Effect of Smad7 expression on metastasis of mouse mammary carcinoma JygMC(A) cells
Effect of Smad7 expression on metastasis of mouse mammary carcinoma JygMC(A) cells
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DOI：
10.1093/jnci/dji399
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发表时间：
2005-12-07
影响因子：
10.3
通讯作者：
Horie, S
中科院分区：
文献类型：
--
作者：
Azuma, H;Ehata, S;Horie, S
背景转化生长因子β（TGF-β）促进癌症晚期的转移。Smad 6、Smad 7和c-Ski通过不同的作用模式阻断TGF-β超家族蛋白的信号传导。我们在小鼠乳腺癌模型中使用腺病毒介导的这些天然抑制剂的基因转移来研究TGF-β超家族信号传导在肿瘤生长和转移中的作用。研究方法：我们通过静脉注射将含有Smad 7、Smad 6、c-Ski、c-Ski突变体c-Ski（ARPG）或LacZ（对照）的小鼠cDNA的腺病毒（AdCMV）全身给予荷有源自小鼠乳腺癌JygMC（A）细胞的肿瘤的裸鼠（>19只小鼠/组），所述肿瘤自发转移到肺和肝，并检查它们对存活和转移的影响。使用高通量蛋白质印迹分析来检测JygMC（A）细胞和原发性肿瘤中47个信号转导蛋白的表达水平。我们还研究了稳定过表达Smad 6或Smad 7的JygMC（A）细胞的增殖、迁移和侵袭。通过Kruskal-Wallis H统计量和Wilcoxon秩和检验进行非参数比较。通过单向方差分析或双侧非配对Student t检验进行参数比较。所有统计学检验均为双侧检验。结果如下：携带来源于JygMC（A）细胞的肿瘤的对照小鼠显示许多转移到肺和肝;所有动物在细胞接种后50天死亡。相比之下，用AdCMV-Smad 7或AdCMV-c-Ski治疗的小鼠显示出转移的显著减少和比对照小鼠统计学上显著更长的存活（Smad 7对LacZ：中位存活= 55天对41天，差异= 14天[95%置信区间{CI} = 6天至22天]，P
Background. Transforming growth factor beta (TGF-beta) facilitates metastasis during the advanced stages of cancer. Smad6, Smad7, and c-Ski block signaling by the TGF-beta superfamily proteins through different modes of action. We used adenovirus-mediated gene transfer of these natural inhibitors in a mouse model of breast cancer to examine the roles of TGF-beta superfamily signaling in tumor growth and metastasis. Methods: We systemically administered, by intravenous injection, adenoviruses (AdCMV) containing the mouse cDNAs for Smad7, Smad6, c-Ski, the c-Ski mutant c-Ski (ARPG), or LacZ (control) to nude mice (>19 mice/group) bearing tumors derived from mouse mammary carcinoma JygMC(A) cells, which spontaneously metastasize to lung and liver, and examined their effects on survival and metastasis. High-throughput western blotting analysis was used to examine the expression levels for 47 signal transduction proteins in JygMC(A) cells and primary tumors. We also investigated the proliferation, migration, and invasion of JygMC(A) cells that stably overexpressed Smad6 or Smad7. Nonparametric comparisons were done by Kruskal-Wallis H statistic and Wilcoxon's rank sum tests. Parametric comparisons were done by one-way analysis of variance or two-sided unpaired Student's t tests. All statistical tests were two-sided. Results: Control mice bearing tumors derived from JygMC(A) cells showed many metastases to the lung and liver; all animals died by 50 days after cell inoculation. By contrast, mice treated with AdCMV-Smad7 or AdCMV-c-Ski demonstrated a dramatic decrease in metastasis and statistically significantly longer survival than control mice (Smad7 versus LacZ: medium survival = 55 days versus 41 days, difference = 14 days [95% confidence interval {CI} = 6 days to 22 days], P