Abstract
High-risk type II endometrial cancers account for ~30% of cases but ~75% of deaths due, in part, to their tendency to metastasize. Histopathological studies of type II endometrial cancers (non-endometrioid, mostly serous) suggest overproduction of activin B and down-regulation of E-cadherin, both of which are associated with reduced survival. Our previous studies have shown that activin B increases the migration of type II endometrial cancer cell lines. However, little is known about the relationship between activin B signaling and E-cadherin in endometrial cancer. We now demonstrate that activin B treatment significantly decreases E-cadherin expression in both a time- and concentration-dependent manner in KLE and HEC-50 cell lines. Interestingly, these effects were not inhibited by knockdown of SMAD2, SMAD3 or SMAD4. Rather, the suppressive effects of activin B on E-cadherin were mediated by MEK-ERK1/2-induced production of the transcription factor SNAIL. Importantly, activin B-induced cell migration was inhibited by forced-expression of E-cadherin or pre-treatment with the activin/TGF-β type I receptor inhibitor SB431542 or the MEK inhibitor U0126. We have identified a novel SMAD-independent pathway linking enhanced activin B signaling to reduced E-cadherin expression and increased migration in type II endometrial cancer.
Highlights
Endometrial cancer is the second most lethal gynecological malignancy in North America
To investigate the relationship between activin B signaling and E-cadherin in serous endometrial carcinoma (TCGA; n=53; [15]), we used the cBioPortal for Cancer Genomics to perform enrichment analysis comparing E-cadherin levels between unaltered samples and those with elevation of at least one component of the activin B ligand-receptor gene set, including inhibin βB (INHBB), type I receptor ACVR1B, and type II receptors ACVR2A and ACVR2B (Figure 1)
Serous tumors with INHBB, ACVR1B, ACVR2A or ACVR2B mRNA levels in the upper quartile displayed reduced levels of E-cadherin protein (P = 0.039) and a trend towards reduced levels of E-cadherin mRNA (P = 0.059). These findings suggest that enhanced activin B signaling may contribute to the downregulation of E-cadherin in type II serous endometrial cancer
Summary
Endometrial cancer is the second most lethal gynecological malignancy in North America. Type I endometrial cancers are generally low-grade endometrioid tumors whereas type II endometrial cancers are mostly of serous, clear cell or high-grade endometrioid histology [4, 5]. Type II endometrial cancers account for ~30% of cases but ~75% of deaths due, in part, to their tendency to metastasize. Serous endometrial carcinomas account for ~40% of all endometrial cancer deaths and are extremely aggressive, with relapse rates as high as 50% and 5-year overall survival rates as low as 18-27% [4, 6, 7]. A deeper understanding of the molecular pathways involved in the invasion and metastatic spread of type II endometrial cancers is needed in order to develop new therapeutic approaches with the potential to improve patient outcomes
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