Ceruloplasmin is a novel adipokine which is overexpressed in adipose tissue of obese subjects and in obesity-associated cancer cells

Abstract

Obesity confers an increased risk of developing specific cancer forms. Although the mechanisms are unclear, increased fat cell secretion of specific proteins (adipokines) may promote/facilitate development of malignant tumors in obesity via cross-talk between adipose tissue(s) and the tissues prone to develop cancer among obese. We searched for novel adipokines that were overexpressed in adipose tissue of obese subjects as well as in tumor cells derived from cancers commonly associated with obesity. For this purpose expression data from human adipose tissue of obese and non-obese as well as from a large panel of human cancer cell lines and corresponding primary cells and tissues were explored. We found expression of ceruloplasmin to be the most enriched in obesity-associated cancer cells. This gene was also significantly up-regulated in adipose tissue of obese subjects. Ceruloplasmin is the body's main copper carrier and is involved in angiogenesis. We demonstrate that ceruloplasmin is a novel adipokine, which is produced and secreted at increased rates in obesity. In the obese state, adipose tissue contributed markedly (up to 22%) to the total circulating protein level. In summary, we have through bioinformatic screening identified ceruloplasmin as a novel adipokine with increased expression in adipose tissue of obese subjects as well as in cells from obesity-associated cancers. Whether there is a causal relationship between adipose overexpression of ceruloplasmin and cancer development in obesity cannot be answered by these cross-sectional comparisons.

Figure 1. Secretion of ceruloplasmin from fat cells.

A. Secretion during differentiation of progenitor cells to fat cells. Data are analysed by ANOVA, repeated measures. B and C. Influence of obesity on plasma levels and secretion from adipose tissue as analyzed with unpaired t-test. D. Relationship between secreted ceruloplasmin and its plasma levels as analyzed with linear regression.

Figure 2. View of the ceruloplasmin (CP) locus in the human genome.

A. CP is located on on the negative (purple) strand of chromosome 3 at position 3q23-q25, flanked by HPS3 on the positive (green) strand and CPHL1 on the negative strand. B. RefSeq mRNA models of the locus. C. Promoter activity signal distribution as measured by CAGE in the locus. The majority of expression comes from the 5′ end of CP. D. Expression (tags per million, TPM) across the locus for the cell lines present in FANTOM5. Cell lines with expression above 10 TPM are shown here; in total 269 cell lines were profiled. Obesity associated cell lines are indicated by black (O.R. > = 1.30) and gray (O.R. > = 1.20) arrows.