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 (p16INK4A-pRb pathway), and up-regulation of many members of the Wnt gene family. In particular, 4.1B-/-iMEFs exhibited nuclear accumulation of β-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. © 2016 Wiley Periodicals, Inc.
The State Key Laboratory of Medical Genetics and School of Life Sciences, Central South University, Changsha, China.
Zi
Z
Wang
College of Life Sciences, Zhengzhou University, Zhengzhou, China.
Jingxin
J
Zhang
The State Key Laboratory of Medical Genetics and School of Life Sciences, Central South University, Changsha, China.
Yayue
Y
Zeng
The State Key Laboratory of Medical Genetics and School of Life Sciences, Central South University, Changsha, China.
Shuming
S
Sun
The State Key Laboratory of Medical Genetics and School of Life Sciences, Central South University, Changsha, China.
Ji
J
Zhang
Department of Histology and Embryology, Xiangya School of Medicine, Central South University, Changsha, China.
Bin
B
Zhang
The State Key Laboratory of Medical Genetics and School of Life Sciences, Central South University, Changsha, China.
Min
M
Zhu
Department of Respiratory Medicine, Respiratory Disease Research Institute, Second XiangYa Hospital of Central South University, Changsha, China.
Ruoyun
R
Ouyang
The State Key Laboratory of Medical Genetics and School of Life Sciences, Central South University, Changsha, China.
Bianyin
B
Ma
Molecular Science and Biomedicine Laboratory, State Key Laboratory for Chemo/Biosensing and Chemometrics, College of Biology, College of Chemistry and Chemical Engineering, Collaborative Innovation Center for Chemistry and Molecular Medicine, Hunan University, Changsha, China.
Mao
M
Ye
College of Life Sciences, Zhengzhou University, Zhengzhou, China.|Laboratory of Membrane Biology, New York Blood Center, New York, New York.
Xiuli
X
An
The State Key Laboratory of Medical Genetics and School of Life Sciences, Central South University, Changsha, China.
Jing
J
Liu
D000818:Animals; D063646:Carcinogenesis / Q000235:genetics* / Q000473:pathology; D002453:Cell Cycle; D002460:Cell Line; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000473:pathology; D058750:Epithelial-Mesenchymal Transition; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology*; D015972:Gene Expression Regulation, Neoplastic; D055786:Gene Knockout Techniques; D020935:MAP Kinase Signaling System; D051379:Mice; D008819:Mice, Nude; D008840:Microfilament Proteins / Q000235:genetics* / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism
C488402:Epb41l3 protein, mouse; D008840:Microfilament Proteins; D051176:beta Catenin; D051057:Proto-Oncogene Proteins c-akt
EMT; Protein 4.1B; malignant transformation; mouse embryonic fibroblast; tumor suppressor