Oral carcinogenesis induced by 4-nitroquinoline 1-oxide in lecithin:retinol acyltransferase gene knockout mice.

TitleOral carcinogenesis induced by 4-nitroquinoline 1-oxide in lecithin:retinol acyltransferase gene knockout mice.
Publication TypeJournal Article
Year of Publication2010
AuthorsLiu L, Tang X-H, Scognamiglio T, Gudas LJ
JournalJ Nutr Biochem
Date Published2010 Oct
Keywords4-Nitroquinoline-1-oxide, Acyltransferases, Animals, Base Sequence, Carcinogens, Carcinoma, Squamous Cell, DNA Primers, Mice, Mice, Inbred C57BL, Mice, Knockout, Mouth Neoplasms, Reverse Transcriptase Polymerase Chain Reaction, Vitamin A

Lecithin:retinol acyltransferase (LRAT) regulates retinol (vitamin A) metabolism by esterifying retinol. LRAT expression is decreased in cultured human squamous cell carcinoma cells of the head and neck relative to normal epithelial cells. We investigated whether the carcinogen 4-nitroquinoline 1-oxide (4-NQO) induced a higher incidence of oral cancer in LRAT knockout (LRAT(-/-)) than in wild-type (Wt) mice. We also investigated retinol deprivation during 4-NQO treatment in LRAT(-/-) mice as a model for rapid retinol deficiency. We observed higher levels of secreted frizzled-related protein (Sfrp) 2, an inhibitor of WNT signaling, in tongue tumors in LRAT(-/-) versus Wt. LRAT(-/-) embryonic stem cells also expressed higher Sfrp2 transcripts, indicating an interaction between retinol and WNT signaling. Cox-2, Cyclin D1, p21, Trop2 and RARβ2 were not differentially expressed in Wt versus LRAT(-/-) tongue tumors. Wt and LRAT(-/-) mice fed a retinol-sufficient diet showed the same oral tumor incidence after 4-NQO treatment. In contrast, tongue tumors developed in 60% of Wt mice and in 100% of LRAT(-/-) mice fed a retinol-deficient diet during 4-NQO treatment (P=.22); moreover, the bromodeoxyuridine labeling index was 21.0 ± 2.4% in LRAT(-/-) normal tongue epithelium as compared to 9.9 ± 0.8% in Wt normal tongue epithelium (P<.001). Thus, partial retinol deficiency during carcinogen treatment (achieved in LRAT(-/-)) resulted in more proliferating cells in tongue epithelia from LRAT(-/-) mice and, ultimately, a greater probability of carcinogenesis.

Alternate JournalJ. Nutr. Biochem.
PubMed ID19954945
PubMed Central IDPMC2941705
Grant ListR01 DE010389 / DE / NIDCR NIH HHS / United States
R01 DE10389 / DE / NIDCR NIH HHS / United States