Transforming growth factor β stimulation of colorectal cancer cell lines: Type II receptor bypass and changes in adhesion molecule expression
Transforming growth factor β stimulation of colorectal cancer cell lines: Type II receptor bypass and changes in adhesion molecule expression
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DOI：
10.1073/pnas.96.6.3087
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发表时间：
1999-03-16
影响因子：
11.1
通讯作者：
Bodmer, WF
中科院分区：
文献类型：
--
作者：
Ilyas, M;Efstathiou, JA;Bodmer, WF
II型转化生长因子（TGF）-β受体基因（TGFBR 2）在复制错误阳性（RER+）的结直肠癌中的核苷酸重复序列中经常发生突变。这些突变被认为是为了逃避TGF-β的生长抑制而选择的，而不是因为突变率增加而代表旁观者事件。我们研究了TGFBR 2突变在12种结直肠癌细胞系中的作用。其中6个是RER+，这些被证明有纯合的TGFBR 2突变。然后测试所有细胞系响应于TGF-β刺激的增殖变化。尽管II型TGF-β受体的纯合突变，但两种RER+细胞系Lore和Sm 48在无血清条件下受TGF-β 1刺激时显示出统计学显著的生长抑制。这表明在某些情况下可以绕过II型TGF-β受体以维持生长抑制。我们接下来研究是否有任何替代模式，通过TGFBR 2突变可能会产生选择性优势，如粘附分子表达的变化。用TGF-β 1刺激所有细胞系，并通过ELISA检测粘附分子。RER+和RER-细胞系之间未发现一致的变化，尽管在单个细胞系中发现了E-钙粘蛋白、β-连环蛋白和γ-连环蛋白的变化。我们得出结论：（i）II型TGF-β受体活性可以被绕过，因此RER+癌症中的TGFBR 2突变可能，至少有时，只是“旁观者”事件;（ii）TGF-β可以影响粘附分子表达，因此TGFBR 2突变可能通过其他逃避生长抑制的效应产生选择性优势。
The type II transforming growth Factor (TGF)-beta receptor gene (TGFBR2) is often mutated in nucleotide repeat sequences in colorectal cancers that are replication error positive (RER+). These mutations are thought to be selected for escape from growth inhibition by TGF-beta rather than representing bystander events because of an increased mutation rate. We investigated the role of TGFBR2 mutations in 12 colorectal cancer cell lines. Six of these were RER+, and these were shown to have homozygous TGFBR2 mutations. All cell lines then were tested for changes in proliferation in response to TGF-beta stimulation. Despite homozygous mutation of the type II TGF-beta receptor, two RER+ cell lines, Lore and Sm48, showed statistically significant growth inhibition when stimulated by TGF-beta 1 in serum-free conditions. This shows that the type II TGF-beta receptor can be bypassed in certain cases to maintain growth inhibition. We nest investigated whether there was any alternative mode through which TGFBR2 mutation may give a selective advantage, such as a change in adhesion molecule expression. All cell lines were stimulated with TGF-beta 1 and adhesion molecules detected by ELISA. No consistent changes were identified between the RER+ and the RER- cell lines, although changes in E-cadherin, beta-catenin, and gamma-catenin were identified in individual cell lines. We conclude that (i) type II TGF-beta receptor activity can be bypassed and thus TGFBR2 mutations in RER+ cancers may, at least sometimes, be just "bystander" events and (ii) TGF-beta can affect adhesion molecule expression so that TGFBR2 mutation may give rise to a selective advantage through an effect other escape from growth inhibition.