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EMBO Reports:果蝇揭示肠癌中关键性转录因子

来源:生物谷 2014-10-09 09:31

2014年10月9日讯 /生物谷BIOON/  近日,西班牙研究人员弄清楚了一种称为Mirror的转录因子是如何调节果蝇肠道中肿瘤样生长的。相关研究结果发表在EMBO Reports杂志上。

每年在全球范围内,大肠癌导致超过五十万人死亡。该疾病起源于胃肠道的上皮细胞,主要是由于肠道细胞中的分子信号活动异常导致的。

研究人员已经能够利用果蝇作为模型系统来研究大肠癌发生发展过程中的关键分子事件,并利用果蝇来确定人类疾病相关的新遗传调控机制。

两个信号通路--Wnt信号和EGFR/ Ras途径的突变是已知会激活果蝇肠肿瘤样生长的突变。在果蝇中,研究人员揭示了Decapentaplegic(Dpp)通路的激活会抑制这些肠道肿瘤的生长,但是,这种抑制效应会由Mirror转录因子(Mirror转录因子是Irx转录因子的特定类型)抵消。。

在人类中,Dpp是骨形态发生蛋白,其是转化生长因子-β信号传导途径的一种组分。研究人员在果蝇中发现:在人类结肠癌由良性腺瘤过渡到更积极的癌症过程中,Irx转录因子如Mirror转录因子可能会在果蝇和人类癌症中起到相类似的作用,即减少肿瘤细胞响应转化生长因子-β的能力。

转化生长因子-β通常作为细胞生长的制动因子,因此Irx转录因子如Mirror可能有利于癌细胞的生长,导致果蝇和人类中癌细胞增殖。(生物谷Bioon.com)

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Iro/Irx transcription factors negatively regulate Dpp/TGF-beta pathway activity during intestinal tumorigenesis

òscar Martorell, Francisco M Barriga, Anna Merlos‐Suárez, Camille Stephan‐Otto Attolini, Jordi Casanova, Eduard Batlle, Elena Sancho, Andreu Casali

Activating mutations in Wnt and EGFR/Ras signaling pathways are common in colorectal cancer (CRC). Remarkably, clonal co‐activation of these pathways in the adult Drosophila midgut induces “tumor‐like” overgrowths. Here, we show that, in these clones and in CRC cell lines, Dpp/TGF‐β acts as a tumor suppressor. Moreover, we discover that the Iroquois/IRX‐family‐protein Mirror downregulates the transcription of core components of the Dpp pathway, reducing its tumor suppressor activity. We also show that this genetic interaction is conserved in human CRC cells, where the Iro/IRX proteins IRX3 and IRX5 diminish the response to TGF‐β. IRX3 and IRX5 are upregulated in human adenomas, and their levels correlate inversely with the gene expression signature of response to TGF‐β. In addition, Irx5 expression confers a growth advantage in the presence of TGF‐β, but is selected against in its absence. Together, our results identify a set of Iro/IRX proteins as conserved negative regulators of Dpp/TGF‐β activity. We propose that during the characteristic adenoma‐to‐carcinoma transition of human CRC, the activity of IRX proteins could reduce the sensitivity to the cytostatic effect of TGF‐β, conferring a growth advantage to tumor cells prior to the acquisition of mutations in TGF‐β pathway components.

 

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