Bone morphogenetic protein 2 is expressed by, and acts upon, mature epithelial cells in the colon
Bone morphogenetic protein 2 is expressed by, and acts upon, mature epithelial cells in the colon
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DOI：
10.1053/j.gastro.2003.10.067
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发表时间：
2004-01-01
期刊：
影响因子：
29.4
通讯作者：
Peppelenbosch, MP
中科院分区：
文献类型：
--
作者：
Hardwick, JCH;Van den Brink, GR;Peppelenbosch, MP
背景与目的：近期发现骨形态发生蛋白（BMP）受体la在幼年性息肉病中发生突变，Smad4在结肠癌中频繁发生突变，提示BMP在结肠上皮和结肠癌中发挥作用。我们研究了BMP2在结肠中的作用。方法：采用逆转录聚合酶链反应和免疫印迹法检测BMP受体在细胞系中的表达。我们利用MTT法和免疫印迹法研究了BMP2对细胞系分化、增殖和凋亡标志物的影响。我们利用免疫组织化学方法评估了BMP2及其受体和信号转导元件在小鼠和人结肠组织中的表达。我们还通过免疫组织化学和免疫印迹法评估小鼠结肠组织，研究了BMP拮抗剂noggin在小鼠体内的作用。最后，我们研究了家族性腺瘤性息肉患者微腺瘤中BMP2的表达。结果：BMP受体（BMPR） la、BMPR lb和BMPR 11均在结肠上皮细胞系中表达。BMP2体外抑制结肠上皮细胞生长，促进细胞凋亡和分化，抑制细胞增殖。BMP2、BMPRla、BMPRlb、BMPRII、磷酸化Smad1和Smad4主要在正常成人和小鼠结肠上皮表面的成熟结肠细胞中表达。Noggin在体内抑制小鼠结肠上皮细胞凋亡和增殖。家族性腺瘤性息肉患者的微腺瘤中BMP2表达缺失。结论：这些数据表明BMP2在成熟结肠上皮细胞中作为肿瘤抑制因子促进细胞凋亡。
Background & Aims: The recent findings of bone morphogenetic protein (BMP) receptor la mutations in juvenile polyposis and frequent Smad4 mutations in colon cancer suggest a role for BMPs in the colonic epithelium and colon cancer. We investigated the role of BMP2 in the colon. Methods: We assessed BMP receptor expression in cell lines using the reverse-transcribed polymerase chain reaction and immunoblotting. We investigated the effect of BMP2 on cell lines using the MTT assay and by immunoblotting for markers of differentiation, proliferation, and apoptosis. We assessed the expression of BMP2, its receptors, and signal transduction elements in mouse and human colon tissue using immunohistochemistry. We also investigated the effect of the BMP antagonist noggin in vivo in mice by assessing colon tissue with immunohistochemistry and immunoblotting. Finally, we investigated the expression of BMP2 in microadenomas from familial adenomatous polyposis patients. Results: BMP receptors (BMPR) la, BMPR lb, and BMPR 11 are all expressed in colonic epithelial cell lines. BMP2 inhibits colonic epithelial cell growth in vitro, promoting apoptosis and differentiation and inhibiting proliferation. BMP2, BMPRla, BMPRlb, BMPRII, phosphorylated Smad1, and Smad4 are expressed predominantly in mature colonocytes at the epithelial surface in normal adult human and mouse colon. Noggin inhibits apoptosis and proliferation in mouse colonic epithelium in vivo. BMP2 expression is lost in the microadenomas of familial adenomatous polyposis patients. Conclusions: These data suggest that BMP2 acts as a tumor suppressor promoting apoptosis in mature colonic epithelial cells.