P53-WWOX-TIAF1為腫瘤抑制軸心

Abstract

Tumor suppressor WWOX or WOX1 is frequently lost in many malignant tumors. Here we demonstrated that Wwox exon 1-ablation mouse embryonic fibroblasts (Wwox-/- MEF) migrated individeually and faster than wild type Wwox+/+ cells. Normally, the wild type cells aligned together tightly and migrated collectively. The proliferation rates have no significant different between WOX1 knockout cells and wild type cells. Transiently overexpressed WOX1 suppressed the migration of breast MDA-MB-231 and MCF-7 cells. Knockdown of WOX1 by small interfering RNA, or ectopic expression with dominant-negative WOX1 increased the migration. WOX1 interacts with p53 and TIAF1 (TGF-beta1-induced antiapoptotic factor). Previously we have determined that co-expression of WOX1, TIAF1, and/or p53 induces apoptosis. Here, we demonstrated that co-expression of WOX1, TIAF1, and/or p53 suppressed cancer cell migration and anchorage-independent cell growth. Remarkably, in migration assay, when wild type MEF cells met knockout cells, the knockout failed to recognize the wild type cells, although they were from the same mice strain. Upon reaching out with their dendrites to the wild type, the knockout cells then moved backward without aligning or regrouping with the wild type cells. The result suggests that WOX1 is involved in cell-cell interaction. Interestingly, when two distinct cell types, expressing with or without WOX1, encountered each other, they migrated faster. Stimulation of TGF-beta1 and TGF-beta2 promoted cell migration of Wwox+/+ MEF cells but not that of Wwox-/- MEF cells. Taken together, WOX1 not only suppresses cell migration but also participates in cell-cell recognition. Besides, WOX1 plays a regulatory role in the TGF-beta-mediated cell migration. WOX1/p53/TIAF1 is a potential axis of tumor suppression.