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International Journal of Molecular... Oct 2022TRAF2- and NCK-interacting kinase (TNIK) has emerged as a promising therapeutic target for colorectal cancer because of its essential role in regulating the... (Review)
Review
TRAF2- and NCK-interacting kinase (TNIK) has emerged as a promising therapeutic target for colorectal cancer because of its essential role in regulating the Wnt/β-catenin signaling pathway. Colorectal cancers contain many mutations in the Wnt/β-catenin signaling pathway genes upstream of TNIK, such as the adenomatous polyposis coli () tumor suppressor gene. TNIK is a regulatory component of the transcriptional complex composed of β-catenin and T-cell factor 4 (TCF4). Inhibition of TNIK is expected to block the aberrant Wnt/β-catenin signaling caused by colorectal cancer mutations. Here we present structural insights into TNIK inhibitors targeting the ATP-binding site. We will discuss the effects of the binding of different chemical scaffolds of nanomolar inhibitors on the structure and function of TNIK.
Topics: Humans; beta Catenin; Wnt Proteins; Protein Serine-Threonine Kinases; Colorectal Neoplasms; Wnt Signaling Pathway
PubMed: 36361804
DOI: 10.3390/ijms232113010 -
Frontiers in Aging 2023Rothmund-Thomson syndrome (RTS) is a rare autosomal recessive disorder characterized by a range of clinical symptoms, including poikiloderma, juvenile cataracts, short... (Review)
Review
Rothmund-Thomson syndrome (RTS) is a rare autosomal recessive disorder characterized by a range of clinical symptoms, including poikiloderma, juvenile cataracts, short stature, sparse hair, eyebrows/eyelashes, nail dysplasia, and skeletal abnormalities. While classically associated with mutations in the gene, which encodes a DNA helicase involved in DNA replication and repair, three additional genes have been recently identified in RTS: , encoding a subunit of the APC/C complex; which encodes a nuclease/helicase involved in DNA repair; and , encoding a poorly characterized protein implicated in excitatory synapse formation and splicing. Here, we review the clinical spectrum of RTS patients, analyze the genetic basis of the disease, and discuss molecular functions of the affected genes, drawing some novel genotype-phenotype correlations and proposing avenues for future studies into this enigmatic disorder.
PubMed: 38021400
DOI: 10.3389/fragi.2023.1296409 -
Italian Journal of Pediatrics Aug 2020Hepatoblastoma (HB) is the most common malignant liver tumor in children. Abnormal activation of the Wnt/β-catenin signaling pathway plays an important role in the... (Review)
Review
Hepatoblastoma (HB) is the most common malignant liver tumor in children. Abnormal activation of the Wnt/β-catenin signaling pathway plays an important role in the formation and development of HB. Genes in HB show a global hypomethylation change, accompanied by hypermethylation of specific tumor suppressor genes (TSGs). This article reviews the hypermethylation changes in several TSGs, such as RASSF1A, SOCS1, APC, HHIP, and P16, and analyzes the pathways and mechanisms of TSGs regulating gene expression. The role of the methylation-regulating enzymes DNA methyltransferases (DNMTs) and ten-eleven translocation (TET) family members enzymes in the methylation changes of HB was analyzed, and it was speculated that the occurrence of HB is partly due to the obstruction of liver differentiation in the early stage of differentiation. The origin cells may be incompletely differentiated hepatocytes remaining in the liver of children after birth. Therefore, further studying the role of methylation regulating enzymes in methylation changes in HB is a promising future research direction.
Topics: DNA Methylation; Genes, Tumor Suppressor; Hepatoblastoma; Humans; Liver Neoplasms
PubMed: 32758256
DOI: 10.1186/s13052-020-00877-6 -
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 -
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 -
Clinics in Colon and Rectal Surgery Nov 2023Desmoid tumors (DT) represent the second high risk of tumor in familial adenomatous polyposis (FAP) patients. Although FAP-associated DTs (FAP-DT) are caused by germline... (Review)
Review
Desmoid tumors (DT) represent the second high risk of tumor in familial adenomatous polyposis (FAP) patients. Although FAP-associated DTs (FAP-DT) are caused by germline mutations in the adenomatous polyposis coli (APC) gene, extracolonic manifestations, sex, family history, genotype, and the ileal pouch anal anastomosis procedure are all linked to the development of DTs in FAP patients. Multidisciplinary management has replaced aggressive surgery as the preferred treatment of DTs. There is growing evidence to support the use of active surveillance strategy as first-line treatment for FAP-DT patients. Radiotherapy for intra-abdominal desmoids is now rarely used because of severe late toxicity. Pharmacotherapy, however, represents a promising future with the improvement of traditional cytotoxic drugs and the investigation of targeted drugs. Although nonsurgery treatment has been used widely nowadays, surgery remains the mainstay when symptomatic or life-threatening DTs are present. Further research will be needed for more optimal clinical practice.
PubMed: 37795470
DOI: 10.1055/s-0043-1767709 -
Cancer Research and Treatment Oct 2023Loss-of-function mutations in the adenomatous polyposis coli (APC) gene are common in metastatic colorectal cancer (mCRC). However, the characteristic of APC specific...
