近日,，佛羅里達(dá)州梅奧診所的研究人員發(fā)現(xiàn)現(xiàn)今普遍認(rèn)為的一種能抑制癌細(xì)胞生長(zhǎng)的分子實(shí)際上有助于致命甲狀腺腫瘤的生長(zhǎng),，相關(guān)研究論文發(fā)表在Journal of Cell Science雜志上,。
研究發(fā)現(xiàn)，在未分化甲狀腺癌中,，F(xiàn)OXO3a轉(zhuǎn)錄因子不抑制促癌基因,，而是致命腫瘤的生長(zhǎng)刺激因子。在人類(lèi)未分化甲狀腺癌的實(shí)驗(yàn)室模型中,，F(xiàn)OXO3a沉默后,，腫瘤細(xì)胞生長(zhǎng)緩慢，但是當(dāng)它重新恢復(fù)表達(dá)時(shí),，腫瘤細(xì)胞會(huì)生長(zhǎng)得更快,。
FOXO3a是一已知的腫瘤生長(zhǎng)抑制因子，因?yàn)槠淠芡ㄟ^(guò)開(kāi)啟細(xì)胞核內(nèi)的基因,、觸發(fā)細(xì)胞死亡來(lái)響應(yīng)所有細(xì)胞應(yīng)激形式,。癌癥，反過(guò)來(lái)通過(guò)將FOXO3a出核,，進(jìn)入細(xì)胞質(zhì)中來(lái)關(guān)閉FOXO3a,。促進(jìn)FOXO3a出核的分子是Akt，Akt促使癌癥細(xì)胞存活,。
該研究小組利用Akt蛋白受體阻滯劑來(lái)增加核中FOXO3a,，抑制未分化甲狀腺癌細(xì)胞的生長(zhǎng)。
研究表明Akt抑制劑的使用將FOXO3a保持在細(xì)胞核中,，幫助殺死癌細(xì)胞,，而FOXO3a本身不加速腫瘤細(xì)胞的成長(zhǎng)。（生物谷：Bioon.com）
doi:10.1242/jcs.097428
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Foxo3a drives proliferation in anaplastic thyroid carcinoma via transcriptional regulation of cyclin A1: A paradigm shift that impacts current therapeutic strategies
Laura A. Marlow, Christina A. von Roemeling, Simon J. Cooper, Yilin Zhang, Stephen D. Rohl, Shilpi Arora, Irma M. Gonzales, et al.
The Forkhead transcription factor, FoxO3a, is a known suppressor of primary tumor growth via transcriptional regulation of key genes regulating cell cycle arrest and apoptosis. In many types of cancer, in response to growth factor signaling, FoxO3a is phosphorylated by Akt, resulting in its exclusion from the nucleus. Here we show that FoxO3a remains nuclear in anaplastic thyroid carcinoma (ATC). This correlates with lack of Akt phosphorylation at S473 in ATC cell lines and patient ATC tissues, providing a potential explanation for nuclear FoxO3a. Mechanistically, nuclear FoxO3a promotes cell cycle progression by transcriptional upregulation of cyclin A1, promoting proliferation of human ATC cells. Silencing FoxO3a with a reverse genetics approach leads to down-regulation of CCNA1 mRNA and protein. This combined data implicates an entirely novel function for FoxO3a in ATC promotion by enhancing cell cycle progression and tumor growth via transcriptional upregulation of cyclin A1. This is clinically relevant since we detected highly elevated CCNA1 mRNA and protein levels in ATC patient tumor tissues. Our data indicate therapeutic inactivation of FoxO3a may lead to attenuation of tumor expansion in ATC. This new paradigm also suggests caution related to current dogma focused upon reactivation of FoxO3a as a therapeutic strategy against cancers harboring active PI3-K and Akt signaling pathways.
