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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 -
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 -
Gastroenterology Jan 2021Mutations in the APC gene and other genes in the Wnt signaling pathway contribute to development of colorectal carcinomas. R-spondins (RSPOs) are secreted proteins that...
BACKGROUND & AIMS
Mutations in the APC gene and other genes in the Wnt signaling pathway contribute to development of colorectal carcinomas. R-spondins (RSPOs) are secreted proteins that amplify Wnt signaling in intestinal stem cells. Alterations in RSPO genes have been identified in human colorectal tumors. We studied the effects of RSPO1 overexpression in Apc mutant mice.
METHODS
An adeno associated viral vector encoding RSPO1-Fc fusion protein, or control vector, was injected into Apcmice. Their intestinal crypts were isolated and cultured as organoids. which were incubated with or without RSPO1-Fc and an inhibitor of transforming growth factor beta receptor (TGFBR). Livers were collected from mice and analyzed by immunohistochemistry. Organoids and adenomas were analyzed by quantitative reverse-transcription PCR, single cell RNA sequencing, and immunohistochemistry.
RESULTS
Intestines from Apc mice injected with the vector encoding RSPO1-Fc had significantly deeper crypts, longer villi, with increased EdU labeling, indicating increased proliferation of epithelial cells, in comparison to mice given control vector. AAV-RSPO1-Fc-transduced Apc mice also developed fewer and smaller intestinal tumors and had significantly longer survival times. Adenomas of Apc mice injected with the RSPO1-Fc vector showed a rapid increase in apoptosis and in the expression of Wnt target genes, followed by reduced expression of messenger RNAs and proteins regulated by the Wnt pathway, reduced cell proliferation, and less crypt branching than adenomas of mice given the control vector. Addition of RSPO1 reduced the number of adenoma organoids derived from Apc mice and suppressed expression of Wnt target genes but increased phosphorylation of SMAD2 and transcription of genes regulated by SMAD. Inhibition of TGFBR signaling in organoids stimulated with RSPO1-Fc restored organoid formation and expression of genes regulated by Wnt. The TGFBR inhibitor restored apoptosis in adenomas from Apc mice expressing RSPO1-Fc back to the same level as in the adenomas from mice given the control vector.
CONCLUSIONS
Expression of RSPO1 in Apc mice increases apoptosis and reduces proliferation and Wnt signaling in adenoma cells, resulting in development of fewer and smaller intestinal tumors and longer mouse survival. Addition of RSPO1 to organoids derived from adenomas inhibits their growth and promotes proliferation of intestinal stem cells that retain the APC protein; these effects are reversed by TGFB inhibitor. Strategies to increase the expression of RSPO1 might be developed for the treatment of intestinal adenomas.
Topics: Adenoma; Animals; Disease Models, Animal; Intestinal Neoplasms; Mice; Organoids; Thrombospondins; Transforming Growth Factor beta; Wnt Signaling Pathway
PubMed: 32941878
DOI: 10.1053/j.gastro.2020.09.011 -
Molecular Cancer Dec 2021Epstein-Barr virus (EBV) represents an important pathogenic factor of lymphoma and is significantly associated with poor clinical outcome of diffuse large B-cell...
BACKGROUND
Epstein-Barr virus (EBV) represents an important pathogenic factor of lymphoma and is significantly associated with poor clinical outcome of diffuse large B-cell lymphoma (DLBCL). Circular RNAs (circRNAs) play an essential role in lymphoma progression. However, the underlying mechanism of circRNA on DLBCL progression related to EBV remains largely unknown.
METHODS
CircRNA was screened by high-throughput sequencing in tumor samples of 12 patients with DLBCL according to EBV infection status. Expression of circEAF2, as well as the relationship with clinical characteristics and prognosis, were further analyzed in tumor samples of 100 DLBCL patients using quantitative real-time PCR. Gain- and loss-of-function experiments were conducted to investigate the biological functions of circEAF2 both in vitro and in vivo. The underlying mechanism of circRNA on DLBCL progression were further determined by RNA sequencing, RNA pull down assay, dual-luciferase reporter assay, rescue experiments and western blotting.
