-
Advances in Experimental Medicine and... 2009Mutational inactivation of the tumor suppressor gene APC (Adenomatous polyposis coli) is thought to be an initiating step in the progression of the vast majority... (Review)
Review
Mutational inactivation of the tumor suppressor gene APC (Adenomatous polyposis coli) is thought to be an initiating step in the progression of the vast majority ofcolorectal cancers. Attempts to understand APC function have revealed more than a dozen binding partners as well as several subcellular localizations including at cell-cell junctions, associated with microtubules at the leading edge of migrating cells, at the apical membrane, in the cytoplasm and in the nucleus. The present chapter focuses on APC localization and functions in the nucleus. APC contains two classical nuclear localization signals, with a third domain that can enhance nuclear import. Along with two sets of nuclear export signals, the nuclear localization signals enable the large APC protein to shuttle between the nucleus and cytoplasm. Nuclear APC can oppose beta-catenin-mediated transcription. This down-regulation of nuclear beta-catenin activity by APC most likely involves nuclear sequestration of beta-catenin from the transcription complex as well as interaction of APC with transcription corepressor CtBP. Additional nuclear binding partners for APC include transcription factor activator protein AP-2alpha, nuclear export factor Crm1, protein tyrosine phosphatase PTP-BL and perhaps DNA itself. Interaction of APC with polymerase beta and PCNA, suggests a role for APC in DNA repair. The observation that increases in the cytoplasmic distribution of APC correlate with colon cancer progression suggests that disruption of these nuclear functions of APC plays an important role in cancer progression. APC prevalence in the cytoplasm of quiescent cells points to a potential function for nuclear APC in control of cell proliferation. Clear definition of APC's nuclear function(s) will expand the possibilities for early colorectal cancer diagnostics and therapeutics targeted to APC.
Topics: Active Transport, Cell Nucleus; Adenomatous Polyposis Coli Protein; Animals; Cell Nucleus; Colorectal Neoplasms; Cytoplasm; Genes, APC; Humans; Nuclear Export Signals; Nuclear Proteins; Phosphorylation; beta Catenin
PubMed: 19928349
DOI: 10.1007/978-1-4419-1145-2_2 -
European Journal of Cell Biology 2022Adenomatous Polyposis Coli (APC) protein is mostly known as a tumor suppressor that regulates Wnt signaling, but is also an important cytoskeletal protein. Mutations in... (Review)
Review
Adenomatous Polyposis Coli (APC) protein is mostly known as a tumor suppressor that regulates Wnt signaling, but is also an important cytoskeletal protein. Mutations in the APC gene are linked to colorectal cancer and various neurological disorders and intellectual disabilities. Cytoskeletal functions of APC appear to have significant contributions to both types of these disorders. As a cytoskeletal protein, APC can regulate both actin and microtubule cytoskeletons, which together form the main machinery for cell migration. As APC is a multifunctional protein with numerous interaction partners, the complete picture of how APC regulates cell motility is still unavailable. However, some molecular mechanisms begin to emerge. Here, we review available information about roles of APC in cell migration and propose a model explaining how microtubules, using APC as an intermediate, can initiate leading edge protrusion in response to external signals by stimulating Arp2/3 complex-dependent nucleation of branched actin filament networks via a series of intermediate events.
Topics: Actins; Adenomatous Polyposis Coli Protein; Cell Movement; Genes, APC; Humans; Microtubules
PubMed: 35483122
DOI: 10.1016/j.ejcb.2022.151228 -
Digestive Diseases and Sciences Jul 2023The most prevalent type of intestinal polyposis, colorectal adenomatous polyposis (CAP), is regarded as a precancerous lesion of colorectal cancer with obvious genetic... (Review)
Review
The most prevalent type of intestinal polyposis, colorectal adenomatous polyposis (CAP), is regarded as a precancerous lesion of colorectal cancer with obvious genetic characteristics. Early screening and intervention can significantly improve patients' survival and prognosis. The adenomatous polyposis coli (APC) mutation is believed to be the primary cause of CAP. There is, however, a subset of CAP with undetectable pathogenic mutations in APC, known as APC (-)/CAP. The genetic predisposition to APC (-)/CAP has largely been associated with germline mutations in some susceptible genes, including the human mutY homologue (MUTYH) gene and the Nth-like DNA glycosylase 1 (NTHL1) gene, and DNA mismatch repair (MMR) can cause autosomal recessive APC (-)/CAP. Furthermore, autosomal dominant APC (-)/CAP could occur as a result of DNA polymerase epsilon (POLE)/DNA polymerase delta 1 (POLD1), axis inhibition protein 2 (AXIN2), and dual oxidase 2 (DUOX2) mutations. The clinical phenotypes of these pathogenic mutations vary greatly depending on their genetic characteristics. Therefore, in this study, we present a comprehensive review of the association between autosomal recessive and dominant APC (-)/CAP genotypes and clinical phenotypes and conclude that APC (-)/CAP is a disease caused by multiple genes with different phenotypes and interaction exists in the pathogenic genes.
