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A Novel Human Ghrelin Variant (In1-Ghrelin) and Ghrelin-O-Acyltransferase Are Overexpressed in Breast Cancer: Potential Pathophysiological Relevance

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posted on 16.08.2012, 00:00 by Manuel D. Gahete, José Córdoba-Chacón, Marta Hergueta-Redondo, Antonio J. Martínez-Fuentes, Rhonda D. Kineman, Gema Moreno-Bueno, Raúl M. Luque, Justo P. Castaño
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.


This work has been supported by FPU-AP20052473 (Ministerio de Ciencia e Innovación to Manuel D. Gahete), FI06-00804 (Instituto de Salud Carlos III to José Córdoba-Chacón), SAF2007-63075 (Ministerio de Ciencia e Innovación to Marta Hergueta-Redondo), NIDDK30677/VA-Merit-Award (National Institutes of Health and Jesse Brown VA Medical Center to Rhonda D. Kineman), SAF2007-63075/FMM07 (Ministerio de Ciencia e Innovación to Gema Moreno-Bueno), RYC-2007-00186/BFU2008-01136-BFI (Ramón y Cajal and Ministerio de Ciencia e Innovación to Raul M. Luque), and BIO-0139/CTS-01705/BFU2007-60180-BFI (Ministerio de Ciencia e Innovación and Junta de Andalucía to Justo P. Castaño).


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This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication. DOI: 10.1371/journal.pone.0023302


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