Msx1 loss suppresses formation of the ectopic crypts developed in the Apc-deficient small intestinal epithelium

Abstract

The first step in the development of human colorectal cancer is aberrant activation of the Wnt signaling pathway. Wnt signaling hyperactivation is predominantly caused by loss-of-function mutations in the adenomatous polyposis coli (APC) gene that encodes the pathway negative regulator. In order to identify genes affected by the Apc loss, we performed expression profiling of intestinal epithelium isolated from mice harboring a conditional Apc allele. The gene encoding transcriptional factor msh homeobox 1 (Msx1) displayed robust upregulation upon Apc inactivation. Histological analysis of the Apc-deficient epithelium revealed that in the small intestine, the Msx1 protein was localized exclusively in ectopic crypts, i.e., in pockets of proliferating cells abnormally positioned on the villi. Ablation of the Msx1 gene leads to the disappearance of ectopic crypts and loss of differentiated cells. Moreover, tumors arising from Msx1-deficient cells display altered morphology reminiscent of villous adenomas. In human tumor specimens, MSX1 displayed significantly increased expression in colonic neoplasia with a descending tendency during the lesion progression towards colorectal carcinoma. In summary, the results indicate that Msx1 represents a novel marker of intestinal tumorigenesis. In addition, we described the previously unknown relationship between the Msx1-dependent formation of ectopic crypts and cell differentiation.

A narrative review of the roles of muscle segment homeobox transcription factor family in cancer

“…Whereas in colorectal cancer, compared to the adjacent normal tissues, MSX1 was shown to be down-regulated in COAD (9). However, the expression of MSX1 was also found to be significantly high in some colorectal cancer tissues (18,85).…”

“…Transcription factors regulate each other in the regulatory network of signaling pathways, the expression of MSX can also be regulated by corresponding transcription factors in specific signaling pathways such as growth factor signals in tumors (40). In colorectal carcinoma, WNT/ β-catenin signaling activated MSX1 expression while the promoter of MSX1 was activated by β-catenin (18). Previous studies have suggested that MSX2 can also function as a downstream effector of WNT signaling in human ovarian endometrioid adenocarcinoma cells and human teratoma cells (49)(50)(51).…”

“…The expression of MSX1 or MSX2 is also often deregulated in many tumors (9,10) and the MSX family mediates various cellular processes in cancers such as proliferation (11), invasion (12), metastasis (13), apoptosis (14), differentiation (15), drug resistance (16), tumor stemness (17), tumor angiogenesis (8), etc. Furthermore, MSX transcription factors exhibit either promotive or inhibitive effects on cancers through complex downstream regulatory mechanisms (11,14,18,19).…”

Human Colorectal Cancer from the Perspective of Mouse Models

“…Moreover, tamoxifen-induced recombination of the Apc cKO alleles in Apc cKO/cKO Lgr5-EGFP-IRES-CreERT2 and Apc cKO/cKO Villin-CreERT2 animals allowed tissue-specific Apc inactivation in intestinal stem cells or in all intestinal epithelium cells, respectively [109,110]. In the latter strains, massive crypt hyperproliferation followed by intestinal microadenoma formation was observed already several days after tamoxifen administration (Figure 3) [111].…”

“…The middle microphotograph shows the hyperplastic crypt compartment developed in Apc cKO/cKO Villin-CreERT2 mice seven days after tamoxifen administration; the right image shows microadenomas (red arrowheads) formed in the Apc cKO/cKO Lgr5-EGFP-IRES-CreERT2 small intestine 21 days after tamoxifen administration. Sections were counterstained with hematoxylin (blue nuclear signal); scale bar: 0.3 mm (adopted from Reference [111]).…”