Topics: Humans; Adenomatous Polyposis Coli; Mutation; Genetic Association Studies; Genetic Predisposition to Disease; Genotype; Germ-Line Mutation; Phenotype; Genes, APC
PubMed: 36862359
DOI: 10.1007/s10620-023-07890-9 -
Best Practice & Research. Clinical... 2009A multimodal approach of complementary techniques targeting primarily truncating, deletion and rearrangement mutations provides a robust screening protocol that... (Review)
Review
A multimodal approach of complementary techniques targeting primarily truncating, deletion and rearrangement mutations provides a robust screening protocol that identifies the vast majority of pathogenic germline APC gene mutations in FAP patients. Patients in whom no mutation is identified through this mutation protocol, may be sub-cohorts representing a different FAP pathogenesis including MYH associated polyposis and somatic cell mosaicism for APC gene mutations.
Topics: Adenomatous Polyposis Coli; DNA Glycosylases; DNA Mutational Analysis; Gene Expression Regulation, Neoplastic; Genes, APC; Genetic Predisposition to Disease; Genetic Testing; Human Genome Project; Humans; Mosaicism; Mutation; Predictive Value of Tests
PubMed: 19414146
DOI: 10.1016/j.bpg.2009.02.010 -
PloS One 2022Adenomatous polyposis coli (APC) is the most commonly mutated gene in colon cancer and can cause familial adenomatous polyposis (FAP). Hypermethylation of the APC...
Adenomatous polyposis coli (APC) is the most commonly mutated gene in colon cancer and can cause familial adenomatous polyposis (FAP). Hypermethylation of the APC promoter can also promote the development of breast cancer, indicating that APC is not limited to association with colorectal neoplasms. However, no pan-cancer analysis has been conducted. We studied the location and structure of APC and the expression and potential role of APC in a variety of tumors by using The Cancer Genome Atlas and Gene Expression Omnibus databases and online bioinformatics analysis tools. The APC is located at 5q22.2, and its protein structure is conserved among H. sapiens, M. musculus with C. elaphus hippelaphus. The APC identity similarity between homo sapiens and mus musculus reaches 90.1%. Moreover, APC is highly specifically expressed in brain tissues and bipolar cells but has low expression in most cancers. APC is mainly expressed on the cell membrane and is not detected in plasma by mass spectrometry. APC is low expressed in most tumor tissues, and there is a significant correlation between the expressed level of APC and the main pathological stages as well as the survival and prognosis of tumor patients. In most tumors, APC gene has mutation and methylation and an enhanced phosphorylation level of some phosphorylation sites, such as T1438 and S2260. The expressed level of APC is also involved in the level of CD8+ T-cell infiltration, Tregs infiltration, and cancer-associated fibroblast infiltration. We conducted a gene correlation study, but the findings seemed to contradict the previous analysis results of the low expression of the APC gene in most cancers. Our research provides a comparative wholesale understanding of the carcinogenic effects of APC in various cancers, which will help anti-cancer research.
Topics: Adenomatous Polyposis Coli; Adenomatous Polyposis Coli Protein; Animals; DNA Methylation; Genes, APC; Humans; Mice; Promoter Regions, Genetic
PubMed: 35303016
DOI: 10.1371/journal.pone.0265655 -
Advances in Experimental Medicine and... 2009Colon cancer closely follows the paradigm of a single "gatekeeper gene." Mutations inactivating the APC (adenomatous polyposis coli) gene are found in approximately 80%... (Review)
Review
Colon cancer closely follows the paradigm of a single "gatekeeper gene." Mutations inactivating the APC (adenomatous polyposis coli) gene are found in approximately 80% of all human colon tumors and heterozygosity for such mutations produces an autosomal dominant colon cancer predisposition in humans and in murine models. However, this tight association between a single genotype and phenotype belies a complex association of genetic and epigenetic factors that together generate the broad phenotypic spectrum ofboth familial and sporadic colon cancers. In this Chapter, we give a general overview of the structure, function and outstanding issues concerning the role of Apc in human and experimental colon cancer. The availability of increasingly close models for human colon cancer in genetically tractable animal species enables the discovery and eventual molecular identification of genetic modifiers of the Apc-mutant phenotypes, connecting the central role of Apc in colon carcinogenesis to the myriad factors that ultimately determine the course of the disease.
