Activin type 2 receptor restoration in MSI-H colon cancer suppresses growth and enhances migration with activin
Activin type 2 receptor restoration in MSI-H colon cancer suppresses growth and enhances migration with activin
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DOI：
10.1053/j.gastro.2006.11.018
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发表时间：
2007-02-01
期刊：
影响因子：
29.4
通讯作者：
Carethers, John M.
中科院分区：
文献类型：
--
作者：
Jung, Barbara H.;Beck, Stayce E.;Carethers, John M.
背景与目的：高频微卫星不稳定（MSI - H）的结肠癌在其发病机制中，肿瘤抑制基因会发生移码突变。在超过80%的MSI - H结肠癌中，ACVR2基因的第10外显子多聚腺苷酸序列发生突变，同时伴有蛋白质缺失。ACVR2通过SMAD蛋白的磷酸化传递激活素的生长效应，从而影响基因转录。激活素在结肠癌中的功能作用尚未得到研究。我们建立并鉴定了一个细胞模型，用于研究激活素信号如何影响生长。
方法：bMLH1和ACVR2突变的HCT116细胞先前已稳定转入2号染色体（HCT116 + chr2），恢复了野生型ACVR2的单个调控拷贝，但未恢复bMLH1。对HCT116 + chr2和亲本HCT116细胞（以及HEC59、ACVR2和hMSH2互补的HEC59 + chr2细胞）进行了基因互补和生物学功能评估。
结果：HCT116 + chr2细胞和HEC59 + chr2细胞，而非ACVR2突变的HCT116或HEC59细胞，获得了野生型ACVR2以及ACVR2野生型信使RNA的表达。在激活素处理下，互补的ACVR2蛋白与ACVR1形成复合物，产生核磷酸化SMAD2和激活素特异性基因转录。恢复ACVR2的细胞在激活素处理后生长减缓，S期减少，但细胞迁移增加。ACVR2小干扰RNA逆转了互补细胞中的这些效应。
结论：ACVR2互补的MSI - H结肠癌恢复了激活素 - SMAD信号传导，在配体刺激后生长减缓，细胞周期减慢，但细胞迁移增加。激活素在结肠癌中具有生长抑制作用，并类似于转化生长因子β增强迁移，这表明激活素作用的缺失有助于MSI - H结肠癌的发病机制。
Background & Aims: Colon cancers with high-frequency microsatellite instability (MSI-H) develop frameshift mutations in tumor suppressors as part of their pathogenesis. ACVR2 is mutated at its exon 10 polyadenine tract in > 80% of MSI-H colon cancers, coinciding with loss of protein. ACVR2 transmits the growth effects of activin via phosphorylation of SMAD proteins to affect gene transcription. The functional effect of activin in colon cancers has not been studied. We developed and characterized a cell model in which we studied how activin signaling affects growth. Methods: bMLH1 and ACVR2 mutant HCT116 cells were previously stably transferred with chromosome 2 (HCT116+chr2), restoring a single regulated copy of wild-type ACVR2 but not bMLH1. Both HCT116+chr2 and parental HCT116 cells (as well as HEC59 and ACVR2 and hMSH2 complemented HEC59+chr2 cells) were assessed for genetic complementation and biologic function. Results: HCT116+chr2 cells and HEC59+chr2 cells, but not ACVR2-mutant HCT116 or HEC59 cells, acquired wild-type ACVR2 as well as expression of ACVR2 wildtype messenger RNA. Complemented ACVR2 protein complexed with ACVR1 with activin treatment, generating nuclear phosphoSMAD2 and activin-specific gene transcription. ACVR2-restored cells showed decreased growth and reduced S phase but increased cellular migration following activin treatment. ACVR2 small interfering RNA reversed these effects in complemented cells. Conclusions: ACVR2-complemented MSI-H colon cancers restore activin-SMAD signaling, decrease growth, and slow their cell cycle following ligand stimulation but show increased cellular migration. Activin is growth suppressive and enhances migration similar to transforming growth factor beta in colon cancer, indicating that abrogation of the effects of activin contribute to the pathogenesis of MSI-H colon cancers.