with survival. CONCLUSION It is possible that the microsatellite instability status, but not circulating cancer cells, constitutes a prognostic predictive factor in advanced gastric carcinoma. Confirmation of this hypothesis requires continuation of patient follow-up.
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Affiliation(s)
- J Czopek
- Department of Pathology, Jagiellonian University Medical College, Kraków, Poland
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Abstract
CtBP family proteins are conserved among vertebrates and invertebrates and function as transcriptional corepressors. They repress transcription in a histone deacetylase-dependent or -independent manner. CtBPs play important roles during development and oncogenesis. In this review, their unusual properties, the mechanisms of transcriptional repression, regulation, and their biological functions are discussed.
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Affiliation(s)
- G Chinnadurai
- Institute for Molecular Virology, Saint Louis University School of Medicine, 3681 Park Avenue, St. Louis, MO 63110, USA.
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