Cell adhesion molecule BVES functions as a suppressor of tumor cells extrusion in hepatocellular carcinoma metastasis

Abstract

Background Tumor cells detachment from primary lesions is an early event for hepatocellular carcinoma (HCC) metastasis, in which cell adhesion molecules play an important role. The role of mechanical crowding has attracted increasing attention. Previous studies have found that overcrowding can induce live cells extrusion to maintain epithelial cell homeostasis, and normally, live extruded cells eventually die through a process termed anoikis, suggesting the potential of tumor cells resistant to anoikis might initiate metastasis from primary tumors by cell extrusion. We have demonstrated transmembrane adhesion molecule blood vessel epicardial substance (BVES) suppression as an early event in HCC metastasis. However, whether its suppression is involved in HCC cell extrusion, especially in HCC metastasis, remains unknown. This study aims to investigate the role of BVES in tumor cells extrusion in HCC metastasis, as well as the underlying mechanisms. Methods Cells extrusion was observed by silicone chamber, petri dish inversion, and three-dimensional cell culture model. Polymerase chain reaction, western blotting, immunohistochemistry, immunofluorescence, co-immunoprecipitation, and RhoA activity assays were used to explore the underlying mechanisms of cell extrusion regulated by BVES. An orthotopic xenograft model was established to investigate the effects of BVES and cell extrusion in HCC metastasis in vivo. Results Tumor cell extrusion was observed in HCC cells and tissues. BVES expression was decreased both in HCC and extruded tumor cells. BVES overexpression led to the decrease in HCC cells extrusion in vitro and in vivo. Moreover, our data showed that BVES co-localized with ZO-1 and GEFT, regulating ZO-1 expression and localization, and GEFT distribution, thus modulating RhoA activity. Conclusion The present study revealed that BVES downregulation in HCC enhanced tumor cells extrusion, thus promoting HCC metastasis, which contributed to a more comprehensive understanding of tumor metastasis, and provided clues for developing novel HCC therapy strategies.

Development and validation of a novel anoikis-related gene signature for predicting prognosis in ovarian cancer

“…Inhibition of anoikis in TME may contributed to tumor migration and metastasis [38,39]. Anoikis resistance was found to be caused by multiple complex pathways [9,[40][41][42].…”

“…Inhibition of anoikis in TME may contributed to tumor migration and metastasis [ 38 , 39 ]. Anoikis resistance was found to be caused by multiple complex pathways [ 9 , 40 – 42 ]. Targeting the ANRGs may provide a novel approach to overcome metastasis of OC.…”

“…It can regulate the dynamic balance of the microenvironment by eliminating dislocated cells upon cell detachment from the extracellular matrix (ECM) [ 8 ]. Anoikis plays an essential role in tumor invasion and metastasis [ 9 , 10 ]. The initiation of anoxia apoptosis resistance can help isolated cells escape the death signal pathway, allowing cells to survive under adverse conditions [ 11 , 12 ].…”

Identification and experimental verification of an anoikis and immune related signature in prognosis for lung adenocarcinoma

“…Anoikis, as a form of programmed cell death, is characterized by the loss of cell adhesion to the extracellular matrix (ECM) or the improper adhesion resulting in rapid apoptosis of normal epithelial cells (4)(5)(6). In contrast to normal cells, tumor cells have to develop strong resistance to anoikis in order to keep cancer cells alive in metastasis and proliferation (7)(8)(9)(10). Tumor cells can survive in an inappropriate ECM only after the tumor cells initiate the anti-anoikis feature.…”