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Oncogene Jul 2015Disruption of Apc (adenomatous polyposis coli) within hepatocytes activates Wnt signalling, perturbs differentiation and ultimately leads to neoplasia. Apc negatively...
Disruption of Apc (adenomatous polyposis coli) within hepatocytes activates Wnt signalling, perturbs differentiation and ultimately leads to neoplasia. Apc negatively regulates Wnt signalling but is also involved in organizing the cytoskeleton and may have a role in chromosome segregation. In vitro studies have implicated Apc in the control of genomic stability. However, the relevance of this data has been questioned in vivo as Apc is lost earlier than the onset of genomic instability. Here we analyse the relationship between immediate loss of Apc and the acquisition of genomic instability in hepatocytes. We used Cre-lox technology to inactivate Apc and in combination with p53 in vivo, to define the consequences of gene loss on cell cycle regulation, proliferation, death and aneuploidy. We show that, although Apc loss leads to increased proliferation, it also leads to increased apoptosis, the accumulation of p53, p21 and markers of double-strand breaks and DNA repair. Flow cytometry revealed an increased 4N DNA content, consistent with a G2 arrest. Levels of anaphase bridges were also elevated, implicating failed chromosome segregation. This was accompanied by an increase in centrosome number, which demonstrates a role for Apc in maintaining euploidy. To address the role of p53 in these processes, we analysed combined loss of Apc and p53, which led to a further increase in proliferation, cell death, DNA damages and repair and a bypass of G2 arrest than was observed with Apc loss. However, we observed only a marginal effect on anaphase bridges and centrosome number, which could be due to increased cell death. Our data therefore establishes, in an in vivo setting, that APC loss leads to a DNA damage signature and genomic instability in the liver and that additional loss of p53 leads to an increase in the DNA damage signal but not to an immediate increase in the genomic instability phenotype.
Topics: Animals; Cell Proliferation; Cells, Cultured; DNA Damage; DNA Repair; Epistasis, Genetic; Female; Genes, APC; Genes, p53; Genomic Instability; Hepatocytes; Hepatomegaly; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; beta-Naphthoflavone
PubMed: 25347740
DOI: 10.1038/onc.2014.342 -
The American Journal of Pathology Aug 2002Gastric cancer is common among the world, but genetic mechanisms of gastric carcinogenesis are not well understood. Gastric polypoid adenomas and flat dysplasias are...
Gastric cancer is common among the world, but genetic mechanisms of gastric carcinogenesis are not well understood. Gastric polypoid adenomas and flat dysplasias are regarded as precursor lesions. However, a detailed molecular study of these lesions has not been done to determine their role as precancerous lesions. We investigated mutations of the APC, beta-catenin, and K-ras genes, and microsatellite instability (MSI) status in 35 adenomas and 47 flat dysplasias without adenocarcinoma, 35 adenomas/dysplasias associated with adenocarcinomas, and 39 adenocarcinomas (20 diffuse type and 19 intestinal type). Somatic APC gene mutations were identified in 76% (59 of 78) of adenomas or flat dysplasias without associated adenocarcinoma, but in only 3% (1 of 30) of adenomas/dysplasias associated with adenocarcinoma, and in only 4% (3 of 69) of adenocarcinomas (P < 0.000001). No mutations of beta-catenin were found in adenocarcinomas, or adenomas/dysplasia without APC mutation. K-ras mutations were detected in 5% (4 of 82) of gastric adenomas/dysplasia without carcinoma, 3% (1 of 39) of adenocarcinomas without associated adenoma/dysplasia, and not in 32 adenocarcinomas with associated adenoma/dysplasia. High level of MSI (MSI-H) was more frequent in gastric adenoma/dysplasia associated with carcinoma (17%, 6 of 35) than in adenomas/dysplasia without carcinoma (3%, 2 of 75; P = 0.01). MSI-H was also more frequent in intestinal type adenocarcinoma (20%, 11 of 54) than in diffuse type (0%, 0 of 20; P = 0.03). APC gene mutations were present in six of nine (67%) of gastric adenomas/dysplasias with low level of MSI, but in none of the eight adenomas/dysplasia with MSI-H phenotype (P = 0.009). Our results indicate that somatic mutation of the APC gene plays an important role in the pathogenesis of gastric adenoma and dysplasia but has a limited role in neoplastic progression to adenocarcinoma. Gastric adenomas or dysplasias without APC mutations but with or without MSI may have a different biological behavior, and are precursors of intestinal-type of gastric adenocarcinomas.
