The balance between two isoforms of LEF-1 regulates colon carcinoma growth.
BACKGROUND
Colon cancer is one of the most aggressive human malignancies, with a very poor prognosis. Although it has been suggested that different isoforms of the lymphoid enhancer factor (LEF-1) have opposing biological activities, the biological outcome of aberrant LEF-1 activation in colon cancer is still unclear. The aim of this study was to evaluate the effect of the different LEF-1 phenotypes on the growth of colon carcinoma cell lines. A deeper understanding of these processes might improve the targeted therapies for colon cancer by regulating the expression of LEF-1.


METHODS
The role of different isoforms of LEF-1 on the growth of human colon carcinoma cell lines (SW480 and HT-29) was studied using various in vitro and in vivo assays. In vitro proliferation, migration, adhesion and apoptosis of the cells stably transfected of different isoforms of LEF-1 were monitored by MTT assay, carboxyfluorescein diacetate-succinimidyl ester staining, annexin V staining, ECM adhesion assay and transwell assay, respectively. In nude mice, the formation of neovasculature in the tumors formed by our constructed cells was measured by immunohistochemistry. All the data were analyzed using a t test, and data were treated as significant when p < 0.05.


RESULTS
Overexpression of truncated LEF-1 (LEF-1-ΔL) in the colon cell lines, SW480 and HT29, inhibited their growth significantly in vitro and in vivo, but the full-length LEF-1 (LEF-1-FL) promoted the proliferation of HT29. Inactivation of Wnt signaling by LEF-1-ΔL reduced the expression of CXCR4 in colon cell lines, which may lead to a decrease in activities such as migration, adhesion and survival. In nude mice, the formation of neovasculature as well as an increase in tumor volume were inhibited by the short isoform of LEF-1. LEF-1-FL, however, caused an increase in all these parameters compared with controls.


CONCLUSIONS
These findings suggest that LEF-1 might play an important role in colon carcinogenesis by acting as a regulator. Enhanced expression of LEF-1-FL, which occurs frequently in colon cancer, may be a new target for clinical therapy.
Department of Medical Oncology, The First Affiliated Hospital of the School of Medicine of Xi'an Jiaotong University, Xi'an, Shaanxi Province, P. R. China. wsh2003@126.com
Shu-Hong
SH
Wang
Ke-Jun
KJ
Nan
Yao-Chun
YC
Wang
Wen-Juan
WJ
Wang
Tao
T
Tian
D000230:Adenocarcinoma / Q000473:pathology / Q000503:physiopathology; D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000502:physiology; D002448:Cell Adhesion / Q000235:genetics / Q000502:physiology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics / Q000502:physiology; D049109:Cell Proliferation; D003110:Colonic Neoplasms / Q000473:pathology* / Q000503:physiopathology*; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics / Q000502:physiology; D019073:HT29 Cells; D006801:Humans; D066298:In Vitro Techniques; D051821:Lymphoid Enhancer-Binding Factor 1 / Q000235:genetics* / Q000502:physiology*; D051379:Mice; D008819:Mice, Nude; D010641:Phenotype; D020033:Protein Isoforms; D019718:Receptors, CXCR4 / Q000502:physiology; D014183:Transplantation, Heterologous; D051153:Wnt Proteins / Q000502:physiology
C527276:CXCR4 protein, human; C497573:LEF1 protein, human; D051821:Lymphoid Enhancer-Binding Factor 1; D020033:Protein Isoforms; D019718:Receptors, CXCR4; D051153:Wnt Proteins