Expression and regulation of the meprin ? gene in human cancer cells

Abstract

A novel mRNA isoform (meprin beta') of the cell-surface protease subunit meprin beta was previously identified in human colon cancer cells. The study reported here revealed that this mRNA isoform was identical within the protein coding region and at the 3' end to the beta isoform of normal intestine but that it contained an extended 5' untranslated region. Meprin beta' mRNA was expressed in the human breast cancer cell lines MCF-7 and SK-BR-3, in the human osteosarcoma cell line U2 Os, and in the human pancreatic cancer cell line BxPC-3. Meprin beta mRNA, but not beta' mRNA, was expressed in human fetal kidney cells. We cloned and sequenced genomic DNA encoding portions of the promoter region of the meprin beta gene. The unique sequences present in the beta' mRNA were present in the human genomic DNA immediately upstream of the transcription start site for the beta mRNA. The human meprin promoter sequence was searched for potential transcription-factor binding sites, and putative activator protein-1, polyoma enhancer activator 3 (PEA3), CCAAT enhancer-binding protein beta, and estrogen-receptor binding sites were identified along with binding sites for the intestine-specific cdx-2 transcription factor. The activity of meprin promoter/luciferase reporter gene constructs transfected into U2 Os cells was highest with constructs containing 83 and 639 bp of promoter DNA. These regions of the promoter each contain a putative PEA3 element. Treatment of the human colon adenocarcinoma cell line HT29-18C1 with 50 or 100 ng/mL phorbol myristal acetate for 8 h increased meprin beta' mRNA levels. Likewise, U2 Os cells transfected with the -639/luciferase or -1800/luciferase constructs showed a phorbol myristal acetate-inducible increase in reporter gene activity, indicating that the PEA3 element within the -639 construct or other elements further upstream respond to phorbol ester.

Cell Surface Processing of CD109 by Meprin β Leads to the Release of Soluble Fragments and Reduced Expression on Extracellular Vesicles

“…Meprin β is also expressed in mesenteric lymph nodes, in which it is affecting the intestinal leukocyte migration (Crisman et al, 2004). Furthermore, the isoform meprin β mRNA, containing an additional 5 sequence, was discovered in human colon adenocarcinoma cell line (HT29-18C1) (Dietrich et al, 1996), human breast cancer cell lines (MCF-7 and SK-BR-3), human osteosarcoma cell line (U-2 OS), and the human pancreatic cancer cell line (BxPC-3), indicating its aspect in cancer (Matters and Bond, 1999). We could also show that single amino acid exchange variants of meprin β identified in cancer patients alter its proteolytic activity on the cell surface (Schäffler et al, 2019).…”

Tetraspanin 8 is an interactor of the metalloprotease meprin β within tetraspanin-enriched microdomains

“…TSPAN8 was found to be highly expressed in colon carcinoma, where it also promotes metastasis (Greco et al, 2010;Richardson et al, 2011;Yue et al, 2013). As meprin β shows a high expression in the intestine and might be upregulated in colon cancer as well (Dietrich et al, 1996;Matters and Bond, 1999), this tumor type represents a promising condition to further investigate the interplay between meprin β and TSPAN8.…”

Hepatocyte nuclear factor 4α in the intestinal epithelial cells protects against inflammatory bowel disease

“…Meprins are metalloproteinases that are highly expressed in the intestinal epithelial cells and composed of two related subunits, α and β, leading to homo- or hetero-oligometric proteins (38). These enzymes degrade a wide range of proteins of extracellular matrix and biologically active peptides (71, 72) and have been shown to be involved in cancer and intestinal inflammation (38, 73, 74). Since the expression of Mep1α is known to be dependent on HNF4α expression and an HNF4α binding site in the promoter region (33), Mep1α could be a direct target for HNF4α in the colon and thus may be of value to determine whether HNF4α is involved in Mep1β activation.…”