Increased expression of the transcription factors CCAAT-enhancer binding protein-? (C/EB?) and C/EBP? (CHOP) correlate with invasiveness of human colorectal cancer

Abstract

Regulation of cell differentiation is most often impaired in malignant tumors and may represent a key mechanism for the progression of the disease. CCAAT‐enhancer binding protein (C/EBP) is a family of transcription factors involved in the regulation of embryonic gut development in rodents, which has also been detected in various malignancies, e.g., liposarcomas and breast and ovarian epithelial tumors. We studied the relationship between C/EBP and tumor histology (Duke's invasive stage and pathological grade) in colorectal cancer. Immunoblotting techniques were used on microdissected fresh frozen tumor specimens, and expression of C/EBPα, C/EBPβ and C/EBPζ (CHOP) was analyzed in addition to that of the cell‐cycle regulator p53 and the proliferation marker PCNA. Expression of C/EBPβ (LAP isoforms) was markedly increased in all tumors compared with normal colon mucosa. Although the inter‐patient variability was large, we found that LIP, the isoform of C/EBPβ known to inhibit transcription, was expressed at higher levels in Duke's stage B tumors compared with Duke's stage A, whereas Duke's C tumors had the lowest LIP expression. A similar relationship was seen for CHOP. The cell‐cycle regulator gene p53 was the only factor that clearly correlated with pathological grade: a decrease in p53 expression was demonstrated. Our data suggest that genetic and cellular events involving C/EBPβ and CHOP are important for tumor invasion and that these events do not appear to be related to the pathological grade of the tumor. Int. J. Cancer 86:337–343, 2000. © 2000 Wiley‐Liss, Inc.

The C/EBP homologous protein CHOP (GADD153) is an inhibitor of Wnt/TCF signals

“…Mutations in the apc or b-catenin genes lead to cytosolic accumulation of b-Catenin, increased transcriptional activity of the b-Catenin/TCF complex and eventually to uncontroled proliferation (for review see Peifer and Polakis, 2000;Clevers, 2004). CHOP is upregulated in some colorectal cancers, and correlates with the invasiveness of these tumours in situ (Rask et al, 2000). However, the available evidence strongly indicates that CHOP is an antiproliferative and proapoptitic protein (Barone et al, 1992;Maytin et al, 2001).…”

“…Expression levels of CHOP and C/EBPb correlate with the invasiveness of human colorectal cancer (Rask et al, 2000), and the cancer chemopreventive substance curcumin enhances CHOP expression in colonocytes (HCT-116) containing a mutant b-Catenin (Scott and Loo, 2004). Curcurmin treatment of HCT-116 cells impairs b-Catenin/TCF-LEF signalling at different steps in these cells, resulting in growth arrest and apoptosis (Jaiswal et al, 2002), but the cellular mediators of this effect remain to be identified.…”

Conditional ablation of C/EBPβ demonstrates its keratinocyte-specific requirement for cell survival and mouse skin tumorigenesis

“…Moreover, overexpression of C/EBPb-2 in a human mammary epithelial cell line lead to anchorage independence and invasive properties (Bundy and Sealy, 2003). C/EBPb is highly expressed in colorectal tumors (Rask et al, 2000) and is associated with ovarian tumor progression (Sundfeldt et al, 1999). Furthermore, C/EBPb can interact with cyclin D1 and appears to be important for the unique pattern of altered gene expression in human cancers that overexpress cyclin D1 (Lamb et al, 2003).…”

“…As a result of the high degree of conservation in their bZIP domains, C/EBP family members form both homodimers and heterodimers (Rask et al, 2000). C/EBPd, another member of the C/EBP family, is upregulated in mouse skin papillomas and squamous cell carcinomas (Kim and Fischer, 1998).…”

Decreased survival of C/EBPβ-deficient keratinocytes is due to aberrant regulation of p53 levels and function

“…In Wilms' tumors, or nephroblastomas, C/EBPb is expressed at high levels in relapsing and metastatic tumors and blocking C/EBPb expression in a Wilms' tumor cell line results in spontaneous apoptosis (Li et al, 2005). Increased expression of C/EBPb is associated with human breast, colorectal and ovarian tumorigenesis (Sundfeldt et al, 1999;Rask et al, 2000;Bundy and Sealy, 2003). In addition, cyclin D1 can interact with C/EBPb to alter gene expression and there is evidence that this interaction is required for the unique patterns of gene expression observed in human cancers that overexpress cyclin D1 (Lamb et al, 2003).…”