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

Abstract

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 RARβ 2 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.