title: A novel human ghrelin variant (In1-ghrelin) and ghrelin-O-acyltransferase are overexpressed in breast cancer: potential pathophysiological relevance.
abstract: 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.
authors.affiliation: Department of Cell Biology, Physiology and Immunology, Instituto Maimónides de Investigación Biomédica de Córdoba, University of Córdoba, Hospital Universitario Reina Sofía, and CIBERobn Fisiopatología de la Obesidad y la Nutrición, Córdoba, Spain.
authors.forename: Manuel D
authors.initials: MD
authors.lastname: Gahete
authors.forename: José
authors.initials: J
authors.lastname: Córdoba-Chacón
authors.forename: Marta
authors.initials: M
authors.lastname: Hergueta-Redondo
authors.forename: Antonio J
authors.initials: AJ
authors.lastname: Martínez-Fuentes
authors.forename: Rhonda D
authors.initials: RD
authors.lastname: Kineman
authors.forename: Gema
authors.initials: G
authors.lastname: Moreno-Bueno
authors.forename: Raúl M
authors.initials: RM
authors.lastname: Luque
authors.forename: Justo P
authors.initials: JP
authors.lastname: Castaño
mesh_terms: D000217:Acyltransferases / Q000235:genetics*; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004247:DNA; D017931:DNA Primers; D005260:Female; D054439:Ghrelin / Q000235:genetics*; D006801:Humans; D008969:Molecular Sequence Data; D010215:Papio; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D017931:DNA Primers; D054439:Ghrelin; D004247:DNA; D000217:Acyltransferases; C542776:MBOAT4 protein, human