Activin B promotes endometrial cancer cell migration by down-regulating E-cadherin via SMAD-independent MEK-ERK1/2-SNAIL signaling

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.

The systemic activin response to pancreatic cancer: implications for effective cancer cachexia therapy

“…Elevated plasma activin A level is also documented with cachexia and mortality in PDAC . Activin B has received much less attention regarding its role in cancer or cancer cachexia . Experimentally, exogenous activin induces weight loss and muscle wasting in mice, while injection of a soluble activin receptor or activin‐receptor blocking antibody induces skeletal muscle hypertrophy and prevents or slows cachexia in mice with cancer or other muscle wasting conditions …”

“…29,30 Activin B has received much less attention regarding its role in cancer or cancer cachexia. [31][32][33] Experimentally, exogenous activin induces weight loss and muscle wasting in mice, 27,28 while injection of a soluble activin receptor or activin-receptor blocking antibody induces skeletal muscle hypertrophy and prevents or slows cachexia in mice with cancer or other muscle wasting conditions. 34,35 Given activin A deregulation in cancer and likely its systemic impact on host biology, we aimed to investigate activin expression and cachexia in murine models of PDAC and in patients and to evaluate the therapeutic utility of blocking the activin receptor ACVR2B-mediated signalling pathway.…”

eIF4E‑related miR‑320a and miR‑340‑5p inhibit endometrial carcinoma cell metastatic capability by preventing TGF‑β1‑induced epithelial‑mesenchymal transition

“…In addition, the expression of Snail was attenuated by miR-320a and miR-340-5p mimics. Snail, which is a key regulator of EMT, induces epithelial cells with migratory and invasive properties during tumor progression (36), and several studies have confirmed that Snail stimulates invasion and metastasis of EC (37,38). Robichaud et al (35) have demonstrated that Snail is regulated by p-eIF4E.…”

Differential Urinary Proteomic Analysis of Endometrial Cancer

“…Cadherin-1 (E-cadherin) is a calcium-dependent transmembrane glycoprotein, relevant in establishing adherent connections between epithelial cells. It is linked to cytoskeletal actin filaments via α-and β-(or possibly γ-) catenin (Schlosshauer et al 2002, Xiong et al 2016. Its role in inhibiting invasion and metastasis is related to prevention of triggering (first step) of the metastatic cascade (Mell et al 2004).…”