Urokinase type plasminogen activator receptor expression in colorectal neoplasms

Abstract

Background-The urokinase type plasminogen activator receptor (uPAR) may play a critical role in cancer invasion and metastasis. Aims-To study the involvement of uPAR in colorectal carcinogenesis. Methods-The cellular expression and localisation of uPAR were investigated in colorectal adenomas and invasive carcinomas by in situ hybridisation, immunohistochemistry, and northern and western blot analyses. Results-uPAR mRNA expression was found mainly in the cytoplasm of dysplastic epithelial cells of 30% of adenomas with mild (19%), moderate (21%), and severe (47%) dysplasia, and in that of carcinomatous cells of 85% of invasive carcinomas: Dukes' stages A (72%), B (93%), and C (91%). Some stromal cells in the adjacent neoplastic epithelium were faintly positive. Immunoreactivity for uPAR was detected in dysplastic epithelial cells of 14% of adenomas and in carcinomatous cells of 49% of invasive carcinomas. uPAR mRNA and protein concentrations were significantly higher in severe than in mild or moderate dysplasia (p<0.05); they were notably higher in Dukes' stage A than in severe dysplasia (p<0.05), and significantly higher in Dukes' stage B than in stage A (p<0.05), but those in stage B were not diVerent from those in stage C or in metastatic colorectal carcinomas of the liver. Conclusions-Colorectal adenoma uPAR, expressed essentially in dysplastic epithelial cells, was upregulated with increasing severity of atypia, and increased notably during the critical transition from severe dysplasic adenoma to invasive carcinoma. These findings implicate uPAR expression in the invasive and metastatic processes of colorectal cancer. (Gut 1998;43:798-805)

Quantitative expression of protein markers of plasminogen activation system in prognosis of colorectal cancer

“…Other investigators have found that uPA and uPAR proteins were located in the basal regions of the tumors of CRC patients and at the invading front of the tumors, but rarely within adenomas showing pseudoinvasion [12,13,16], suggesting that they may play an important role in tumor invasion. Furthermore, uPA and uPAR expression were more intensive and more frequent in Dukes C/B than in Dukes A tumors [13,17], indicating that the proteins were associated with tumor progression. A positive association was found between survival of patients with Dukes B or C colorectal cancer and epithelial uPA or uPAR staining [18,19].…”

Identification of an histone H3 acetylated/K4-methylated-bound intragenic enhancer regulatory for urokinase receptor expression

“…In resected colon cancer, increased transcription factor binding to the þ 1123/ þ 1134 region is associated with elevated u-PAR protein levels U-PAR mRNA levels are elevated in resected colon cancers (Ganesh et al, 1994;Suzuki et al, 1999) and to An intragenic enhancer regulates u-PAR expression H Wang et al accrue evidence for a role of the u-PAR enhancer in driving elevated expression of this gene in this malignancy, we performed electrophoretic mobility shift assays (EMSA), as described previously (Schewe et al, 2003), on a series of resected colon tumors (Figure 10). Incubation of nuclear extract derived from these tissues with the oligonucleotide ( þ 1111/ þ 1138) spanning the intron 1 region, critical for enhancer activity, gave rise to protein-DNA complexes (parenthesis) which, in the most part, were specific as they were abolished with excess non-radioactive oligonucleotide competitor.…”

Clinical significance of urokinase‐type plasminogen activator receptor (uPAR) expression in cancer

“…[69][70][71] The expression pattern of uPAR has been studied at both mRNA and protein levels and found specifically in stromal and malignant cells. Cells at the leading edge of invasively growing tumor glands had uPAR mRNA expression, with signals clearly seen in malignant epithelial cells, in particular at the tumor-stromal interface of invasive foci.…”