The small GTP-binding Ras-like protein DIRAS2 promotes cell proliferation in oral leukoplakia via the RAF/MEK/MAPK pathway

Background

The small GTP-binding Ras-like protein DIRAS2 may function as tumor suppressors in some tumors. However, a precise relation of DIRAS2 to precancerous lesions and their progression into cancer remains uncharted. Methods. DIRAS2 expression was detected in human oral leukoplakia (OLK) tissues and normal epithelial tissues. Using the Crispr/Cas9 and Cre-LoxP technology, homozygous knockout DIRAS2^flox/flox mice were produced, and crossed to K14-Cre mice in which the Cre recombinase specifically expressed in the epithelium. Epithelium specific DIRAS2 conditional knockout mice were generated. 4NQO-induced mouse model of DIRAS2 conditional knockout mice and control mice was used to explore the impact of epithelium specific deletion of DIRAS2 on the progression of tongue precancerous lesions and underlining mechanism was investigated. Results and Conclusion. The expression of DIRAS2 was abnormally higher in human OLK tissues than that in normal mucosa tissues. DIRAS2 conditional knockout in epithelium could inhibit the progression of tongue precancerous lesions in mice induced by 4NQO within the period analyzed. Besides, cell proliferation was decreased and the MAPK signaling cascade proteins were down-regulated expressed in both DIRAS2 knockdown human dysplastic oral keratinocyte cells and the tongue precancerous tissues of DIRAS2 conditional-knockout mice compared with the control, respectively. In summary, DIRAS2 may promote cell proliferation of OLK via the RAF/MEK/MAPK pathway.