Downregulation of Fzd6 and Cthrc1 and upregulation of olfactory receptors and protocadherins by dietary beta-carotene in lungs of Bcmo1-/- mice

Yvonne G.J. van Helden, Roger W. Godschalk, Sandra G. Heil, Annelies Bunschoten, Susanne Hessel, Jaume Amengual, M. Luisa Bonet, Johannes von Lintig, Frederik J. van Schooten, Jaap Keijer

Research output: Contribution to journalArticle

Abstract

An ongoing controversy exists on beneficial versus harmful effects of high beta-carotene (BC) intake, especially for the lung. To elucidate potential mechanisms, we studied effects of BC on lung gene expression. We used a beta-carotene 15,15′-monooxygenase 1 (Bcmo1) knockout mouse (Bcmo1-/-) model, unable to convert BC to retinoids, and wild-type mice (Bcmo1+/+) mice to dissect the effects of intact BC from effects of BC metabolites. As expected, BC supplementation resulted in a higher BC accumulation in lungs of Bcmo1-/- mice than in lungs of Bcmo1+/+ mice. Whole mouse genome transcriptome analysis on lung tissue revealed that more genes were regulated in Bcmo1-/- mice than Bcmo1+/+ mice upon BC supplementation. Frizzled homolog 6 (Fzd6) and collagen triple helix repeat containing 1 (Cthrc1) were significantly downregulated (fold changes -2.99 and -2.60, respectively, false discovery rate < 0.05) by BC in Bcmo1-/-. Moreover, many olfactory receptors and many members of the protocadherin family were upregulated. Since both olfactory receptors and protocadherins have an important function in sensory nerves and Fzd6 and Cthrc1 are important in stem cell development, we hypothesize that BC might have an effect on the highly innervated pulmonary neuroendocrine cell (PNEC) cluster. PNECs are highly associated with sensory nerves and are important cells in the control of stem cells. A role for BC in the innervated PNEC cluster might be of particular importance in smoke-induced carcinogenesis since PNEC-derived lung cancer is highly associated with tobacco smoke.

Original languageEnglish (US)
Pages (from-to)1329-1337
Number of pages9
JournalCarcinogenesis
Volume31
Issue number8
DOIs
StatePublished - May 14 2010
Externally publishedYes

ASJC Scopus subject areas

  • Cancer Research

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    van Helden, Y. G. J., Godschalk, R. W., Heil, S. G., Bunschoten, A., Hessel, S., Amengual, J., Luisa Bonet, M., von Lintig, J., van Schooten, F. J., & Keijer, J. (2010). Downregulation of Fzd6 and Cthrc1 and upregulation of olfactory receptors and protocadherins by dietary beta-carotene in lungs of Bcmo1-/- mice. Carcinogenesis, 31(8), 1329-1337. https://doi.org/10.1093/carcin/bgq083