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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 -
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 -
BMC Cancer Oct 2018Several genetic and epigenetic alterations are related to the development and progression of Gastric Cancer (GC), one of those being the deregulated microRNA (miRNA)...
BACKGROUND
Several genetic and epigenetic alterations are related to the development and progression of Gastric Cancer (GC), one of those being the deregulated microRNA (miRNA) expression profile. miRNAs are small noncoding RNAs that negatively regulate the expression of thousands of genes, including oncogenes and tumor suppressor genes. Our group identified, in previous studies, some miRNAs that are differentially expressed in GC when compared to the gastric mucosa without cancer, including hsa-miR-29c and hsa-miR-135b. The aim of the study was to modulate the expression of the miRNAs hsa-miR-29c-5p and hsa-miR-135b-5p and evaluate the expression of their target genes in 2D and 3D cell cultures.
METHODS
hsa-miR-29c-5p and hsa-miR-135b-5p expression profiles were modulated by transfecting mimics and antimiRs, respectively, in 2D and 3D cell cultures. The expression of the proteins coded by the genes CDC42, DNMT3A (target genes of hsa-miR-29c-5p) and APC (target gene of hsa-miR-135b-5p) were measured by Western Blot.
RESULTS
Results showed that mimics and antimiRs transfection significantly altered the expression of both miRNAs, increasing the expression of hsa-miR-29c-5p and reducing the expression of hsa-miR-135b-5p, especially in the 3D culture of the cell lines. When analyzing the proteins expression, we observed that AGP01 and AGP03 cell lines transfected with mimics had a reduction in the levels of CDC42 and DNMT3A and all three cell lines transfected with antimiRs had an increase in the expression of the protein APC.
CONCLUSION
We concluded that three-dimensional culture can be a more representative in vitro model that resembles better the in vivo reality. Our results also showed that hsa-miR-29c-5p is an important regulator of CDC42 and DNMT3A genes in the intestinal subtype gastric cancer and hsa-miR-135b-5p regulates the APC gene in both intestinal and diffuse subtypes of GC. Dysregulation in their expression, and consequently in their respectively signaling pathways, shows how these miRNAs can influence the carcinogenesis of different histological subtypes of gastric cancer.
Topics: Cell Line, Tumor; Computational Biology; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Genes, APC; Humans; MicroRNAs; Models, Biological; Neoplasm Grading; Neoplasm Staging; RNA Interference; Stomach Neoplasms; Transcriptome
PubMed: 30376837
DOI: 10.1186/s12885-018-4980-7 -
Zhongguo Fei Ai Za Zhi = Chinese... Sep 2022Lung cancer is the main cause of cancer-related death globally. Single nucleotide polymorphism (SNP) is one of the important factors leading to the occurrence of lung...
BACKGROUND
Lung cancer is the main cause of cancer-related death globally. Single nucleotide polymorphism (SNP) is one of the important factors leading to the occurrence of lung cancer, but its mechanism has not been elucidated. This study intends to investigate the relationship between SNPs of CDH1, FANCB, APC genes and lung cancer genetic susceptibility.
METHODS
The case-control study design was used. We collected blood samples from 270 lung cancer cases in the Department of Lung Cancer Surgery, Tianjin Medical University General Hospital, as well as blood samples from 445 healthy volunteers as controls, and extracted genomic DNA for genotyping using the Taqman® SNP genotyping kit. The distribution of three SNP loci of CDH1 gene rs201141645, FANCB gene rs754552650 and APC gene rs149353082 in Chinese population was analyzed. Chi-square test and Logistic regression were used to analyze the relationship between different genotypes and the risk of lung cancer.
RESULTS
The distribution frequencies of AA, A/G and GG genotypes at rs754552650 of FANCB gene in the control group were 27.2%, 52.6% and 20.2%, respectively. The distribution frequencies of AA and A/G genotypes were 93.7% and 6.3% in the case group, respectively, and no GG genotype was detected. The A/G genotype of the rs754552650 locus of the FANCB gene was significantly different between the case group and the control group. Compared with the carriers of AA genotype, the individuals with FANCB rs754552650 A/G genotype had a lower risk of lung cancer (OR=0.035, 95%CI: 0.020-0.062, P<0.001). CDH1 gene rs201141645 A/C and CC genotypes only existed in the control group. In addition, only 1 sample was found to have APC rs149353082 genotype in the case group.
CONCLUSIONS
In the Chinese population, the lung cancer risk of the individuals with FANCB rs754552650 A/G genotype was significantly decreased.
Topics: Antigens, CD; Cadherins; Case-Control Studies; China; Fanconi Anemia Complementation Group Proteins; Gene Frequency; Genes, APC; Genetic Predisposition to Disease; Genotype; Humans; Lung Neoplasms; Polymorphism, Single Nucleotide
PubMed: 36172730
DOI: 10.3779/j.issn.1009-3419.2022.102.21 -
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 -
Asian Pacific Journal of Cancer... May 2022Familial adenomatous polyposis (FAP) is a hereditary disorder primarily caused by germline mutations in the APC gene. The most common type of mutation in the APC gene is...
BACKGROUND
Familial adenomatous polyposis (FAP) is a hereditary disorder primarily caused by germline mutations in the APC gene. The most common type of mutation in the APC gene is point mutation, while deletion mutation is much less frequent. The current study was conducted to investigate the mutation spectrum of the APC gene in Vietnamese FAP patients.
METHODS
Patients with the clinical diagnosis of FAP on colorectal endoscopy were screened for mutations in the APC gene using Sanger sequencing. Those who exhibited no point mutation subsequently underwent MLPA assay to detect deletion and duplication mutations. Besides, the relatives of patients with mutated APC genes were recruited for detecting carrier status.
RESULTS
Sixty-three patients with clinical colorectal polyposis were recruited. Mutations in the APC gene were detected in 26/63 patients (41.3%). Genetic analysis of 105 asymptomatic relatives of these 26 patients found mutations in the APC gene in 55 individuals (52.4%).
CONCLUSION
We successfully established the APC gene mutation spectrum in Vietnamese FAP patients for the first time. Of importance, we discovered two novel point mutations in the APC gene. The high prevalence of carrier status in asymptomatic family members of patients with mutation emphasizes the crucial role of appropriate genetic screening for early diagnosis, surveillance, and preventive measurements.
Topics: Adenomatous Polyposis Coli; Adenomatous Polyposis Coli Protein; Asian People; Genes, APC; Humans; Mutation; Point Mutation; Vietnam
PubMed: 35633533
DOI: 10.31557/APJCP.2022.23.5.1517 -
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