Transforming growth factor-β promotes survival of mammary carcinoma cells through induction of antiapoptotic transcription factor DEC1
Transforming growth factor-β promotes survival of mammary carcinoma cells through induction of antiapoptotic transcription factor DEC1
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DOI：
10.1158/0008-5472.can-07-1522
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发表时间：
2007-10-15
期刊：
影响因子：
11.2
通讯作者：
Miyazono, Kohei
中科院分区：
文献类型：
--
作者：
Ehata, Shogo;Hanyu, Aki;Miyazono, Kohei
转化生长因子-β（TGF-β）信号传导促进晚期癌症中的肿瘤生长和转移。在本研究中，我们确定了软骨细胞1（DEC 1，也称为SHARP 2和Stral 3）中的差异表达，作为TGF-β信号传导的下游靶点，可促进乳腺癌细胞的存活。在小鼠乳腺癌细胞系JygMC（A）和4 T1中，TGF-β I型受体激酶抑制剂A-44-03和SB 431542在无血清条件下诱导细胞凋亡。寡核苷酸微阵列和实时逆转录PCR分析显示，TGF-β诱导DEC 1在这些细胞中，和增加的DEC 1抑制的TGF-β I型受体激酶抑制剂，以及显性阴性TGF-β II型受体的表达。DEC 1过表达可抑制A-44-03诱导的JygMC（A）细胞凋亡，而内源性DEC 1敲低可抑制TGF-β促进的细胞存活。此外，DEC 1的显性负突变体在体内阻止JygMC（A）细胞的肺和肝转移。因此，我们的观察结果提供了新的见解，TGF-β介导的细胞存活和癌症转移的分子机制。
Transforming growth factor-beta (TGF-beta) signaling facilitates tumor growth and metastasis in advanced cancer. In the present study, we identified differentially expressed in chondrocytes 1 (DEC1, also known as SHARP2 and Stral3) as a downstream target of TGF-beta signaling, which promotes the survival of breast cancer cells. In the mouse mammary carcinoma cell lines JygMC(A) and 4T1, the TGF-beta type I receptor kinase inhibitors A-44-03 and SB431542 induced apoptosis of cells under serum-free conditions. Oligonucleotide microarray and real-time reverse transcription-PCR analyses revealed that TGF-beta induced DEC1 in these cells, and the increase of DEC1 was suppressed by the TGF-beta type I receptor kinase inhibitors as well as by expression of dominant-negative TGF-beta type II receptor. Overexpression of DEC1 prevented the apoptosis of JygMC(A) cells induced by A-44-03, and knockdown of endogenous DEC1 abrogated TGF-beta-promoted cell survival. Moreover, a dominant-negative mutant of DEC1 prevented lung and liver metastasis of JygMC(A) cells in vivo. Our observations thus provide new insights into the molecular mechanisms governing TGF-beta-mediated cell survival and metastasis of cancer.