Knockout of 4.1B triggers malignant transformation in SV40T-immortalized mouse embryo fibroblast cells.

Protein 4.1B deficiency has been found to promote the tumor development; however, whether 4.1B deficiency participates in malignant transformation is unknown. In this study, we demonstrated that 4.1B gene deletion was sufficient to transform SV40T antigen-immortalized mouse embryonic fibroblasts (iMEFs), as reflected by the ability of 4.1B(-/-)iMEFs to growth in the environments that were growth restrictive for 4.1B(+/+)iMEFs and to form tumors in nude mice, whereas 4.1B(+/+)iMEFs were unable to form tumors in vivo. The histological examination revealed that the tumors generated by 4.1B(-/-) iMEFs were desmoid tumors with features of local invasion. Moreover, loss of 4.1B significantly accelerated cell cycle progression, accompanied by activation of typical proto-oncogene ERK, AKT, and the G1/S regulatory pathway (p16(INK4A)-pRb pathway), and up-regulation of many members of the Wnt gene family. In particular, 4.1B(-/-) iMEFs exhibited nuclear accumulation of -catenin, which is an indicator for desmoid tumor, with down-regulation of E-cadherin expression and up-regulation of snail, zeb1, and vimentin expression, indicating that EMT potentially occurred in transformed 4.1B(-/-) iMEFs. Moreover, we showed that 4.1B interacted with E-cadherin in MEF cells. Thus, our study provides previously unidentified roles and mechanisms of 4.1B in cellular transformation. (c) 2016 Wiley Periodicals, Inc.