Involvement of adenomatous polyposis coli in colorectal tumorigenesis

Abstract

Colorectal cancer arises after a series of mutations in various tumor suppressor and proto-oncogenes, each of which is accompanied by specific alterations and pathological conditions. Recent advances have contributed a great deal of understanding of the molecular basis of events that lead to colorectal tumorigenesis. Mutation in the adenomatous polyposis coli (APC) gene is considered to be one of the earliest events in the colon cancer development. The familial adenomatous polyposis (FAP) and hereditary nonpolyposis colorectal cancer (HNPCC) are the most commonly inherited colorectal cancers. FAP and HNPCC develop due to mutations in APC and DNA mismatch repair (MMR) genes, respectively. APC is known to regulate the levels of beta-catenin, an important mediator of cell-cell adhesion and transcriptional regulator. Mutations in APC gene are also linked with chromosomal instability in colon cancer cells. The role of APC is also implicated in cell migration, cell-cell adhesion, cell cycle control, and apoptosis. This article summarizes the structure-function studies and the role of APC mutations in colon cancer development.

CD4+ lymphocytes modulate prostate cancer progression in mice

“…The Apc mutation is an early event in 80% of sporadic intestinal cancers in humans, 51,52 and the Apc Min/+ mouse has been frequently used for study of familial intestinal adenomatous polyposis (FAP) in humans. 21,22 To examine whether the carcinogenic effect of CD25 + cell depletion might also affect other types of cancers, we inspected intestinal tissues of the same Apc Min/+ mice used for prostate cancer analyses: 8 males (2 trials; total N = 16, as described earlier) with the depletion protocol starting at 6–8 weeks of age.…”

Epigenetic-Genetic Interactions in theAPC/WNT, RAS/RAF, andP53Pathways in Colorectal Carcinoma

“…The development of most colorectal carcinomas (CRC) is thought to be initiated by inactivation of the APC/b-catenin/ Wnt signaling pathway, usually by mutation of one copy of the APC gene followed by a second event that inactivates the other allele (1)(2)(3)(4). The second inactivating event is usually described as allelic deletion or mutation but can be epigenetic methylation of cytosines in CpG islands of the promoter region of APC that results in transcriptional silencing (5,6).…”

“…Most APC mutations alter function of the gene product via point mutation or frameshift mutation that results in a truncated protein lacking all of the axin-binding sites and all but one or two of the 20-amino-acid h-catenin binding sites (10). Mutations of the KRAS or BRAF gene in the RAS/RAF pathway and of the P53 gene are later genetic events in colorectal tumorigenesis (3).…”

“…The second inactivating event is usually described as allelic deletion or mutation but can be epigenetic methylation of cytosines in CpG islands of the promoter region of APC that results in transcriptional silencing (5,6). Altered APC has wideranging downstream effects on cell-cell adhesion, transcriptional regulation, chromosomal instability, cell migration, proliferation and cell cycle control, differentiation, and apoptosis (1)(2)(3)(4).…”

Potential Role of P-gp for Flavone-Induced Diminished Apoptosis and Increased Adenoma Size in the Small Intestine of APCmin/+Mice

“…It was demonstrated by immunohistochemical staining that especially in those parts where an increased volume of adenomas was P-gp Expression and Reduced Intestinal Apoptosis  Adenomatous polyposis coli mutations are generally recognized to be associated with stabilization of ß-catenin, a key effector of the Wnt-signalling pathway (29). Dysregulated ßcatenin may then promote colon cancer development not only by its functions as a transcriptional regulator but also by altered subcellular distribution characterized by reduced plasma membrane localization in association with reduced cell-cell adhesion (29). We therefore investigated whether ß-catenin localization is affected by flavone in the present study.…”