Abstract
The effects of bone morphogenetic proteins (BMPs), members of the transforming growth factor-β (TGF-β) family, in endometrial cancer (EC) have yet to be determined. In this study, we analyzed the TCGA and MSK-IMPACT datasets and investigated the effects of BMP2 and of TWSG1, a BMP antagonist, on Ishikawa EC cells. Frequent ACVR1 mutations and high mRNA expressions of BMP ligands and receptors were observed in EC patients of the TCGA and MSK-IMPACT datasets. Ishikawa cells secreted higher amounts of BMP2 compared with ovarian cancer cell lines. Exogenous BMP2 stimulation enhanced EC cell sphere formation via c-KIT induction. BMP2 also induced EMT of EC cells, and promoted migration by induction of SLUG. The BMP receptor kinase inhibitor LDN193189 augmented the growth inhibitory effects of carboplatin. Analyses of mRNAs of several BMP antagonists revealed that TWSG1 mRNA was abundantly expressed in Ishikawa cells. TWSG1 suppressed BMP7-induced, but not BMP2-induced, EC cell sphere formation and migration. Our results suggest that BMP signaling promotes EC tumorigenesis, and that TWSG1 antagonizes BMP7 in EC. BMP signaling inhibitors, in combination with chemotherapy, might be useful in the treatment of EC patients.
Highlights
High expression of BMP7 mRNA correlated with significantly lower survival of endometrial cancer (EC) patients; the expression of BMP2 mRNA showed a correlation, albeit not significant, with poor EC patient survival (Figure 1D,E)
We investigated the effect of bone morphogenetic proteins (BMPs) signaling on downstream genes in Ishikawa cells, and found that BMP2 induced ID1, SNAIL and SLUG mRNA in a time-dependent manner (Figure 3A)
We have demonstrated tumor promoting effects of BMP signaling in EC cells, by induction of cancer stemness, epithelial-mesenchymal transition (EMT), and migration
Summary
EC is the sixth most common cancer in women, and shows a rising incidence partly due to increasing obesity and longer life-span. EC patients have relatively good prognosis because they are often diagnosed at early stages with symptoms such as abnormal bleeding and lower abdominal pain, but still about 90,000 patients worldwide die from EC per year [1]. EC is divided into endometrioid carcinoma, which is the most common histological subtype with relatively good prognosis, and non-endometrioid carcinoma with worse prognosis [2]. Endometrial carcinosarcoma (ECS) is a rare histologic subtype of EC, which contains both carcinomatous and sarcomatous components, and causes around 16% of deaths due to malignancies of uterine corpus [3,4]. The sarcomatous component is considered to be derived from the carcinomatous component in most cases [4]
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