Transcriptional regulation of the non‐specific cross‐reacting antigen gene, a member of the carcinoembryonic antigen gene family up‐regulated in colorectal carcinomas

Abstract

Human non-specific cross-reacting antigen (NCA), a close relative of the tumor marker human carcinoembryonic antigen (CEA), is also an in vitro homotypic intercellular adhesion molecule capable of inhibiting differentiation when expressed ectopically by myoblasts. Moreover, NCA appears to be overexpressed at the transcriptional level to a greater extent and more frequently in colorectal carcinomas than CEA. This study examines the transcriptional control mechanisms responsible for orchestrating NCA expression. The region within 284 bp upstream of the translational start site of the NCA gene was found to be capable of directing high levels of expression in functional promoter assays. Footprinting experiments identified three cis-acting elements and mobility-shift assays revealed that the first of these elements is bound by the upstream stimulating factors USF1 and USF2 while the other two are bound by the stimulatory proteins Sp1 and Sp3. No cis-acting elements corresponding to CEA footprint FP4 or the silencer CEA FP5 were detected in the NCA promoter, which may contribute to the differential expression of NCA versus CEA in tumorigenesis.Keywords : transcriptional promoter; non-specific cross-reacting antigen; carcinoembryonic antigen gene family ; upstream stimulatory factors 1 and 2; stimulatory proteins 1 and 3.Human carcinoembryonic antigen (CEA) is a 180-kDa gly-many closely related molecules confounded early studies adcophosphatidylinositol-linked cell membrane glycoprotein that dressing CEA expression during carcinogenesis because the was first described over 30 years ago to be highly expressed in anti-CEA polyclonal antibodies then used to quantitate CEA exthe fetal colon and colonic carcinomas [1]. CEA has subse-pression were capable of cross-reacting with other members of quently been shown to be expressed at low levels on the apical the CEA gene family. One such serological cross-reactant is surface of epithelial cells in the colon from fetal life onward [2]. NCA [6, 7] which appears to be functionally similar to CEA. Notwithstanding this expression by normal cells, increases in Like CEA [8], NCA can mediate Ca 2ϩ -independent homotypic serum concentration of CEA have proved to be a useful clinical intercellular adhesion, but can also bind heterotypically with indicator of tumor burden on presentation and of recurrence CEA when expressed on an apposing cell membrane [9, 10]. following resection and as such CEA has been widely used as a Both CEA and NCA have been shown to block terminal differtumor marker in the management of colon cancer.entiation and the accompanying loss of cell proliferative capacMolecular cloning has revealed that the CEA gene is the ity when ectopically expressed in rat L6 myoblasts [11, 12]. prototypic member of a subfamily of the immunoglobulin super-These commonalties suggest that NCA, like CEA, may be capagene family which consists of 29 gene sequences closely linked ble of promoting the emergence of cells with the property of on the long arm of chromosome 19 [3Ϫ5]. Members ...

Towards understanding the mechanisms of actions of carcinoembryonic antigen‐related cell adhesion molecule 6 in cancer progression

“…TATNCCAAT‐less genes can generally be grouped into: (i) constitutively active house‐keeping genes with relatively G/C‐rich promoter regions, SPI sites and often multiple transcriptional start sites; or (ii) genes lacking G/C‐rich regions that have tightly clustered transcriptional start sites that are differentially or developmental regulated . However, in contrast to other TATNCCAAT‐less genes, CEACAM family genes possess features from both groups . They have G/C‐rich promoter regions and SPI sites, but they also have clusters of transcriptional start sites and are differentially expressed.…”

“…Studies on transcriptional regulation of the CEACAM family genes have previously been performed with human CEACAMl and CEA-CAM6 genes. 23 Research on the regulation of other CEACAM family genes in humans and other species is still scarce. The upstream promoter sequences of CEACAM1 and CEACAM6 genes lack the classical TATA and CCAAT boxes.…”

“…24 However, in contrast to other TATNCCAAT-less genes, CEACAM family genes possess features from both groups. 23 They have G/C-rich promoter regions and SPI sites, but they also have clusters of transcriptional start sites and are differentially expressed. CEACAM6 promoters show a sequence homology of 80% within the first 230 nucleotides upstream of the translational start site, where they could share the same transcriptional binding factors.…”

Interdependency of CEACAM-1, -3, -6, and -8 induced human neutrophil adhesion to endothelial cells

“…In many tissues, more than one CEACAM family member are expressed concurrently. For example, CEACAMs 1, 5, and 6 are often expressed in ovarian, endometrial, cervical, breast, lung, and colon carcinomas, and may be useful as biomarkers in cancer [43][44][45][46][47]. A CEACAM5 expressing measles virus has entered phase I trials in ovarian cancer [48].…”

Diet-induced hypoxia responsive element demethylation increases CEACAM6 expression, favouring Crohn's disease-associatedEscherichia colicolonisation

“…The region within 284 bp upstream of the translational start site of the NCA gene was found to be capable of directing high levels of expression in functional promoter assays. The study revealed the role of upstream stimulating factors USF1 and USF2 in the activation of CEACAM6 as well as by the stimulatory proteins Sp1, Sp3 and Sp5 34 35. Another study revealed that expression of recombinant thyroid transcription factor-1 (TTF-1) increased CEACAM6 in a dose-dependent fashion in lung tissue, showing the role of this factor in CEACAM6 gene expression 36.…”