Loss of 4.1N in epithelial ovarian cancer results in EMT and matrix-detached cell death resistance

Abstract

Epithelial ovarian cancer (EOC) is one of the leading causes of death from gynecologic cancers and peritoneal dissemination is the major cause of death in patients with EOC. Although the loss of 4.1N is associated with increased risk of malignancy, its association with EOC remains unclear. To explore the underlying mechanism of the loss of 4.1N in constitutive activation of epithelial-mesenchymal transition (EMT) and matrix-detached cell death resistance, we investigated samples from 268 formalin-fixed EOC tissues and performed various in vitro and in vivo assays. We report that the loss of 4.1N correlated with progress in clinical stage, as well as poor survival in EOC patients. The loss of 4.1N induces EMT in adherent EOC cells and its expression inhibits anoikis resistance and EMT by directly binding and accelerating the degradation of 14-3-3 in suspension EOC cells. Furthermore, the loss of 4.1N could increase the rate of entosis, which aggravates cell death resistance in suspension EOC cells. Moreover, xenograft tumors in nude mice also show that the loss of 4.1N can aggravate peritoneal dissemination of EOC cells. Single-agent and combination therapy with a ROCK inhibitor and a 14-3-3 antagonist can reduce tumor spread to varying degrees. Our results not only define the vital role of 4.1N loss in inducing EMT, anoikis resistance, and entosis-induced cell death resistance in EOC, but also suggest that individual or combined application of 4.1N, 14-3-3 antagonists, and entosis inhibitors may be a promising therapeutic approach for the treatment of EOC.

Entosis: From Cell Biology to Clinical Cancer Pathology

“…An interesting link between loss of cellular adhesion to extracellular matrix, cancer progression and entosis was found in the case of epithelial ovarian cancer (EOC) [ 31 ]. An analysis of 268 archived paraffin-embedded samples found that loss of the 4.1N protein was associated with more malignant phenotype and worse prognosis.…”

4.1N-Mediated Interactions and Functions in Nerve System and Cancer

“…The result from the nude mice model suggests a suppressor role of 4.1N in a unique interesting peritoneal dissemination that is different from lymph node or blood metastases in other cancers ( Xi et al, 2013 ; Wang et al, 2020a ). A previous study proposed that 4.1N suppresses EOC’s intraperitoneal dissemination by regulating 4.1N-interacting adhesion molecules and the F-actin cytoskeleton during the epithelial–mesenchymal transition (EMT) ( Wang et al, 2020a ). Besides, in EOC, a suppressor role of 4.1N in hypoxia-induced EMT and related genes has been demonstrated.…”

“…The loss of 4.1N expression is more related to type II rather than type I EOCs ( Xi et al, 2013 ). 4.1N loss is significantly correlated with a poorer differentiation and aggressive behavior, increased clinical stage progression, lower response to first-line chemotherapeutic treatment, poor overall survival, and progression-free survival in EOC patients ( Xi et al, 2013 ; Wang et al, 2020a ). The result from the nude mice model suggests a suppressor role of 4.1N in a unique interesting peritoneal dissemination that is different from lymph node or blood metastases in other cancers ( Xi et al, 2013 ; Wang et al, 2020a ).…”

“…4.1N loss is significantly correlated with a poorer differentiation and aggressive behavior, increased clinical stage progression, lower response to first-line chemotherapeutic treatment, poor overall survival, and progression-free survival in EOC patients ( Xi et al, 2013 ; Wang et al, 2020a ). The result from the nude mice model suggests a suppressor role of 4.1N in a unique interesting peritoneal dissemination that is different from lymph node or blood metastases in other cancers ( Xi et al, 2013 ; Wang et al, 2020a ). A previous study proposed that 4.1N suppresses EOC’s intraperitoneal dissemination by regulating 4.1N-interacting adhesion molecules and the F-actin cytoskeleton during the epithelial–mesenchymal transition (EMT) ( Wang et al, 2020a ).…”

Harnessing Carcinoma Cell Plasticity Mediated by TGF-β Signaling

“…Carcinoma cells that acquire a mesenchymal-like phenotype through EMT are more resistant to cell death [ 31 ], and numerous studies have shown a correlation between EMT and chemotherapy resistance [ 32 , 33 ]. For example, in lung carcinoma, EMT can elicit resistance to newly developed targeted therapeutics such as alectinib, ceritinib, and lorlatinib in lung tumors associated with ALK translocations, suggesting EMT as a mechanism leading to drug resistance [ 34 ].…”