Lef1 restricts ectopic crypt formation and tumor cell growth in intestinal adenomas

Abstract

Lef1 is induced in intestinal adenomas, in which it restricts ectopic crypt formation and tumor growth.

Resveratrol inhibits development of colorectal adenoma via suppression of LEF1; comprehensive analysis with connectivity map

“…Our results clearly indicated that resveratrol inhibited LEF1 mRNA and protein levels and reduced transcription of Wnt‐related genes (MYC). Considering previous studies, 16,17,34,39–42 we suggest that resveratrol inhibits LEF1 expression and thereby suppresses the transcription of Wnt‐related genes, leading to the inhibition of adenoma formation, although there is a contradictory study regarding LEF1 function 35 …”

“…LEF‐1 directly interacts with β‐catenin and serves as transcription factor LEF‐1/TCF, which promotes transcription of Wnt‐responsive target genes, indicating the pivotal role of LEF1 in the Wnt/β‐catenin signaling pathway in CRA. LEF‐1 is reported to be induced by Wnt‐signal activation including Apc and β‐catenin mutations (accumulation) during colorectal carcinogenesis 34,35 . Moreover, the K‐RAS mutation reportedly induces LEF‐1 expression in human and murine colorectal tumors 36 .…”

“…Considering previous studies, 16,17,34,[39][40][41][42] we suggest that resveratrol inhibits LEF1 expression and thereby suppresses the transcription of Wnt-related genes, leading to the inhibition of adenoma formation, although there is a contradictory study regarding LEF1 function. 35 It is generally accepted that in the early step of CRA development, Apc mutations (two-hit) first occur, followed by additional gene alterations including RAS. That is, the smaller adenomas have fewer gene mutations in addition to the Apc mutation.…”

“…LEF‐1 is reported to be induced by Wnt‐signal activation including Apc and β‐catenin mutations (accumulation) during colorectal carcinogenesis. 34 , 35 Moreover, the K‐RAS mutation reportedly induces LEF‐1 expression in human and murine colorectal tumors. 36 Because K‐RAS mutation and/or β‐catenin mutation are involved in the AOM/DSS‐rat model, 37 , 38 it appears that LEF‐1 expression was induced by these gene mutations, and played an important role in adenoma formation in the rat model (Figure S6 ).…”

Intestinal Apc‐inactivation induces HSP25 dependency

“…To study the effect of BVDU on Apc ‐driven oncogenic transformation in vivo , we first used Villin‐Cre ERT2 ; Apc fl / fl mice to activate epithelial‐wide recombination of Apc alleles in the intestine. As previously reported, upon injection of tamoxifen, these mice develop massive hyperproliferation throughout the epithelium followed by rapid death within a week (Heino et al , 2021). We injected two doses of 2 mg tamoxifen on two consecutive days, either in the presence or absence of BVDU (400 mg/kg), which was administered daily via oral gavage.…”