Topics: Adenocarcinoma; Adenoma; Adult; Aged; Cytoskeletal Proteins; Female; Genes, APC; Genes, ras; Humans; Male; Microsatellite Repeats; Middle Aged; Mutation; Stomach Neoplasms; Trans-Activators; beta Catenin
PubMed: 12163385
DOI: 10.1016/S0002-9440(10)64216-2 -
Biochimica Et Biophysica Acta Feb 2000The wnt signal transduction pathway is involved in many differentiation events during embryonic development and can lead to tumor formation after aberrant activation of... (Review)
Review
The wnt signal transduction pathway is involved in many differentiation events during embryonic development and can lead to tumor formation after aberrant activation of its components. The cytoplasmic component beta-catenin is central to the transmission of wnt signals to the nucleus: in the absence of wnts beta-catenin is constitutively degraded in proteasomes, whereas in the presence of wnts beta-catenin is stabilized and associates with HMG box transcription factors of the LEF/TCF family. In tumors, beta-catenin degradation is blocked by mutations of the tumor suppressor gene APC (adenomatous polyposis coli), or of beta-catenin itself. As a consequence, constitutive TCF/beta-catenin complexes are formed and activate oncogenic target genes. This review discusses the mechanisms that silence the pathway in cells that do not receive a wnt signal and goes on to describe the regulatory steps involved in the activation of the pathway.
Topics: Adaptor Proteins, Signal Transducing; Animals; Arabidopsis Proteins; Axin Protein; Cytoskeletal Proteins; Dishevelled Proteins; Genes, APC; Humans; Mice; Mice, Mutant Strains; Phosphoproteins; Protein Kinases; Proteins; Proto-Oncogene Proteins; Repressor Proteins; Signal Transduction; Trans-Activators; Transcriptional Activation; Tumor Cells, Cultured; Wnt Proteins; Zebrafish Proteins; beta Catenin
PubMed: 10656974
DOI: 10.1016/s0167-4889(99)00158-5 -
Pharmacology & Therapeutics Dec 2015The genetic and epigenetic alterations occurring during the course of multistage colorectal carcinogenesis have been extensively studied in the last few decades. One of... (Review)
Review
The genetic and epigenetic alterations occurring during the course of multistage colorectal carcinogenesis have been extensively studied in the last few decades. One of the most notable findings is that the great majority of colorectal cancers (>80%) have mutations in the adenomatous polyposis coli (APC) tumor suppressor gene. Loss of functional APC protein results in activation of canonical Wnt/β-catanin signaling and initiates intestinal carcinogenesis. Mutational inactivation of APC is the first genetic event, but colorectal cancer cells retain their dependency on constitutive Wnt signal activation even after accumulation of other genetic events. Accordingly, pharmacological blocking of Wnt signaling has been considered an attractive therapeutic approach for colorectal cancer. Several therapeutics targeting various molecular components of the Wnt signaling pathway, including porcupine, frizzled receptors and co-receptor, tankyrases, and cAMP response element binding protein (CREB)-binding protein (CBP), have been developed, and some of those are currently being evaluated in early-phase clinical trials. Traf2- and Nck-interacting protein kinase (TNIK) has been identified as a regulatory component of the T-cell factor-4 and β-catenin transcriptional complex independently by two research groups. TNIK regulates Wnt signaling in the most downstream part of the pathway, and its inhibition is expected to block the signal even in colorectal cancer cells with APC gene mutation. Here we discuss some of the TNIK inhibitors under preclinical development.
