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.
ABSTRACT
Objective@#To explore molecular characteristics of endometrial endometrioid cancer according to The Cancer Genome Atlas (TCGA) based molecular classification of endometrial carcinomas and to confirm simple and clinically applicable surrogate methodologies in pathological practice.@*Methods@#Two hundred and twenty-eight cases of endometrial endometroid adenocarcinomas (EnACs) collected from August 2001 to August 2017 from Peking University Health Science Center, Peking University Third Hospital were molecularly categorized by using Sanger sequencing for the exonuclease domain mutations (EDM) of POLE, and by immunohistochemistry for p53 and mismatch repair (MMR) proteins. The cohort was classified into polymerase-E exonuclease domain mutation (POLE EDM), mismatch repair deficiency (MMR-D), p53 abnormal (p53-abn) and p53 wild type (p53-wt) groups. The correlation between molecular subgroups and the clinical-pathological features including prognosis were analyzed.@*Results@#The cohort was distributed as follows: 11(4.8%) POLE EDM, 47(20.6%) MMR-D, 9(4.0%) p53-abn and 161(70.6%) p53-wt. p53-wt subgroup patients demonstrated significantly higher lymph node metastasis (P=0.011) and more advanced stage (P=0.036) than those of somatic hypermutation group cases (POLE EDM and MMR-D). In the FIGO grade 2-3 EnACs cohort, TCGA molecular subtyping was significantly correlated with progression-free survival and overall survival (P=0.043). POLE EDM subgroup had the best survival, while p53-abn subgroup had the worst.@*Conclusions@#Identification of POLE EDM and MMR-D subgroups provides independent and highly valuable prognostic information beyond established histological classification. Based on immunohistochemistry of MMR, p53 and POLE mutational analysis, this pragmatic molecular classification scheme can be served as a reliable surrogate for TCGA molecular classification, which has potential to be used routinely in Chinese pathological practice.