title: Role of Frizzled6 in the molecular mechanism of beta-carotene action in the lung.
abstract: β-Carotene (BC) is omnipresent in our diet, both as natural food component as well as an additive. BC and its metabolites have important biological functions. For this reason, BC is generally considered to be a health promoting compound. Two human trials, however, have described adverse effects in lung tissue, increasing the risk of lung cancer. We previously applied transcriptomic analyses in a unique animal model, beta-carotene 15,15'-monooxygenase 1 knockout (Bcmo1(-/-)) mice that are, like humans, able to accumulate intact BC. In our search to unravel the molecular action of BC in the lung, we previously identified two genes particularly strongly down-regulated by BC in lung tissue of the male Bcmo1(-/-) mice: frizzled homologue 6 (Fzd6) and collagen triple helix repeat containing 1 (Cthrc1). In the present study, our aim was to further elucidate the role of FZD6 in lung epithelial cells and to provide a mechanistic explanation for BC increased lung cancer risk in humans. We performed whole genome microarray analysis on silenced FZD6 in non-tumor human type II bronchial epithelial BEAS-2B cells using RNAi. To directly link FZD6 to BC-effects on the lung, we compared the FZD6-silenced BEAS-2B gene expression profile to the BC-dependent gene expression profile of Bcmo1(-/-) mouse lungs. A number of relevant genes were regulated in the same direction in FZD6(-) BEAS-2B and in BC-exposed lungs of Bcmo1(-/-) mice and revealed enrichment of the Gene Ontology terms "oncogenes", "cell proliferation" and "cell cycle", which suggests a mediating role of FZD6 in BC-induced uncontrolled proliferation of lung cells.
authors.affiliation: Human and Animal Physiology, Wageningen University, 6708 WD Wageningen, The Netherlands. Electronic address: rosariapiga@tiscali.it.
authors.forename: Rosaria
authors.initials: R
authors.lastname: Piga
authors.affiliation: Human and Animal Physiology, Wageningen University, 6708 WD Wageningen, The Netherlands. Electronic address: dorien.vandartel@wur.nl.
authors.forename: Dorien
authors.initials: D
authors.lastname: van Dartel
authors.affiliation: Human and Animal Physiology, Wageningen University, 6708 WD Wageningen, The Netherlands. Electronic address: annelies.bunschoten@wur.nl.
authors.forename: Annelies
authors.initials: A
authors.lastname: Bunschoten
authors.affiliation: Human and Animal Physiology, Wageningen University, 6708 WD Wageningen, The Netherlands. Electronic address: inge.vanderstelt@wur.nl.
authors.forename: Inge
authors.initials: I
authors.lastname: van der Stelt
authors.affiliation: Human and Animal Physiology, Wageningen University, 6708 WD Wageningen, The Netherlands. Electronic address: jaap.keijer@wur.nl.
authors.forename: Jaap
authors.initials: J
authors.lastname: Keijer
mesh_terms: D000818:Animals; D001980:Bronchi / Q000166:cytology / Q000187:drug effects; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D019587:Dietary Supplements; D015536:Down-Regulation; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism; D051157:Frizzled Receptors / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D020868:Gene Silencing; D006801:Humans; D008168:Lung / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D020411:Oligonucleotide Array Sequence Analysis; D013045:Species Specificity; D019207:beta Carotene / Q000494:pharmacology*; D050559:beta-Carotene 15,15'-Monooxygenase / Q000235:genetics*
chemical_list: C484687:FZD6 protein, human; D051157:Frizzled Receptors; C111048:Fzd6 protein, mouse; D019207:beta Carotene; D050559:beta-Carotene 15,15'-Monooxygenase
keywords: BEAS-2B; Beta-carotene; FZD6; Gene silencing; Lung cancer