Topics: ATP-Binding Cassette Transporters; Colorectal Neoplasms; Genes, APC; Humans; Intracellular Signaling Peptides and Proteins; Protein Serine-Threonine Kinases; TNF Receptor-Associated Factor 2; Wnt Proteins; Wnt Signaling Pathway; beta Catenin
PubMed: 26542362
DOI: 10.1016/j.pharmthera.2015.10.009 -
Molecular Vision Jun 2004Hypertrophy and hyperplasia of the retinal pigment epithelium (RPE) is associated with an inherited predisposition to human familial adenomatous polyposis coli,...
PURPOSE
Hypertrophy and hyperplasia of the retinal pigment epithelium (RPE) is associated with an inherited predisposition to human familial adenomatous polyposis coli, suggesting that expression of the adenomatous polyposis coli (APC) tumor suppressor may regulate RPE proliferation/differentiation. Distinctive APC isoforms exist in different cell types due to alternative splicing of the APC transcripts. We hypothesize that differences in expression patterns of APC protein isoforms are critical to RPE proliferation/differentiation.
METHODS
To investigate these relationships, APC gene expression was characterized in the retinas and RPE from fetal and adult human and mouse, and in the epiretinal membranes (ERM) from 5 patients with proliferative vitreoretinopathy (PVR). Expression patterns of alternative splice-forms of APC transcripts were evaluated by comparative quantitative RT-PCR. Exon 1 of APC encodes a heptad repeat that confers the ability of APC to homodimerize. APC protein isoforms containing or lacking this heptad were characterized by western blot analysis and immunohistochemistry.
RESULTS
Comparative quantitative RT-PCR demonstrated a predominant exon 1 containing, conventional APC splice-form in the early developing fetal RPE and retina, and in all the tested ERM samples from patients with PVR. This method also demonstrated an increased level of exon 1 lacking APC splice-form in the mature RPE and retina. Western blot analysis and immunofluorescence microscopy demonstrated the conventional APC only in the RPE, and the APC isoform without the first heptad repeat in both the retina and RPE. Immunofluorescence microscopy also demonstrated only the conventional APC in the ERM samples tested.
CONCLUSIONS
These results suggest that alternative splicing of APC leads to differential APC expression with potentially unique functions. APC isoform without the first heptad repeat may play a role in cell cycle cessation in the adult retina and RPE, and the down regulation of this APC isoform may contribute to the potential of RPE to migrate and proliferate.
Topics: Adenomatous Polyposis Coli Protein; Aged; Aged, 80 and over; Alternative Splicing; Animals; Blotting, Western; Cell Division; Cell Movement; Down-Regulation; Epiretinal Membrane; Female; Gene Expression Regulation; Genes, APC; Humans; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Microscopy, Fluorescence; Middle Aged; Pigment Epithelium of Eye; Protein Isoforms; Retina; Reverse Transcriptase Polymerase Chain Reaction
PubMed: 15218453
DOI: No ID Found -
The Journal of International Medical... Aug 2022Primitive neuroectodermal tumor (PNET) of the lung is rare in adults, and treatment options vary. We herein describe the disease course and follow-up of PNET in an... (Review)
Review
Primitive neuroectodermal tumor (PNET) of the lung is rare in adults, and treatment options vary. We herein describe the disease course and follow-up of PNET in an adult. A 27-year-old man was admitted to our hospital because of cough and headache, and whole-exome sequencing revealed positive expression of the fusion gene and amplification of the gene. Although the patient received multidisciplinary treatment including chemotherapy regimens of etoposide plus cisplatin; focal radiotherapy focusing on the cerebrum, lung, and kidneys; and a subsequent palliative gastrointestinal operation, he eventually died of multiple organ functional failure. His overall survival period was 18 months, and his progression-free survival period was 4 months. During the treatment, the patient showed remarkable sensitivity to radiotherapy. In conclusion, PNET of the lung in adult patients is extremely rare, and the prognosis is very poor. Involvement of a multidisciplinary team in the development of personalized therapeutic strategies is essential. This patient with gene amplification showed excellent sensitivity to radiotherapy for intrapulmonary and intracranial lesions, suggesting that gene amplification may be related to radiotherapy sensitivity. However, further clinical research is needed.