RESULTS
We identified a novel circRNA circEAF2, which was downregulated in EBV + DLBCL and negatively correlated with EBV infection and DLBCL progression. In EBV-positive B lymphoma cells, circEAF2 overexpression induced lymphoma cell apoptosis and sensitized lymphoma cells to epirubicin. As mechanism of action, circEAF2 specifically targeted EBV-encoded miR-BART19-3p, upregulated APC, and suppressed downstream β-catenin expression, resulting in inactivation of Wnt signaling pathway and inhibition of EBV + DLBCL cell proliferation. In EBV-positive B-lymphoma murine models, xenografted tumors with circEAF2 overexpression presented decreased Ki-67 positivity, increased cell apoptosis and retarded tumor growth.
CONCLUSIONS
CircEAF2 counteracted EBV + DLBCL progression via miR-BART19-3p/APC/β-catenin axis, referring circEAF2 as a potential prognostic biomarker. Therapeutic targeting EBV-encoded miRNA may be a promising strategy in treating EBV-associated lymphoid malignancies.
Topics: Adult; Aged; Animals; Biomarkers, Tumor; Cell Line, Tumor; Disease Models, Animal; Disease Susceptibility; Epstein-Barr Virus Infections; Female; Gene Expression Regulation, Neoplastic; Genes, APC; Herpesvirus 4, Human; Humans; Lymphoma, Large B-Cell, Diffuse; Male; Mice; MicroRNAs; Middle Aged; Models, Biological; RNA, Circular; Transcription Factors; Wnt Signaling Pathway; beta Catenin
PubMed: 34852843
DOI: 10.1186/s12943-021-01458-9 -
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 -
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 -
Oncology Reviews Feb 2021Inactivating mutations of the () gene and consequential upregulation of the Wnt signaling pathway are critical initiators in the development of colorectal cancer (CRC),...
Inactivating mutations of the () gene and consequential upregulation of the Wnt signaling pathway are critical initiators in the development of colorectal cancer (CRC), the third most common cancer in the United States for both men and women. Emerging evidence suggests mutations are also found in gastric, breast and other cancers. The gene, located on chromosome 5q, is responsible for negatively regulating the b-catenin/Wnt pathway by creating a destruction complex with Axin/Axin2, GSK-3b, and CK1. In the event of an mutation, b-catenin accumulates, translocates to the cell nucleus and increases the transcription of Wnt target genes that have carcinogenic consequences in gastrointestinal epithelial stem cells. A literature review was conducted to highlight carcinogenesis related to mutations, as well as preclinical and clinical studies for potential therapies that target steps in inflammatory pathways, including IL-6 transduction, and Wnt pathway signaling regulation. Although a range of molecular targets have been explored in murine models, relatively few pharmacological agents have led to substantial increases in survival for patients with colorectal cancer clinically. This article reviews a range of molecular targets that may be efficacious targets for tumors with mutations.
PubMed: 34267890
DOI: 10.4081/oncol.2021.534 -
Cancer Research May 2017The p53-inducible and genes are frequently silenced in colorectal cancer. To address the relevance of function for suppression of intestinal tumor formation, we...
