Collagen and calcium-binding EGF domains 1 is frequently inactivated in ovarian cancer by aberrant promoter hypermethylation and modulates cell migration and survival

Abstract

BACKGROUND: Collagen and calcium-binding EGF domains 1 (CCBE1) is an uncharacterised gene that has down-regulated expression in breast cancer. As CCBE1 maps to 18q21.32, a region frequently exhibiting loss of heterozygosity in ovarian cancer, the aim of this study was to determine the expression and function of CCBE1 in ovarian cancer. METHODS: Expression and methylation patterns of CCBE1 were determined in ovarian cancer cell lines and primary tumours. CCBE1 contains collagen repeats and an aspartic acid/asparagine hydroxylation/EGF-like domain, suggesting a function in extracellular matrix remodelling and migration, which was determined using small-interfering RNA (siRNA)-mediated knockdown and over-expression of CCBE1 in cell lines. RESULTS: CCBE1 is expressed in normal ovary, but is reduced in ovarian cancer cell lines and primary carcinomas. Pharmacological demethylation/deacetylation in ovarian cancer cell lines re-induced CCBE1 expression, indicating that epigenetic mechanisms contribute to its silencing in cancer. CCBE1 promoter hypermethylation was detected in 6/11 (55%) ovarian cancer cell lines and 38/ 81 (41%) ovarian carcinomas. siRNA-mediated knockdown of CCBE1 in ovarian cancer cell lines enhanced their migration; conversely, re-expression of CCBE1 reduced migration and survival. Hence, loss of CCBE1 expression may promote ovarian carcinogenesis by enhancing migration and cell survival. CONCLUSIONS: These data suggest that CCBE1 is a new candidate tumour suppressor in ovarian cancer.

Analysis of Secretome Changes Uncovers an Autocrine/Paracrine Component in the Modulation of Cell Proliferation and Motility by c-Myc

“…siRNA-mediated knockdown of the ECM protein CCBE1 in ovarian cancer cell lines was shown to enhanced cell migration. Accordingly CCBE1 was found frequently inactivated in ovarian cancer 61 . We found CCBE1 more than 6 times down-regulated by c-Myc in our secretome analysis (Table 1).…”

Epigenetic Biomarkers in the Management of Ovarian Cancer: Current Prospectives

“…Methylation induced silencing of PTEN has also been frequently observed in primary epithelial ovarian carcinomas (Kurose et al, 2001). CTGF (encodes the connective tissue growth factor) (Kikuchi et al, 2007;Barbolina et al, 2009), CCBE1 (hypothesized to be involved in regulation of cell motility) (Barton et al, 2010), HIC1 (a p53 target gene) (Rathi et al, 2002), CDH13 (Makarla et al, 2005), and CDH1 (the loss of which correlates with the upregulation of matrix metalloproteinases and metastasis-promoting protein a 5integrin) (Sawada et al, 2008) act as metastasis suppressors. Caslini et al, 2006;Cai et al, 2009 3.…”

Loss of heterozygosity at chromosomes 1p35-pter, 4q, and 18q and protein expression differences between adenocarcinomas of the distal stomach and gastric cardia

“…A recent study demonstrated that apoptosis regulator MCL1 (induced myeloid leukemia cell differentiation protein Mcl-1) is targeted for degradation by FBXW7 [23]. Another candidate gene, collagen and calcium-binding EGF domains 1 (CCBE1) located on 18q21.32, is downregulated in breast and ovarian cancers [24,25]. Previous work has demonstrated that CCBE1 can cause primary generalized lymph vessel dysplasia in humans [26].…”