Tumor Promoting Effect of BMP Signaling in Endometrial Cancer

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.

Bone Morphogenetic Protein Signaling in Cancer; Some Topics in the Recent 10 Years

“…High expression of BMP2 and BMP7 mRNA is associated with poorer survival in patients with endometrial cancer, albeit not significantly for BMP2 ( Fukuda et al, 2021 ). In addition, mutations in ACVR1, the gene encoding ALK2, are more frequently observed in endometrial cancer (>6%) than in most other cancers.…”

“…However, how BMP signaling affects the progression of ACVR1 mutation-negative DIPG cells remains unknown. It should also be noted that mutations in the ACVR1 gene are observed in other types of cancers, including endometrial cancer, although the frequencies of the ACVR1 mutations are lower than those in DIPG ( Fukuda et al, 2021 ).…”

“…In HCC, treatment with LDN-212854 repressed ID1 and EpCAM expression in cancer cells in vivo , suggesting that the repression of the BMP-9-induced CSC phenotype was attenuated by the inhibitor ( Chen et al, 2021 ). In brain tumors, ovarian cancer, lung cancer, oral squamous cell carcinoma, endometrial cancer, and melanoma, the therapeutic benefits of ALK2 inhibitors are suggested ( Langenfeld et al, 2013 ; Hao et al, 2014 ; Hover et al, 2015 ; Peng et al, 2016 ; Newman et al, 2018 ; Yin et al, 2018 ; Mihajlović et al, 2019 ; Zhou et al, 2020 ; Fukuda et al, 2021 ; Kalal et al, 2021 ). Our research group recently reported that a BMP type I receptor inhibitor, RK-783, inhibited the growth of ovarian cancer cells in vivo ( Fukuda et al, 2020 ).…”

“…DMH1 reduces the growth of cetuximab-resistant oral squamous cell carcinoma ( Yin et al, 2018 ). LDN-193189 augmented the growth-inhibitory effects of carboplatin ( Fukuda et al, 2021 ).…”

Identification of EMT-Related Genes and Prognostic Signature With Significant Implications on Biological Properties and Oncology Treatment of Lower Grade Gliomas

“…Also, comparing the available evidence, we found that the four genes used to construct the EMTsig were closely related to EMT. BMP2 is a member of the TGFβ family and induces the process of EMT through the BMP signaling pathway ( Fukuda et al, 2021 ). SFRP2 is an upstream repressor of the WNT signaling pathway and has an inhibitory effect on the EMT process ( Duan et al, 2017 ).…”