Topics: Adenomatous Polyposis Coli; Adenomatous Polyposis Coli Protein; Animals; Colorectal Neoplasms; Genes, APC; Humans; Mutation
PubMed: 19928355
DOI: 10.1007/978-1-4419-1145-2_8 -
Medicine Apr 2020The methylation status of the adenomatous polyposis coli (APC) promoter has been shown to be associated with the occurrence of gastric cancer, but this finding remains... (Meta-Analysis)
Meta-Analysis
BACKGROUND
The methylation status of the adenomatous polyposis coli (APC) promoter has been shown to be associated with the occurrence of gastric cancer, but this finding remains controversial. The aim of this study was to investigate the relationship between methylation of the APC gene promoter and gastric cancer.
METHODS
We searched the Web of Science, EMBASE, Medline, and Cochrane Central Register of Controlled Trials (CENTRAL) databases from the date of creation until August 1, 2019. According to the inclusion criteria, the relationship between the methylation status of the APC gene promoter and gastric cancer was investigated. The incidence of APC promoter methylation in the tissues or blood of patients with and without gastric cancer was compared. The results are expressed as the odds ratio (OR) and 95% confidence interval (CI). The pooled OR of each study was estimated using a fixed effects model or a random effects model to generate forest plots. We further validated the results using the MethHC database.
RESULTS
Eight studies (985 samples) were included. Our meta-analysis showed that the incidence of APC promoter methylation in patients with gastric cancer was higher than that of patients without gastric cancer (OR = 3.86, 95% CI 1.71-8.74, P = .001). Methylation of the APC promoter is associated with the incidence of gastric cancer, and it increases the risk of gastric cancer.
CONCLUSION
This study provides a new strategic direction for research on gastric cancer. Methylation of the APC promoter may be a potential biomarker for the diagnosis of gastric cancer, but the results of this work require further confirmation.
Topics: Adenomatous Polyposis Coli; Biomarkers, Tumor; Computational Biology; DNA Methylation; Genes, APC; Genetic Predisposition to Disease; Humans; Incidence; Promoter Regions, Genetic; Risk Factors; Stomach Neoplasms
PubMed: 32312003
DOI: 10.1097/MD.0000000000019828 -
Bioscience Reports Mar 2020To study the correlation between adenomatous polyposis coli (APC) gene 3' untranslated region (UTR) single nucleotide polymorphisms (SNPs) and their interactions with...
OBJECTIVE
To study the correlation between adenomatous polyposis coli (APC) gene 3' untranslated region (UTR) single nucleotide polymorphisms (SNPs) and their interactions with environmental factors and the risk of colorectal cancer (CRC) in a Chinese Han population.
METHODS
Genotypes of APC gene 3'UTR rs1804197, rs41116, rs448475, and rs397768 loci in 340 Chinese Han patients with CRC and 340 healthy controls were analyzed. All patients with CRC were analyzed for progression-free survival (PFS) during a 3-year follow-up.
RESULTS
The risk of CRC in subjects carrying the APC gene rs1804197 A allele was 2.95-times higher than for the C allele carriers. The interactions of the rs1804197 SNP with body mass index (BMI) and smoking were associated with the risk of CRC. The risk of CRC in the APC gene rs397768 G allele carriers was 1.68-times higher than in the A allele carriers. The interaction between the rs397768 locus SNP and gender was also associated with the risk of CRC. The 3-year PFS of patients with APC gene rs1804197 AA genotype, CA genotype, and CC genotype CRC decreased in this order, with significant difference. In addition, the 3-year PFS of rs397768 locus GG genotype, AG genotype, and AA genotype CRC patients decreased in this order, and the difference was significant.
