Bone morphogenetic proteins induce pancreatic cancer cell invasiveness through a Smad1-dependent mechanism that involves matrix metalloproteinase-2
Bone morphogenetic proteins induce pancreatic cancer cell invasiveness through a Smad1-dependent mechanism that involves matrix metalloproteinase-2
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DOI：
10.1093/carcin/bgn274
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发表时间：
2009-02-01
期刊：
影响因子：
4.7
通讯作者：
Blobe, Gerard C.
中科院分区：
文献类型：
--
作者：
Gordon, Kelly J.;Kirkbride, Kellye C.;Blobe, Gerard C.
骨形态发生蛋白（BMPs）在人类癌症中起着越来越重要的作用。在这里，我们证明BMP信号通路在人胰腺癌细胞中是完整的和功能性的，与正常胰腺组织相比，人胰腺癌标本中的几个BMP信号成分和转录靶点上调。功能上，BMP家族的多个成员，包括BMP-2、BMP-4和BMP-7，在人胰腺癌细胞系Panc-1中诱导上皮到间充质转化（EMT），这可以通过形态学改变和E-cadherin表达的丧失来证明。bmp介导的EMT导致Panc-1细胞侵袭性增加，部分原因是基质金属蛋白酶(MMP)-2的表达和活性增加，MMP -2是胰腺癌细胞侵袭性的已知介质。伴随EMT， BMP降低转化生长因子(TGF)- β超家族受体，转化生长因子- β III型受体（T β RIII）的表达，我们之前已经证明在胰腺癌进展过程中表达缺失。维持T β RIII表达可抑制bmp介导的侵袭并抑制Smad1的激活。此外，Smad1是bmp诱导的侵袭所必需的，并且部分负责bmp介导的MMP-2活性增加。这些数据表明，BMP信号通过Smad1诱导和MMP-2的上调，是胰腺癌侵袭的重要介质，也是治疗这种致命疾病的潜在治疗靶点。
Bone morphogenetic proteins (BMPs) have an emerging role in human cancers. Here we demonstrate that the BMP-signaling pathway is intact and functional in human pancreatic cancer cells, with several BMP signaling components and transcriptional targets upregulated in human pancreatic cancer specimens compared with normal pancreatic tissue. Functionally, multiple BMP family members, including BMP-2, BMP-4 and BMP-7, induce an epithelial to mesenchymal transition (EMT) in the human pancreatic cancer cell line Panc-1, as demonstrated by morphological alterations and loss of E-cadherin expression. BMP-mediated EMT results in an increase in invasiveness of Panc-1 cells, in part through increased expression and activity of matrix metalloproteinase (MMP)-2, a known mediator of pancreatic cancer cell invasiveness. Accompanying EMT, BMP reduces expression of the transforming growth factor (TGF)-beta superfamily receptor, transforming growth factor-beta type III receptor (T beta RIII), for which we have previously demonstrated loss of expression during pancreatic cancer progression. Maintaining T beta RIII expression inhibits BMP-mediated invasion and suppresses Smad1 activation. Further, Smad1 is required for BMP-induced invasiveness and partially responsible for BMP-mediated increases in MMP-2 activity. These data suggest that BMP signaling, through Smad1 induction and upregulation of MMP-2, is an important mediator of pancreatic cancer invasiveness and a potential therapeutic target for treating this deadly disease.