1. Department of Pathology, School of Basic Medical Sciences, Third Hospital, Peking University Health Science Center, Beijing 100191, China 2. Institute of Systems Biomedicine, Beijing Key Laboratory of Tumor Systems Biology, School of Basic Medical Sciences, Peking University Health Science Center, Peking University, Beijing 100191, China 3. College of Life Science, Zhengzhou University, Zhengzhou 450051, China 4. Red Cell Physiology Laboratory, New York Blood Center, New York, NY 10065, USA
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 matrixdetached 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.
. [J]. Protein & Cell, 2021, 12(2): 107-127.
Dandan Wang, Letian Zhang, Ajin Hu, Yuxiang Wang, Yan Liu, Jing Yang, Ningning Du, Xiuli An, Congying Wu, Congrong Liu. Loss of 4.1N in epithelial ovarian cancer results in EMT and matrix-detached cell death resistance. Protein Cell, 2021, 12(2): 107-127.
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