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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 RAR?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.

SUBMITTER: Liu L

PROVIDER: S-EPMC2941705 | biostudies-literature | 2010 Oct

REPOSITORIES: biostudies-literature

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

Liu Limin L Tang Xiao-Han XH Scognamiglio Theresa T Gudas Lorraine J LJ

The Journal of nutritional biochemistry 20091201 10

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 m ...[more]

PMID: 19954945

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Project description:BACKGROUND:Oral squamous cell carcinoma (OSCC) is the sixth largest group of malignancies globally and the single largest group of malignancies in the Indian subcontinent. Despite the advances in treatment and therapeutic modalities the five year survival rate of OSCC has not changed in the last few decades, and remains less than 40%. Several studies have focused on defining molecular markers that can either detect cancer at an early stage or can predict patient's outcome. However, such markers are still undefined. Keratins (K) are epithelia predominant intermediate filament proteins which are expressed in a differentiation dependent and site specific manner. Keratins are being used as biomarkers in different epithelial disorders including cancer. They are associated with desmoplakin and ?6?4 integrin which are components of desmosomes and hemidesmosomes respectively. MATERIALS AND METHODS:4-Nitroquinoline 1-Oxide (4NQO) was used as a carcinogen for the development of various stages of oral carcinogenesis in rat lingual mucosa. Two-Dimentional gel electrophoresis was performed for the separation of Keratins followed by western blotting for their specific identification. Western blotting and RT PCR was carried out for desmoplakin and ?6?4 integrin respectively to understand their levels. Immunohistochemical analysis was carried out to further study the localization of desmoplakin and ?6 integrin. RESULTS:In this study we have analysed the alterations in Keratins and associated proteins during sequential stages of 4NQO induced rat oral carcinogenesis. Our results showed that the alterations primarily begin after the dysplastic changes in the lingual epithelium like the elevation of Keratins 5/6a, ectopic expression of Keratin 8, increase in suprabasal expression of ?6 integrin and increase in desmoplakin levels. Most of these alterations persisted till the development of SCC except desmoplakin, the levels of which were downregulated in papillomatous lesions and SCC. Many of these alterations have also been documented in human oral carcinogensis. CONCLUSION:Thus, 4NQO model of rat lingual carcinogenesis reproduces majority of the changes that are seen in human oral carcinogenesis and it can be exploited for the development of biomarkers.

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

Publications

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

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