Topics: Adult; Disease Progression; Gene Amplification; Genes, APC; Humans; Male; Neuroectodermal Tumors, Primitive; Prognosis
PubMed: 35983861
DOI: 10.1177/03000605221118704 -
Cancer Research Jul 2008The Adenomatous polyposis coli (Apc) gene is mutated in up to 80% of sporadic colorectal cancers. After Apc loss, there is deregulation of the Wnt signaling pathway and... (Review)
Review
The Adenomatous polyposis coli (Apc) gene is mutated in up to 80% of sporadic colorectal cancers. After Apc loss, there is deregulation of the Wnt signaling pathway and transactivation of T-cell factor/leukemia enhancing factor target genes such as C-Myc. This review focuses on recent data highlighting the importance of the C-Myc oncogene and its transcriptional targets in establishing all of the phenotypes caused by the deletion of the Apc tumor suppressor gene within the intestinal epithelium. The importance of investigating Apc and C-Myc gene function in the correct tissue context is also discussed.
Topics: Adenomatous Polyposis Coli Protein; Animals; Cell Proliferation; Cell Transformation, Neoplastic; Genes, APC; Humans; Intestinal Mucosa; Loss of Heterozygosity; Models, Biological; Phenotype; Precancerous Conditions; Proto-Oncogene Proteins c-myc
PubMed: 18593890
DOI: 10.1158/0008-5472.CAN-07-5558 -
Molecular Medicine Reports Jan 2018Although persistent infections with high‑risk human papilloma virus (HPV) constitute the most significant cofactor for the development of cervical cancer, they are...
Although persistent infections with high‑risk human papilloma virus (HPV) constitute the most significant cofactor for the development of cervical cancer, they are insufficient on their own. Mutations or epigenetic inactivation of the tumor suppressor adenomatous polyposis coli (APC), the two acting as prominent oncogenic mechanisms in a number of types of cancer, are frequently associated with aberrant activation of the Wnt/β‑catenin pathway. According to these observations, it was hypothesized that APC alteration may lead to β‑catenin deregulation and the abnormal expression of direct targets of the Wnt pathway in HPV‑infected cervical cancer cells. The present study confirmed that the stabilization of β‑catenin correlates with enhanced transcriptional activity of the β‑catenin/T‑cell factor complex in cervical cancer cell lines. Sequence analysis of the 'hot‑spot' in the mutation cluster region did not exhibit genetic alterations that may be associated with APC gene inactivation. In addition, it was identified that there was a good correlation with the hypermethylation status of the APC promoter 1A and the abnormal accumulation of endogenous β‑catenin in cell lines and biopsies infected with HPV16, although not HPV18. Removal of the epigenetic markers led to an increase in APC levels and a reduction of β‑catenin expression in two transcriptional targets of the Wnt pathway: Matrix metalloproteinase‑7 and vascular endothelial growth factor. The present study suggested that the increase in Wnt activity in certain cervical cancer‑derived cells may be associated with an alteration in the methylation status of the APC gene promoter 1A.
