Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.21.69 (APC)
 16,337 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mutations in apc which lead to activation of the Wnt signaling pathway are a hallmark of sporadic colon cancers but occur infrequently in colon cancers arising in patients with inflammatory bowel disease (IBD). There is evidence, however, that other components of the Wnt pathway may be altered in IBD-related colon cancer. In this study, we examined the expression the Wnt pathway components frizzled (Fz), the cell surface receptor, and disheveled (DVL), a family of cytoplasmic signal transduction molecules, in IBD and IBD-related colon cancer. Paraffin sections of normal and malignant colon tissues were obtained from patients with a history of ulcerative colitis and from controls with sporadic colon cancer. Tissue sections were stained with antibodies directed against Fz1/2 receptors and DVL1, DVL2 and DVL3 and antigen expression visualized by immunohistochemistry. Fz1/2 receptors were minimally expressed in normal IBD mucosa, were not expressed in IBD colon cancer, but exhibited strong expression in dysplastic tissues adjacent to the cancers. DVL1 was not expressed in IBD normal mucosa or normal mucosa from non-IBD patients, but was expressed in all cancers. DVL2 and DVL3 were expressed in all normal mucosa samples tested, and in sporadic colon cancer, but were not expressed in colon cancers arising in IBD patients. The characteristics of Fz and DVL expression in IBD tissues reported herein provides evidence of the importance of Wnt signaling in IBD and IBD-related colon cancer and, specifically, the significance of non-APC components of this pathway. Fz may serve as a marker for dyspasia in IBD patients and DVL1 is a potential therapeutic target for IBD-related colon cancer.
 ...
PMID:Expression of Wnt pathway components frizzled and disheveled in colon cancer arising in patients with inflammatory bowel disease. 1767 21

Tumor cells acquire metastasis-associated (MA) phenotypes following genetic alterations in them which cause deregulation of different signaling pathways. Earlier, we reported that an upregulation of the Wnt-beta-catenin pathway (WP) is one of the genetic salient features of triple-negative breast cancer (TNBC), and WP signaling is associated with metastasis in TNBC. Using cBioPortal, here we found that collective % of alteration(s) in WP genes, CTNNB1, APC and DVL1 among breast-invasive-carcinomas was 21% as compared to 56% in PAM50 Basal. To understand the functional relevance of WP in the biology of heterogeneous/metastasizing TNBC cells, we undertook this comprehensive study using 15 cell lines in which we examined the role of WP in the context of integrin-dependent MA-phenotypes. Directional movement of tumor cells was observed by confocal immunofluorescence microscopy and quantitative confocal-video-microscopy while matrigel-invasion was studied by MMP7-specific casein-zymography. WntC59, XAV939, sulindac sulfide and beta-catenin siRNA (1) inhibited fibronectin-directed migration, (2) decreased podia-parameters and motility-descriptors, (3) altered filamentous-actin, (4) decreased matrigel-invasion and (5) inhibited cell proliferation as well as 3D clonogenic growth. Sulindac sulfide and beta-catenin siRNA decreased beta-catenin/active-beta-catenin and MMP7. LWnt3ACM-stimulated proliferation, clonogenicity, fibronectin-directed migration and matrigel-invasion were perturbed by WP-modulators, sulindac sulfide and GDC-0941. We studied a direct involvement of WP in metastasis by stimulating brain-metastasis-specific MDA-MB231BR cells to demonstrate that LWnt3ACM-stimulated proliferation, clonogenicity and migration were blocked following sulindac sulfide, GDC-0941 and beta-catenin knockdown. We present the first evidence showing a direct functional relationship between WP activation and integrin-dependent MA-phenotypes. By proving the functional relationship between WP activation and MA-phenotypes, our data mechanistically explains (1) why different components of WP are upregulated in TNBC, (2) how WP activation is associated with metastasis and (3) how integrin-dependent MA-phenotypes can be regulated by mitigating the WP.
 ...
PMID:Wnt-beta-catenin pathway signals metastasis-associated tumor cell phenotypes in triple negative breast cancers. 2728 9