PURPOSE
Loss-of-function mutations in the adenomatous polyposis coli (APC) gene are common in metastatic colorectal cancer (mCRC). However, the characteristic of APC specific mutations in mCRC is poorly understood. Here, we explored the clinical and molecular characteristics of N-terminal and C-terminal side APC mutations in Chinese patients with mCRC.
MATERIALS AND METHODS
Hybrid capture-based next-generation sequencing was performed on tumor tissues from 275 mCRC pati-ents to detect mutations in 639 tumor-associated genes. The prognostic value and gene-pathway difference between APC specific mutations in mCRC patients were analyzed.
RESULTS
APC mutations were highly clustered, accounting for 73% of all mCRC patients, and most of them were truncating mutations. The tumor mutation burden of the N-terminal side APC mutations group (n=76) was significantly lower than that of the C-terminal side group (n=123) (p < 0.001), further confirmed by the public database. Survival analysis showed that mCRC patients with N-terminus side APC mutations had longer overall survival than C-terminus side. Tumor gene pathway analysis showed that gene mutations in the RTK/RAS, Wnt and transforming growth factor β signaling pathways of the C-terminal group were significantly higher than those of the N-terminal group (p < 0.05). Additionally, KRAS, AMER1, TGFBR2, and ARID1A driver mutations were more common in patients with C-terminal side APC mutations.
CONCLUSION
APC specific mutations have potential function as mCRC prognostic biomarkers. There are obvious differences in the gene mutation patterns between the C-terminus and N-terminus APC mutations group, which may have certain guiding significance for the subsequent precise treatment of mCRC.
Topics: Humans; Prognosis; Colorectal Neoplasms; Adenomatous Polyposis Coli; Mutation; Colonic Neoplasms; Rectal Neoplasms
PubMed: 37114476
DOI: 10.4143/crt.2023.415 -
Gastroenterology May 2023Aberrant DNA methylation is frequent in colorectal cancer (CRC), but underlying mechanisms and pathologic consequences are poorly understood.
BACKGROUND & AIMS
Aberrant DNA methylation is frequent in colorectal cancer (CRC), but underlying mechanisms and pathologic consequences are poorly understood.
METHODS
We disrupted active DNA demethylation genes Tet1 and/or Tdg from Apc mice and characterized the methylome and transcriptome of colonic adenomas. Data were compared to human colonic adenocarcinomas (COAD) in The Cancer Genome Atlas.
RESULTS
There were increased numbers of small intestinal adenomas in Apc mice expressing the Tdg allele, whereas Tet1-deficient and Tet1/Tdg-double heterozygous Apc colonic adenomas were larger with features of erosion and invasion. We detected reduction in global DNA hypomethylation in colonic adenomas from Tet1- and Tdg-mutant Apc mice and hypermethylation of CpG islands in Tet1-mutant Apc adenomas. Up-regulation of inflammatory, immune, and interferon response genes was present in Tet1- and Tdg-mutant colonic adenomas compared to control Apc adenomas. This up-regulation was also seen in murine colonic organoids and human CRC lines infected with lentiviruses expressing TET1 or TDG short hairpin RNA. A 127-gene inflammatory signature separated colonic adenocarcinomas into 4 groups, closely aligned with their microsatellite or chromosomal instability and characterized by different levels of DNA methylation and DNMT1 expression that anticorrelated with TET1 expression. Tumors with the CpG island methylator phenotype (CIMP) had concerted high DNMT1/low TET1 expression. TET1 or TDG knockdown in CRC lines enhanced killing by natural killer cells.
CONCLUSIONS
Our findings reveal a novel epigenetic regulation, linked to the type of genomic instability, by which TET1/TDG-mediated DNA demethylation decreases methylation levels and inflammatory/interferon/immune responses. CIMP in CRC is triggered by an imbalance of methylating activities over demethylating activities. These mice represent a model of CIMP CRC.
Topics: Animals; Humans; Mice; Adenocarcinoma; Adenoma; Carcinogenesis; Cell Transformation, Neoplastic; Colonic Neoplasms; Colorectal Neoplasms; CpG Islands; DNA Methylation; DNA-Binding Proteins; Epigenesis, Genetic; Mixed Function Oxygenases; Phenotype; Proto-Oncogene Proteins
PubMed: 36764492
DOI: 10.1053/j.gastro.2023.01.039 -
Cancer Management and Research 2021The canonical model for hereditary cancer predisposition is a cancer predisposition gene (CPG) that drives either one or both of two fundamental hallmarks of cancer,... (Review)
Review
The canonical model for hereditary cancer predisposition is a cancer predisposition gene (CPG) that drives either one or both of two fundamental hallmarks of cancer, defective genomic integrity and deregulated cell proliferation, ultimately resulting in the accumulation of mutations within cells. Thus, the genes most commonly associated with cancer-predisposing genetic syndromes are tumor suppressor genes that regulate DNA repair (eg, genes) and/or cell cycle (eg, ). In recent years, however, the spectrum of high-penetrance CPGs has expanded considerably to include genes in non-canonical pathways such as oncogenic signaling, metabolism, and protein translation. We propose here that, given the variety of pathways that may ultimately affect genome integrity and cell proliferation, the model of cancer genetic predisposition needs to be expanded to account for diverse mechanisms. This synthesis calls for modeling and multi-omic studies applying novel experimental and computational approaches to understand cancer genetic predisposition.
PubMed: 34103990
DOI: 10.2147/CMAR.S311548