| Autor: |
Pattison, Amanda M., Barton, Joshua R., Entezari, Ariana A., Zalewski, Alicja, Rappaport, Jeff A., Snook, Adam E., Waldman, Scott A. |
| Zdroj: |
Cancer Biology and Therapy; September 2020, Vol. 21 Issue: 9 p799-805, 7p |
| Abstrakt: |
ABSTRACTMost sporadic colorectal cancer reflects acquired mutations in the adenomatous polyposis coli (APC) tumor suppressor gene, while germline heterozygosity for mutant APCproduces the autosomal dominant disorder Familial Adenomatous Polyposis (FAP) with a predisposition to colorectal cancer. In these syndromes, loss of heterozygosity (LOH) silences the remaining normal allele of APC, through an unknown mechanism, as the initiating step in transformation. Guanylyl cyclase C receptor (GUCY2C) and its hormones, uroguanylin and guanylin, have emerged as a key signaling axis opposing mutations driving intestinal tumorigenesis. Indeed, uroguanylin and guanylin are among the most commonly repressed genes in colorectal cancer. Here, we explored the role of APCheterozygosity in mechanisms repressing hormone expression which could contribute to LOH. In genetic mouse models of APC loss, uroguanylin and guanylin expression were quantified following monoallelic or biallelic deletion of the Apcgene. Induced biallelic loss of APC repressed uroguanylin and guanylin expression. However, monoallelic APC loss in Apcmin/+mice did not alter hormone expression. Similarly, in FAP patients, normal colonic mucosa (monoallelic APCloss) expressed guanylin while adenomas and an invasive carcinoma (biallelic APCloss) were devoid of hormone expression. Thus, uroguanylin and guanylin expression by normal intestinal epithelial cells persists in the context of APC heterozygosity and is lost only after tumor initiation by APCLOH. These observations reveal a role for loss of the hormones silencing the GUCY2C axis in tumor progression following biallelic APCloss, but not in mechanisms creating the genetic vulnerability in epithelial cells underlying APCLOH initiating tumorigenesis. |
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