EPLIN is a crucial regulator for extrusion of RasV12-transformed cells

Abstract

At the initial stage of carcinogenesis, a mutation occurs in a single cell within a normal epithelial layer. We have previously shown that RasV12-transformed cells are apically extruded from the epithelium when surrounded by normal cells. However, the molecular mechanisms underlying this phenomenon remain elusive. Here, we demonstrate that Cav-1-containing microdomains and EPLIN (also known as LIMA1) are accumulated in RasV12-transformed cells that are surrounded by normal cells. We also show that knockdown of Cav-1 or EPLIN suppresses apical extrusion of RasV12-transformed cells, suggesting their positive role in the elimination of transformed cells from epithelia. EPLIN functions upstream of Cav-1 and affects its enrichment in RasV12-transformed cells that are surrounded by normal cells. Furthermore, EPLIN regulates non-cell-autonomous activation of myosin-II and protein kinase A (PKA) in RasV12-transformed cells. In addition, EPLIN substantially affects the accumulation of filamin A, a vital player in epithelial defense against cancer (EDAC), in the neighboring normal cells, and vice versa. These results indicate that EPLIN is a crucial regulator of the interaction between normal and transformed epithelial cells.

Rab5-regulated endocytosis plays a crucial role in apical extrusion of transformed cells

“…When normal or RasV12-transformed cells were cultured alone, EPLIN was mainly localized at cell-cell adhesions (Fig. 6A) (7,27). In contrast, in RasV12-transformed cells that were surrounded by normal cells, EPLIN was translocated from cell-cell contacts to the cytoplasmic region (Fig.…”

“…Next, we examined EPLIN, which forms a complex with E-cadherin at cell-cell adhesions (27). EPLIN has also been reported to play an active role in apical extrusion of the transformed cells through the activation of protein kinase A (PKA) (7,28). When normal or RasV12-transformed cells were cultured alone, EPLIN was mainly localized at cell-cell adhesions (Fig.…”

“…During this process, normal epithelial cells can recognize and actively eliminate the neighboring transformed cells through dynamic regulation of the cytoskeletal protein filamin, a phenomenon called EDAC (epithelial defense against cancer) (6), implying a notion that the normal epithelium has antitumor activity that does not involve immune systems. In addition, EPLIN (epithelial protein lost in neoplasm) is accumulated in transformed cells when they are surrounded by normal epithelial cells, and the EPLIN accumulation plays a crucial role in apical extrusion of the transformed cells (7). However, the molecular mechanisms of elimination of transformed cells still remain largely unknown, including the link between EDAC and EPLIN accumulation.…”

Spatial integration of E-cadherin adhesion, signalling and the epithelial cytoskeleton

“…This localized contraction enables apical constriction during invagination [73] or defines the topography of cell extrusion (apical or basal side of the epithelial monolayer). At the molecular level, cell extrusion directionality is driven by specific oncogenes (Ras, APC) [74,75] and the engagement of N-WASP or crosslinking proteins such as filamins or EPLIN [45,76,77].…”

Human phosphatase CDC14A regulates actin organization through dephosphorylation of epithelial protein lost in neoplasm

“…Downregulation of eplin frequently occurs in cancer tissues and contributes to the epithelia-to-mesenchymal transition (EMT) that enhances cancer cell metastasis and chemo-resistance of tumors (23,(33)(34)(35)(36)(37).…”