Dysregulated Expression of Stem Cell Factor Bmi1 in Precancerous Lesions of the Gastrointestinal Tract

Abstract

Purpose: It is important to identify the definitive molecular switches involved in the malignant transformation of premalignant tissues. Cellular senescence is a specific characteristic of precancerous tissues, but not of cancers, which might reflect tumorigenesis-protecting mechanisms in premalignant lesions. Polycomb protein Bmi1, which is a potent negative regulator of the p16INK4 gene, suppresses senescence in primary cells and is overexpressed in various cancers. We hypothesized that Bmi1 expression would also be dysregulated in precancerous lesions in human digestive precancerous tissues. Experimental Design: Bmi1 expression was investigated in cancerous and precancerous tissues of the digestive tract. The expression of p16, h-catenin, and Gli1 and the in vivo methylation status of the p16 gene were also analyzed in serial sections of colonic precancerous lesions. Results: Bmi1 was clearly overexpressed across a broad spectrum of gastrointestinal cancers, and the expression of Bmi1 increased in a manner that reflected the pathologic malignant features of precancerous colonic tissues (low-grade dysplasia, 12.9 F 2.0%; high-grade dysplasia, 82.9 F 1.6%; cancer, 87.5 F 2.4%). p16 was also strongly expressed in high-grade dysplasia, but not in cancers. p16 promoter methylation was detected only in some Bmi1-positive neoplastic cells. Conclusions: Bmi1overexpression was correlated with the malignant grades of human digestive precancerous tissues, which suggests that advanced Bmi1dysregulation might predict malignant progression. The abnormal Bmi1 expression might link to malignant transformation via the disturbance of orderly histone modification.

Type I collagen inhibits differentiation and promotes a stem cell-like phenotype in human colorectal carcinoma cells

“…Bmi1 is involved in self-renewal in haematopoietic and neuronal cells (Lessard and Sauvageau, 2003;Molofsky et al, 2003). In addition, Bmi1 expression is dysregulated in preneoplastic colorectal epithelium and overexpression correlates with malignant progression (Tateishi et al, 2006), supporting a role for Bmi1 in human colorectal cancer progression. Previous studies have shown that HRA-19 cells, which have a low inherent tumourigenicity, acquired a 100% take rate in xenografts when embedded in type I collagen gel (Del-Buono et al, 1991), suggesting a functional significance to colon cancer cell -collagen interactions.…”

PHLDA1 Expression Marks the Putative Epithelial Stem Cells and Contributes to Intestinal Tumorigenesis

“…Despite these substantive advances in mice, limited progress has been made regarding the assessment of candidate ISC markers in humans. Conflicting data exist on BMI1 mRNA and protein expression in human small and large intestine (9)(10)(11), and systematic assessment of LGR5, ASCL2, and OLFM4 is hindered by a lack of appropriate antibodies and has been limited to surrogate in situ hybridization studies. OLFM4 is perhaps the best studied candidate in humans, showing mRNA expression at the crypt base throughout the intestinal tract (12).…”

The overexpression of polycomb group proteins Bmi1 and EZH2 is associated with the progression and aggressive biological behavior of hepatocellular carcinoma

“…7 PcG proteins are part of the conserved cellular memory system that prevents changes in cell identity by repressing the transcriptional state of several loci in the genome. Bmi1 is overexpressed in several carcinomas, [7][8][9][10][11] including liver carcinoma. 12 Polycomb-Repressive Complex 2 (PRC2) members, for example EZH2, are also associated with cancer 9,13,14 and several studies have shown that EZH2 is highly expressed in aggressive prostate and breast carcinomas.…”