Acceleration of Smad2 and Smad3 phosphorylation via c-Jun NH(2)-terminal kinase during human colorectal carcinogenesis.
Acceleration of Smad2 and Smad3 phosphorylation via c-Jun NH(2)-terminal kinase during human colorectal carcinogenesis.
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DOI：
10.1158/0008-5472.157.65.1
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发表时间：
2005-01
期刊：
影响因子：
11.2
通讯作者：
Hideo Yamagata;K. Matsuzaki;Shigeo Mori;Katsunori Yoshida;Y. Tahashi;F. Furukawa;Go Sekimoto;
中科院分区：
文献类型：
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作者：
Hideo Yamagata;K. Matsuzaki;Shigeo Mori;Katsunori Yoshida;Y. Tahashi;F. Furukawa;Go Sekimoto;
正常上皮细胞转化为肿瘤与转化生长因子-β（TGF-β）功能的转变有关：肿瘤抑制活性降低和致癌活性增加。然而，在人类结直肠癌发生过程中这种功能改变的具体机制仍有待阐明。TGF-β信号转导涉及在连接区（pSmad 2/3L）和COOH末端区（pSmad 2/3C）磷酸化的Smad 2/3。使用对每个磷酸化位点特异的抗体，我们在此表明，Smad 2和Smad 3在正常结直肠上皮细胞的COOH-末端区域磷酸化，而不是在接头区域，并且pSmad 2/3C主要位于其细胞核中。然而，在31例散发性结直肠腺癌中，Smad 2和Smad 3的连接区被磷酸化。特别是，晚期浸润性和转移性癌症通常表现出高度的Smad 2/3L磷酸化。在11个腺瘤中，它们的磷酸化程度介于正常上皮细胞和腺癌之间。而pSmad 2L仍然在细胞质中，pSmad 3L只位于细胞核中的Ki-67免疫反应阳性腺癌。相反，pSmad 3C随着肿瘤分期的进展而逐渐降低。癌组织中活化的c-Jun氨基末端激酶可直接磷酸化Smad 2/3L。尽管Smad 4基因的Mad同源性2区测序显示在一个腺癌中密码子361处发生G/A替换，但该突变与磷酸化无关。在肿瘤中未观察到II型TGF-β受体和Smad 2基因突变。总之，pSmad 3C，这有利于肿瘤抑制活性的TGF-β，被发现减少，而c-Jun NH（2）-末端激酶倾向于诱导Smad 2/3L的磷酸化在人类结直肠腺瘤-癌序列。
Conversion of normal epithelial cells to tumors is associated with a shift in transforming growth factor-beta (TGF-beta) function: reduction of tumor suppressor activity and increase of oncogenic activity. However, specific mechanisms of this functional alteration during human colorectal carcinogenesis remain to be elucidated. TGF-beta signaling involves Smad2/3 phosphorylated at linker regions (pSmad2/3L) and COOH-terminal regions (pSmad2/3C). Using antibodies specific to each phosphorylation site, we herein showed that Smad2 and Smad3 were phosphorylated at COOH-terminal regions but not at linker regions in normal colorectal epithelial cells and that pSmad2/3C were located predominantly in their nuclei. However, the linker regions of Smad2 and Smad3 were phosphorylated in 31 sporadic colorectal adenocarcinomas. In particular, late-stage invasive and metastatic cancers typically showed a high degree of phosphorylation of Smad2/3L. Their extent of phosphorylation in 11 adenomas was intermediate between those in normal epithelial cells and adenocarcinomas. Whereas pSmad2L remained in the cytoplasm, pSmad3L was located exclusively in the nuclei of Ki-67-immunoreactive adenocarcinomas. In contrast, pSmad3C gradually decreased as the tumor stage progressed. Activated c-Jun NH(2)-terminal kinase in cancers could directly phosphorylate Smad2/3L. Although Mad homology 2 region sequencing in the Smad4 gene revealed a G/A substitution at codon 361 in one adenocarcinoma, the mutation did not correlate with phosphorylation. No mutations in the type II TGF-beta receptor and Smad2 genes were observed in the tumors. In conclusion, pSmad3C, which favors tumor suppressor activity of TGF-beta, was found to decrease, whereas c-Jun NH(2)-terminal kinase tended to induce the phosphorylation of Smad2/3L in human colorectal adenoma-carcinoma sequence.