| First Author | Cheng K | Year | 2023 |
| Journal | Sci Rep | Volume | 13 |
| Issue | 1 | Pages | 16920 |
| PubMed ID | 37805544 | Mgi Jnum | J:341499 |
| Mgi Id | MGI:7540180 | Doi | 10.1038/s41598-023-44158-8 |
| Citation | Cheng K, et al. (2023) Muscarinic receptor agonist-induced betaPix binding to beta-catenin promotes colon neoplasia. Sci Rep 13(1):16920 |
| abstractText | M(3) muscarinic receptors (M(3)R) modulate beta-catenin signaling and colon neoplasia. CDC42/RAC guanine nucleotide exchange factor, betaPix, binds to beta-catenin in colon cancer cells, augmenting beta-catenin transcriptional activity. Using in silico, in vitro, and in vivo approaches, we explored whether these actions are regulated by M(3)R. At the invasive fronts of murine and human colon cancers, we detected co-localized nuclear expression of betaPix and beta-catenin in stem cells overexpressing M(3)R. Using immunohistochemistry, immunoprecipitation, proximity ligand, and fluorescent cell sorting assays in human tissues and established and primary human colon cancer cell cultures, we detected time-dependent M(3)R agonist-induced cytoplasmic and nuclear association of betaPix with beta-catenin. betaPix knockdown attenuated M(3)R agonist-induced human colon cancer cell proliferation, migration, invasion, and expression of PTGS2, the gene encoding cyclooxygenase-2, a key player in colon neoplasia. Overexpressing betaPix dose-dependently augmented beta-catenin binding to the transcription factor TCF4. In a murine model of sporadic colon cancer, advanced neoplasia was attenuated in conditional knockout mice with intestinal epithelial cell deficiency of betaPix. Expression levels of beta-catenin target genes and proteins relevant to colon neoplasia, including c-Myc and Ptgs2, were reduced in colon tumors from betaPix-deficient conditional knockout mice. Targeting the M(3)R/betaPix/beta-catenin axis may have therapeutic potential. |
