A novel human ghrelin variant (in1-ghrelin) and ghrelin-O-acyltransferase are overexpressed in breast cancer: Potential pathophysiological relevance
Entity
UAM. Departamento de BioquímicaPublisher
Public Library of ScienceDate
2011-08-11Citation
10.1371/journal.pone.0023302
Plos One 6.8 (2011): e23302
ISSN
1932-6203 (online)DOI
10.1371/journal.pone.0023302Funded by
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 Innovacio´n and Junta de Andalucía to Justo P. CastañoSubjects
MedicinaAbstract
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
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Google Scholar:Gahete, Manuel D.
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Córdoba-Chaćon, José
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Hergueta-Redondo, Marta
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Martińez-Fuentes, Antonio J.
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Kineman, Rhonda D.
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Moreno Bueno, Gema
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Luque, Raúl M.
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Castaño, Justo P.
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