A novel human ghrelin variant (In1-ghrelin) and ghrelin-O-acyltransferase are overexpressed in breast cancer: potential pathophysiological relevance

• Published in: PloS one 2011-08, Vol.6 (8), p.e23302-e23302
• Main Authors: Gahete, Manuel D, Córdoba-Chacón, José, Hergueta-Redondo, Marta, Martínez-Fuentes, Antonio J, Kineman, Rhonda D, Moreno-Bueno, Gema, Luque, Raúl M, Castaño, Justo P
• Format: Article
• Language: English
• Subjects: Acyltransferase; Acyltransferases - genetics; Alternative splicing; Amino Acid Sequence; Amino acids; Animals; Apoptosis; Base Sequence; Biochemistry; Biological activity; Biology; Blotting, Western; Breast cancer; Breast Neoplasms - enzymology; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; Cancer; Cell growth; Cell Line, Tumor; Cell Proliferation; Cytokines; DNA; DNA Primers; Endocrinology; Estrogens; Exons; Female; Genes; Ghrelin; Ghrelin - genetics; Growth factors; Growth hormones; Human tissues; Humans; Immunology; Kinases; Medicine; Metabolism; Molecular Sequence Data; mRNA; Papio; Peptides; Physiology; Polypeptides; Post-translation; Prostate cancer; Reverse Transcriptase Polymerase Chain Reaction; RNA; Substrates; Tissues; Tumors
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0023302

The human ghrelin gene, which encodes the ghrelin and obestatin peptides, contains 5 exons (Ex), with Ex1-Ex4 encoding a 117 amino-acid (aa) preproprotein that is known to be processed to yield a 28-aa (ghrelin) and/or a 23-aa (obestatin) mature peptides, which possess biological activities in multiple tissues. However, the ghrelin gene also encodes additional peptides through alternative splicing or post-translational modifications. Indeed, we previously identified a spliced mRNA ghrelin variant in mouse (In2-ghrelin-variant), which is regulated in a tissue-dependent manner by metabolic status and may thus be of biological relevance. Here, we have characterized a new human ghrelin variant that contains Ex0-1, intron (In) 1, and Ex2 and lacks Ex3-4. This human In1-ghrelin variant would encode a new prepropeptide that conserves the first 12aa of native-ghrelin (including the Ser3-potential octanoylation site) but has a different C-terminal tail. Expression of In1-variant was detected in 22 human tissues and its levels were positively correlated with those of ghrelin-O-acyltransferase (GOAT; p = 0.0001) but not with native-ghrelin expression, suggesting that In1-ghrelin could be a primary substrate for GOAT in human tissues. Interestingly, levels of In1-ghrelin variant expression in breast cancer samples were 8-times higher than those of normal mammary tissue, and showed a strong correlation in breast tumors with GOAT (p = 0.0001), ghrelin receptor-type 1b (GHSR1b; p = 0.049) and cyclin-D3 (a cell-cycle inducer/proliferation marker; p = 0.009), but not with native-ghrelin or GHSR1a expression. Interestingly, In1-ghrelin variant overexpression increased basal proliferation of MDA-MB-231 breast cancer cells. Taken together, our results provide evidence that In1-ghrelin is a novel element of the ghrelin family with a potential pathophysiological role in breast cancer.