Topics: Biopsy; Cell Line, Tumor; DNA Methylation; DNA Mutational Analysis; Female; Gene Expression; Gene Expression Regulation, Neoplastic; Gene Silencing; Genes, APC; Genes, Reporter; Humans; Mutation; Papillomavirus Infections; Promoter Regions, Genetic; Transcription, Genetic; Uterine Cervical Neoplasms; Wnt Signaling Pathway; beta Catenin
PubMed: 29115417
DOI: 10.3892/mmr.2017.7853 -
European Journal of Gastroenterology &... Mar 2014Familial adenomatous polyposis is characterized by the development of multiple (>100) colorectal adenomas throughout the colorectum. This disorder can be caused by a... (Review)
Review
Familial adenomatous polyposis is characterized by the development of multiple (>100) colorectal adenomas throughout the colorectum. This disorder can be caused by a germline mutation in the adenomatous polyposis coli gene and can be diagnosed either clinically or genetically. After diagnosis with the condition, patients should undergo prophylactic proctocolectomy with a neoreservoir, usually an ileoanal pouch, at an appropriate time. Individuals with a family history of this disease who have not been diagnosed should be advised to attend genetic counseling and to enroll in appropriate clinical and genetic surveillance programs. Recent progress in endoscopic technology, including high-resolution endoscopy, capsule endoscopy, and double-balloon endoscopy, has made possible more detailed and wide-ranging investigation of the gastrointestinal tract. Although there has been limited evidence, further studies on these new endoscopic technologies might alter the surveillance strategies for familial adenomatous polyposis.
Topics: Adenomatous Polyposis Coli; Anticarcinogenic Agents; Capsule Endoscopy; Genes, APC; Genetic Testing; Germ-Line Mutation; Humans; Mutation; Population Surveillance; Proctocolectomy, Restorative
PubMed: 24161962
DOI: 10.1097/MEG.0000000000000010 -
Thoracic Cancer Nov 2021The aim of this study was to quantitatively analysis the diagnostic performance of adenomatous polyposis coli (APC) gene promoter methylation in serum or... (Meta-Analysis)
Meta-Analysis
BACKGROUND
The aim of this study was to quantitatively analysis the diagnostic performance of adenomatous polyposis coli (APC) gene promoter methylation in serum or sputum/bronchoalveolar lavage fluid (BLAF) as a biomarker for lung cancer identification through pooling of open published data.
METHODS
The relevant electronic MEDLINE, EMBASE, Ovid, web of science and CNKI databases were systematically searched to identify the studies related to APC gene promoter methylation for lung cancer diagnosis. Data of true positive (tp), false positive (fp), false negative (fn) and true negative (tn) were extracted from the publications included in the study. The pooled diagnostic sensitivity, specificity and area under summary receiver operating characteristic (SROC) curve (AUC-SROC) of APC gene promoter methylation were calculated. Publication bias was evaluated by Begg's funnel plot and Egger's line regression test.
RESULTS
Fourteen studies associated with APC gene promoter methylation and lung cancer were identified in the databases and finally included in the meta-analysis. The data was pooled using a random effect model due to significant statistical heterogeneity across the 14 studies (p < 0.05). Using the APC gene promoter methylation as a reference for lung cancer identification, the pooled diagnostic sensitivity and specificity were 0.43 (95% CI: 0.40-0.45), and 0.92 (95% CI: 0.90-0.95), respectively with combined diagnostic positive likelihood ratio (+LR) and negative likelihood ratio (-LR) of 7.15 (95% CI: 3.62-14.12) and 0.63 (95% CI: 0.57-0.71). The pooled diagnostic odds ratio (DOR) and AUC-SROC of APC gene promoter methylation for lung cancer diagnosis were 9.84 (95% CI: 5.77-16.79) and 0.7, respectively. The Begg's funnel plot and Egger's line regression test both indicated statistical publication bias (t = 5.40, p < 0.05).
CONCLUSIONS
APC gene promoter methylation in serum or sputum/BLAF is a potential biomarker for lung cancer diagnosis with high specificity. However, due to its low sensitivity, it may not be suitable for lung cancer screening in the general population.
Topics: Biomarkers, Tumor; Bronchoalveolar Lavage Fluid; DNA Methylation; Early Detection of Cancer; Genes, APC; Humans; Lung Neoplasms; Sputum
PubMed: 34545707
DOI: 10.1111/1759-7714.14151