2014年10月9日訊 /生物谷BIOON/ 近日，西班牙研究人員弄清楚了一種稱為Mirror的轉錄因子是如何調節果蠅腸道中腫瘤樣生長的。相關研究結果發表在EMBO Reports雜誌上。
每年在全球範圍內，大腸癌導致超過五十萬人死亡。該疾病起源於胃腸道的上皮細胞，主要是由於腸道細胞中的分子信號活動異常導致的。
研究人員已經能夠利用果蠅作為模型系統來研究大腸癌發生發展過程中的關鍵分子事件，並利用果蠅來確定人類疾病相關的新遺傳調控機制。
兩個信號通路--Wnt信號和EGFR/ Ras途徑的突變是已知會激活果蠅腸腫瘤樣生長的突變。在果蠅中，研究人員揭示了Decapentaplegic（Dpp）通路的激活會抑制這些腸道腫瘤的生長，但是，這種抑制效應會由Mirror轉錄因子（Mirror轉錄因子是Irx轉錄因子的特定類型）抵消。。
在人類中，Dpp是骨形態發生蛋白，其是轉化生長因子-β信號傳導途徑的一種組分。研究人員在果蠅中發現：在人類結腸癌由良性腺瘤過渡到更積極的癌症過程中，Irx轉錄因子如Mirror轉錄因子可能會在果蠅和人類癌症中起到相類似的作用，即減少腫瘤細胞響應轉化生長因子-β的能力。
轉化生長因子-β通常作為細胞生長的制動因子，因此Irx轉錄因子如Mirror可能有利於癌細胞的生長，導致果蠅和人類中癌細胞增殖。（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.