Cten is targeted by Kras signalling to regulate cell motility in the colon and pancreas.
Cten is targeted by Kras signalling to regulate cell motility in the colon and pancreas.
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DOI：
10.1371/journal.pone.0020919
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Ilyas M
中科院分区：
文献类型：
--
作者：
Al-Ghamdi S;Albasri A;Cachat J;Ibrahem S;Muhammad BA;Jackson D;Nateri AS;Kindle KB;Ilyas M
CTEN/TNS 4是结肠直肠癌（CRC）中的癌基因，其增强细胞运动性，尽管Cten调节的机制尚不清楚。我们在一系列CRC细胞系中发现了Cten高表达与KRAS/BRAF突变之间的关联（p = 0.03），并假设Kras可能调节Cten。 为了测试这一点，在CRC细胞系SW 620和DLD 1（高Cten表达者和KRAS突变体）中敲低Kras（使用小干扰（si）RNA）。在每种细胞系中，Kras敲低通过Cten的下调反映。由于Kras通过Braf发出信号，我们测试了CRC细胞系Colo 205（其显示高Cten表达并且对于BRAF是突变体但对于KRAS是野生型）中Kras敲低的效果。Cten水平不受Kras敲低的影响，而Braf敲低导致Cten表达减少，表明Kras通过Braf信号调节Cten。蛋白酶体抑制后Cten mRNA的定量和蛋白质分析表明，调节是Cten转录。Kras基因敲低抑制细胞运动。为了测试这是否可以通过Cten介导，用Kras特异性siRNA和Cten表达载体共转染SW 620细胞。恢复Cten表达能够恢复细胞运动性，尽管Kras敲低（transwell迁移和创伤测定，两者p<0.001）。由于KRAS在许多癌症中发生突变，我们研究了这种关系是否可以在其他肿瘤模型中得到证明。在胰腺癌细胞系Colo 357和PSN-1（高Cten表达者和KRAS突变体）中重复实验。在两种细胞系中，Kras显示调节Cten，并且Cten的强制表达能够在PSN-1中Kras敲低后挽救细胞运动性的丧失（transwell迁移测定，p<0.001）。我们的结论是，在结肠和胰腺中，Cten是Kras的下游靶点，并且可能是Kras调节细胞运动的机制。
CTEN/TNS4 is an oncogene in colorectal cancer (CRC) which enhances cell motility although the mechanism of Cten regulation is unknown. We found an association between high Cten expression and KRAS/BRAF mutation in a series of CRC cell lines (p = 0.03) and hypothesised that Kras may regulate Cten. To test this, Kras was knocked-down (using small interfering (si)RNA) in CRC cell lines SW620 and DLD1 (high Cten expressors and mutant for KRAS). In each cell line, Kras knockdown was mirrored by down-regulation of Cten Since Kras signals through Braf, we tested the effect of Kras knockdown in CRC cell line Colo205 (which shows high Cten expression and is mutant for BRAF but wild type for KRAS). Cten levels were unaffected by Kras knockdown whilst Braf knockdown resulted in reduced Cten expression suggesting that Kras signals via Braf to regulate Cten. Quantification of Cten mRNA and protein analysis following proteasome inhibition suggested that regulation was of Cten transcription. Kras knockdown inhibited cell motility. To test whether this could be mediated through Cten, SW620 cells were co-transfected with Kras specific siRNAs and a Cten expression vector. Restoring Cten expression was able to restore cell motility despite Kras knockdown (transwell migration and wounding assay, p<0.001 for both). Since KRAS is mutated in many cancers, we investigated whether this relationship could be demonstrated in other tumour models. The experiments were repeated in the pancreatic cancer cell lines Colo357 & PSN-1(both high Cten expressors and mutant for KRAS). In both cell lines, Kras was shown to regulate Cten and forced expression of Cten was able to rescue loss of cell motility following Kras knockdown in PSN-1 (transwell migration assay, p<0.001). We conclude that, in the colon and pancreas, Cten is a downstream target of Kras and may be a mechanism through which Kras regulates of cell motility.
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DOI：
10.1083/jcb.125.5.1067
发表时间：
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期刊：
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影响因子：
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