BMP 信号在子宫内膜癌中的促瘤作用。
Tumor Promoting Effect of BMP Signaling in Endometrial Cancer.
机构信息
Science for Life Laboratory, Department of Medical Biochemistry and Microbiology, Box 582, Uppsala University, SE-751 23 Uppsala, Sweden.
Department of Molecular Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan.
出版信息
Int J Mol Sci. 2021 Jul 23;22(15):7882. doi: 10.3390/ijms22157882.
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 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 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.
骨形态发生蛋白（BMPs）是转化生长因子-β（TGF-β）家族的成员，其在子宫内膜癌（EC）中的作用尚未确定。在本研究中，我们分析了 TCGA 和 MSK-IMPACT 数据集，并研究了 BMP2 和 BMP 拮抗剂 TWSG1 对 Ishikawa EC 细胞的影响。TCGA 和 MSK-IMPACT 数据集中的 EC 患者存在 BMP 配体和受体的高频突变和高 mRNA 表达。与卵巢癌细胞系相比，Ishikawa 细胞分泌更多的 BMP2。外源性 BMP2 刺激通过诱导 c-KIT 增强 EC 细胞球体形成。BMP2 还诱导 EC 细胞发生 EMT，并通过诱导 SLUG 促进迁移。BMP 受体激酶抑制剂 LDN193189 增强了顺铂的生长抑制作用。对几种 BMP 拮抗剂的 mRNAs 分析表明，TWSG1 在 Ishikawa 细胞中大量表达。TWSG1 抑制 BMP7 诱导的，但不抑制 BMP2 诱导的，EC 细胞球体形成和迁移。我们的结果表明，BMP 信号促进 EC 肿瘤发生，并且 TWSG1 在 EC 中拮抗 BMP7。BMP 信号抑制剂与化疗联合使用可能对 EC 患者的治疗有用。
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