The p53-inducible and genes are frequently silenced in colorectal cancer. To address the relevance of function for suppression of intestinal tumor formation, we generated mice with deletions of the and/or genes separately or in combination. Combined deletion of increased the number of intestinal stem cells as well as Paneth and Goblet cells, resulting in enlarged intestinal crypts. -deficient mice displayed an increased tumor burden and grade and decreased survival. -deficient adenomas showed elevated proliferation and decreased apoptosis and displayed pronounced bacterial infiltration, which may be due to an observed decrease in infiltrating immune cells and downregulation of barrier proteins. mRNA induction in -deficient tumors was enriched for miR-34a/b/c seed-matching sites and for mRNAs encoding proteins related to epithelial-mesenchymal transition, stemness, and Wnt signaling. Accordingly, cells explanted from -deficient adenomas formed tumor organoids at an increased rate. Several upregulated miR-34 targets displayed elevated expression in primary human colorectal cancers that was associated with lymph-node metastases ( and ) and upregulation of and in primary colorectal cancer was associated with poor patient survival. In conclusion, our results show that suppress tumor formation caused by loss of and control intestinal stem cell and secretory cell homeostasis by downregulation of multiple target mRNAs. .
Topics: Animals; Apoptosis; Cell Line, Tumor; Cell Proliferation; Cell Transformation, Neoplastic; Cluster Analysis; Disease Models, Animal; Female; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Genes, APC; Intestinal Mucosa; Intestinal Neoplasms; Male; Mice; Mice, Knockout; MicroRNAs; Models, Biological; Prognosis; RNA Interference; Reproducibility of Results; Wnt Signaling Pathway
PubMed: 28363996
DOI: 10.1158/0008-5472.CAN-16-2183 -
Gastroenterology Jan 2022Inactivation of the Apc gene is a critical early event in the development of sporadic colorectal cancer (CRC). Expression of serine-threonine kinase receptor-associated...
BACKGROUND & AIMS
Inactivation of the Apc gene is a critical early event in the development of sporadic colorectal cancer (CRC). Expression of serine-threonine kinase receptor-associated protein (STRAP) is elevated in CRCs and is associated with poor outcomes. We investigated the role of STRAP in Apc mutation-induced intestinal tumor initiation and progression.
METHODS
We generated Strap intestinal epithelial knockout mice (Strap) by crossing mice containing floxed alleles of Strap (Strap) with Villin-Cre mice. Then we generated Apc;Strap;Vill-Cre (Apc;Strap) mice for RNA-sequencing analyses to determine the mechanism of function of STRAP. We used human colon cancer cell lines (DLD1, SW480, and HT29) and human and mouse colon tumor-derived organoids for STRAP knockdown and knockout and overexpression experiments.
RESULTS
Strap deficiency extended the average survival of Apc mice by 80 days and decreased the formation of intestinal adenomas. Expression profiling revealed that the intestinal stem cell signature, the Wnt/β-catenin signaling, and the MEK/ERK pathway are down-regulated in Strap-deficient adenomas and intestinal organoids. Correlation studies suggest that these STRAP-associated oncogenic signatures are conserved across murine and human colon cancer. STRAP associates with MEK1/2, promotes binding between MEK1/2 and ERK1/2, and subsequently induces the phosphorylation of ERK1/2. STRAP activated Wnt/β-catenin signaling through MEK/ERK-induced phosphorylation of LRP6. STRAP was identified as a target of mutated Apc and Wnt/β-catenin signaling as chromatin immunoprecipitation and luciferase assays revealed putative binding sites of the β-catenin/TCF4 complex on the Strap promoter.
CONCLUSIONS
STRAP is a target of, and is required in, Apc mutation/deletion-induced intestinal tumorigenesis through a novel feed-forward STRAP/MEK-ERK/Wnt-β-catenin/STRAP regulatory axis.
Topics: Animals; Cell Proliferation; Cell Transformation, Neoplastic; Colorectal Neoplasms; Disease Progression; Extracellular Signal-Regulated MAP Kinases; Feedback, Physiological; Gene Expression Regulation, Neoplastic; Genes, APC; HT29 Cells; Humans; Mice, Inbred C57BL; Mice, Knockout; Mitogen-Activated Protein Kinase Kinases; Mutation; RNA-Binding Proteins; Tumor Cells, Cultured; Wnt Signaling Pathway; Mice
PubMed: 34520730
DOI: 10.1053/j.gastro.2021.09.010