Abstract 5351: The carcinogenesis rate is increased in MAL knock-out mice

Abstract

Abstract Background: The MAL gene was originally identified by Alonso during a study for differentially expressed genes in T-cell development. The MAL protein, which spans the membrane four times, is involved in normal apical transport and accurate sorting in distinct epithelial cells. The recent study on MAL gene down-regulation in primary human epithelial malignancies suggest that the loss of the MAL gene may be closely linked with a variety of human epithelial malignancies. In our previous study, we revealed that MAL was remarkably down-regulated in human head and neck squamous cell carcinoma. Exogenous expression of MAL in HNSCC cell lines could inhibit the proliferation, invasion, and induce apoptosis of cancer cells in vitro and suppress tumor growth in vivo. These data support that MAL, as a candidate tumor suppressor, contributes to carcinogenesis and development of HNSCC. Methods: To further confirm the role of MAL gene in development of carcinoma, a MAL gene knockout mouse model was produced. And the genotype and phenotype was investigated by our study group. The genotypes of MAL-/- and MAL+/+ mice were identified by RT-PCR, Western blot and Immunohistochemistry. The histopathology of main organs and tissues (esophagus, stomach, small intestine, colon, oral mucosa, etc.) were analyzed with H & E staining. Chemical carcinogenesis agent (4-nitroquinoline-N-oxide, 4NQO) was used to induce oral mucosa carcinomas. Results: MAL gene knockout mouse model was successfully established and passed on from generation to generation more than 3 years. The genotypes of MAL-/-, MAL+/-, MAL+/+ mice were identified. Phenotypic investigation found that MAL-/- mice raised no obvious spontaneous phenotype in 12 months and the incidence of spontaneous tumor was zero. Nevertheless, we found that there were significant differences between MAL-/- and MAL+/+ mice in the incidence rate, occurrence time and growth speed of tongue and esophageal squamous carcinoma which induced by a low dose of 4NQO water feeding for 16 weeks (P<0.01). We also found that the occurrence of esophageal squamous cell carcinoma performed the same changes as oral mucosa. Conclusions: Our results suggest that MAL gene knockout mouse significantly increased the susceptibility of cancer. The molecular mechanism about the tumor susceptibility becomes more important, and will be significant for developing cancer prevention and treatment methods. Citation Format: Wantao Chen, Xiangbing Wu, Wei Cao, Xu Wang. The carcinogenesis rate is increased in MAL knock-out mice. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5351. doi:10.1158/1538-7445.AM2014-5351