A STAT-responsive Element in the Promoter of the Episialin/MUC1 Gene Is Involved in Its Overexpression in Carcinoma Cells

Abstract

The mucin-like glycoprotein episialin (MUC1) is highly overproduced by a number of human carcinomas. We have shown previously in a variety of mammalian cell lines that overexpression of this very large transmembrane molecule diminishes cellular adhesion, suggesting that episialin/MUC1 overexpression may play an important role in tumor invasion and metastasis. By using in situ hybridization, we show here that episialin/ MUC1 mRNA expression can be increased more than 10-fold in breast carcinoma cells relative to the expression in adjacent normal breast epithelium. In search of the molecular mechanism of this overexpression, we observed that the episialin/MUC1 promoter contains a candidate binding site for transcription factors of the STAT family ϳ500 base pairs upstream of the transcription start site. Cytokines and/or growth factors such as interleukin-6 or interferon-␥ can activate STATs. In the human breast carcinoma cell line T47D, both compounds are able to stimulate transcription of a luciferase reporter gene under the control of a 750-base pair MUC1 promoter fragment proximal to the transcription start site. The observed increase is entirely mediated by the single STAT-binding site, since mutation of this site abolishes stimulation of the reporter by interleukin-6 and interferon-␥. In addition, mutation of the STAT site also decreased the promoter activity in nonstimulated T47D cells, suggesting that the STAT-binding site is among the elements that are involved in the overexpression of MUC1 in tumor cells. Episialin/MUC11 (also known as MUC1, PEM, CA 15-3 antigen, or EMA) is a transmembrane molecule with a large extracellular mucin-like domain. In normal cells episialin/ MUC1 is exclusively present at the apical side of the cell, but in carcinoma cells normal polarization is lost and episialin/MUC1 co-localizes with adhesion molecules such as integrins and cadherins. The long and relatively rigid extracellular domain of episialin/MUC1 can shield these adhesion molecules and diminish cellular adhesion, if present at a sufficiently high density on the cell surface (1-3). Overexpression of episialin/MUC1 in carcinoma cells has been frequently reported (4 -6) and is expected to have a similar effect on cellular behavior as loss of E-cadherin, the major epithelial cell-cell adhesion molecule, which has been shown to promote invasion and metastasis of carcinoma cells (for review see Refs. 7-9). Therefore, we have proposed that episialin/MUC1 also plays an important role in invasion and metastasis in vivo (10). Indeed, transgenic mice overexpressing episialin/MUC1 develop more aggressive lung tumors than nontransgenic mice, 2 whereas episialin/MUC1 null mice show a slower rate of tumor progression (11).Recent reports have shown that episialin overexpression in various types of neoplasia correlates with poor survival (12)(13)(14). Episialin/MUC1 is also the antigen that is measured in the CA 15-3 assay (the main blood marker to detect recurrence of breast cancer), and it is a molecule that is widely considered as ...

MUC1 expression in human prostate cancer cell lines and primary tumors

“…As found for normal breast epithelia, breast cancer, and uterine cell lines, 18,26,39 we observed strong cytokine influences on MUC1 expression in normal prostate epithelia and certain prostate cancer cell lines (PC-3). In other prostate cancer cell lines, MUC1 either was constitutively expressed at high levels (DU-145) or not detected under any condition (LnCaP and derivative cell lines).…”

“…In light of studies indicating that MUC1 expression is stimulated by steroid hormones and cytokines in other systems, 18,25,26 we evaluated the ability of IFN-g, TNF-a, and DHT to induce MUC1 expression in PrEC and prostate cancer cell lines. PrEC expressed moderately higher amounts of MUC1 after treatment with IFN-g or TNF-a alone; however, combined cytokine treatment produced a highly synergistic increase in MUC1 expression.…”

MUC1-induced alterations in a lipid metabolic gene network predict response of human breast cancers to tamoxifen treatment

“…The MUC1 oncoprotein is aberrantly overexpressed in about 90% of human breast tumors (1,17). MUC1 overexpression is conferred, at least in part, by up-regulation of MUC1 mRNA levels at the transcriptional level (18)(19)(20)(21). MUC1 interacts with ER and certain other transcription factors, and thereby contributes to the regulation of gene expression (7,22).…”

The cell surface mucin MUC1 limits the severity of influenza A virus infection

“…16 In addition, production of the antiinflammatory IL-10 and type I interferon (IFN) has been shown to correlate with increased MUC1 expression. [17][18][19] Investigations in mice with Helicobacter pylori-induced gastritis revealed that Muc1 expression negatively regulates the NLRP3 inflammasome, which mediates production of IL-1b. 20 Taken together, these data suggest that in addition to a barrier role to infection, MUC1 may also be involved with regulation of inflammation in response to infection.…”