Kang Myoung Hee, Kang Han Na, Kim Jung Lim, Kim Jun Suk, Oh Sang Cheul, Yoo Young A
Graduate School of Medicine, Department of Internal Medicine, Korea University College of Medicine, Korea University, Seoul 136-705, Korea.
Oncol Rep. 2009 Sep;22(3):525-34. doi: 10.3892/or_00000467.
Although dysregulation of bone morphogenetic protein (BMP) signaling has been linked to various types of cancers, the relationship between abnormal activation of these signaling pathways and tumorigenesis is not clear. The purpose of the current study was to clarify how BMP2 is involved in colon cancer aggressiveness. The data showed that SW480 and DLD-1 cells displayed different responses to short- and long-term exposure to BMP2. During the first 24 h of exposure to BMP2, these cells were growth-inhibited, whereas surviving cells became resistant to growth inhibition, showing epithelial-to-mesenchymal transformation (EMT) and enhanced motility and invasiveness. Interestingly, in highly metastatic mesenchymal colon carcinoma cells (CT26), blockade of BMP2 signaling by BMP2 siRNA prevented EMT, motility and invasiveness; rather, blockade of BMP2 signaling caused a mesenchymal-to-epithelial transition (MET). The levels of phosphorylated Akt were very different between the two cell types; the BMP2-sensitive SW480 and DLD-1 cells had much higher levels of expression than the BMP2-resistant SW480 and DLD-1 and CT26 cells. CT26 cells, following exposure to BMP2 and activation of Akt, escaped the EMT-induced cellular motility and invasiveness. Moreover, LY294002 treatment of BMP2-sensitive SW480 cells blocked cell growth and enhanced motility and invasiveness. Together, these results suggest that suppression of the PI3 kinase/Akt pathway is correlated with the development of BMP2 resistance and invasion in BMP2-induced EMT in colon cancer.
尽管骨形态发生蛋白（BMP）信号通路失调与多种癌症相关，但这些信号通路的异常激活与肿瘤发生之间的关系尚不清楚。本研究的目的是阐明BMP2如何参与结肠癌的侵袭性。数据显示，SW480和DLD-1细胞对短期和长期暴露于BMP2表现出不同的反应。在暴露于BMP2的最初24小时内，这些细胞的生长受到抑制，而存活的细胞对生长抑制产生抗性，表现出上皮-间质转化（EMT）以及运动性和侵袭性增强。有趣的是，在高转移性间质性结肠癌细胞（CT26）中，BMP2 siRNA阻断BMP2信号通路可阻止EMT、运动性和侵袭性；相反，阻断BMP2信号通路会导致间质-上皮转化（MET）。两种细胞类型中磷酸化Akt的水平差异很大；对BMP2敏感的SW480和DLD-1细胞的表达水平远高于对BMP2有抗性的SW480和DLD-1以及CT26细胞。CT26细胞在暴露于BMP2并激活Akt后，逃脱了EMT诱导的细胞运动性和侵袭性。此外，用LY294002处理对BMP2敏感的SW480细胞可阻断细胞生长并增强运动性和侵袭性。总之，这些结果表明，PI3激酶/Akt通路的抑制与结肠癌中BMP2诱导的EMT过程中BMP2抗性和侵袭的发展相关。