CONCLUSION
The rs1804197 locus in the 3'UTR region of the APC gene and its interactions with BMI and smoking are associated with the risk of CRC in a Chinese Han population. In addition, the interaction between rs397768 locus SNP and gender is related to the risk of CRC.
Topics: 3' Untranslated Regions; Adenomatous Polyposis Coli; Adult; Aged; Alleles; Asian People; Case-Control Studies; China; Colorectal Neoplasms; Epistasis, Genetic; Ethnicity; Female; Gene Frequency; Gene-Environment Interaction; Genes, APC; Genetic Predisposition to Disease; Genotype; Heterozygote; Humans; Male; Middle Aged; Polymorphism, Single Nucleotide; Risk Factors
PubMed: 32159210
DOI: 10.1042/BSR20192429 -
Journal of Visceral Surgery Apr 2020Nearly 5% of colorectal cancers are hereditary colorectal cancers, including adenomatous polyposis. The aim of this review was to highlight the current management of... (Review)
Review
Nearly 5% of colorectal cancers are hereditary colorectal cancers, including adenomatous polyposis. The aim of this review was to highlight the current management of adenomatous polyposis. The two main genetic conditions responsible for adenomatous polyposis are familial adenomatous polyposis (FAP) (caused by an autosomal dominant mutation of the APC gene) and MUTYH-associated polyposis (MAP) (caused by bi-allelic recessive mutations of the MUTYH (MutY human homolog) gene). FAP is characterized by the presence of >1000 polyps and a young age at diagnosis (mean age of 10). In the absence of screening, the risk of colorectal cancer at age 40 is 100%. It is recommended to start screening at the age of 10-12 years. For patients with FAP and MAP, it is also recommended to screen the upper gastrointestinal tract (stomach and duodenum). In FAP, prophylactic surgery aims to reduce the risk of death without impairment of patient quality of life. The best age for prophylactic surgery is not well-defined; in Europe, prophylactic surgery is usually performed at age 20 as the risk of cancer increases sharply during the third decade. There are three main surgical procedures employed: total colectomy with an ileorectal anastomosis, restorative coloproctectomy with a J pouch anastomosis and coloproctectomy with a stoma. Restorative coloproctectomy with J pouch anastomosis is the reference procedure; however, disease can vary in severity from one patient to another and this must be taken into account to decide which procedure should be performed. In conclusion, the management of adenomatous polyposis is complex but is well-defined by guidelines, particularly in France.
Topics: Adenomatous Polyposis Coli; Age Factors; Anastomosis, Surgical; Colectomy; DNA Glycosylases; Endoscopy, Gastrointestinal; Genes, APC; Genetic Markers; Humans; Laparoscopy; Mutation; Quality of Life
PubMed: 32113818
DOI: 10.1016/j.jviscsurg.2019.12.003 -
Modern Pathology : An Official Journal... Apr 2022Osteoma is a benign bone forming tumor predominantly arising on the surface of craniofacial bones. While the vast majority of osteomas develops sporadically, a small...
Osteoma is a benign bone forming tumor predominantly arising on the surface of craniofacial bones. While the vast majority of osteomas develops sporadically, a small subset of cases is associated with Gardner syndrome, a phenotypic variant of familial adenomatous polyposis caused by mutations in the APC gene resulting in aberrant activation of WNT/β-catenin signaling. In a sequencing analysis on a cohort of sporadic, non-syndromal osteomas, we identified hotspot mutations in the CTNNB1 gene (encoding β-catenin) in 22 of 36 cases (61.1%), harbouring allelic frequencies ranging from 0.04 to 0.53, with the known S45P variant representing the most frequent alteration. Based on NanoString multiplex expression profiling performed in a subset of cases, CTNNB1-mutated osteomas segregated in a defined "WNT-cluster", substantiating functionality of CTNNB1 mutations which are associated with β-catenin stabilization. Our findings for the first time convincingly show that osteomas represent genetically-driven neoplasms and provide evidence that aberrant WNT/β-catenin signaling plays a fundamental role in their pathogenesis, in line with the well-known function of WNT/β-catenin in osteogenesis. Our study contributes to a better understanding of the molecular pathogenesis underlying osteoma development and establishes a helpful diagnostic molecular marker for morphologically challenging cases.
Topics: Adenomatous Polyposis Coli Protein; Genes, APC; Humans; Mutation; Osteoma; beta Catenin
PubMed: 34725446
DOI: 10.1038/s41379-021-00956-x