Accumulation of annexin A2 and S100A10 prevents apoptosis of apically delaminated, transformed epithelial cells

Significance

When epithelial cells detach from the basal substratum and are extruded into the apical lumen, they will be subjected to physical stresses including the increased reactive oxygen species (ROS) and eventually undergo apoptosis. Oncogenically transformed epithelial cells often become resistant to apoptosis upon apical extrusion; however, the underlying molecular mechanisms still remain obscure. Here, we demonstrate that ANXA2 (Annexin A2) accumulates in apically extruded transformed cells. In addition, ANXA2 contributes to resistance to ROS-mediated apoptosis by suppressing p38MAPK, a stress-activated protein kinase, thereby promoting the formation of multilayered epithelia. Thus, ANXA2 is a potential therapeutic target to prevent the development of precancerous lesions.

Abstract

In various epithelial tissues, the epithelial monolayer acts as a barrier. To fulfill its function, the structural integrity of the epithelium is tightly controlled. When normal epithelial cells detach from the basal substratum and delaminate into the apical lumen, the apically extruded cells undergo apoptosis, which is termed anoikis. In contrast, transformed cells often become resistant to anoikis and able to survive and grow in the apical luminal space, leading to the formation of multilayered structures, which can be observed at the early stage of carcinogenesis. However, the underlying molecular mechanisms still remain elusive. In this study, we first demonstrate that S100A10 and ANXA2 (Annexin A2) accumulate in apically extruded, transformed cells in both various cell culture systems and murine epithelial tissues in vivo. ANXA2 acts upstream of S100A10 accumulation. Knockdown of ANXA2 promotes apoptosis of apically extruded RasV12-transformed cells and suppresses the formation of multilayered epithelia. In addition, the intracellular reactive oxygen species (ROS) are elevated in apically extruded RasV12 cells. Treatment with ROS scavenger Trolox reduces the occurrence of apoptosis of apically extruded ANXA2-knockdown RasV12 cells and restores the formation of multilayered epithelia. Furthermore, ROS-mediated p38MAPK activation is observed in apically delaminated RasV12 cells, and ANXA2 knockdown further enhances the p38MAPK activity. Moreover, the p38MAPK inhibitor promotes the formation of multilayered epithelia of ANXA2-knockdown RasV12 cells. These results indicate that accumulated ANXA2 diminishes the ROS-mediated p38MAPK activation in apically extruded transformed cells, thereby blocking the induction of apoptosis. Hence, ANXA2 can be a potential therapeutic target to prevent multilayered, precancerous lesions.