近日，佛罗里达州梅奥诊所的研究人员发现现今普遍认为的一种能抑制癌细胞生长的分子实际上有助于致命甲状腺肿瘤的生长，相关研究论文发表在Journal of Cell Science杂志上。
研究发现，在未分化甲状腺癌中，FOXO3a转录因子不抑制促癌基因，而是致命肿瘤的生长刺激因子。在人类未分化甲状腺癌的实验室模型中，FOXO3a沉默后，肿瘤细胞生长缓慢，但是当它重新恢复表达时，肿瘤细胞会生长得更快。
FOXO3a是一已知的肿瘤生长抑制因子，因为其能通过开启细胞核内的基因、触发细胞死亡来响应所有细胞应激形式。癌症，反过来通过将FOXO3a出核，进入细胞质中来关闭FOXO3a。促进FOXO3a出核的分子是Akt，Akt促使癌症细胞存活。
该研究小组利用Akt蛋白受体阻滞剂来增加核中FOXO3a，抑制未分化甲状腺癌细胞的生长。
研究表明Akt抑制剂的使用将FOXO3a保持在细胞核中，帮助杀死癌细胞，而FOXO3a本身不加速肿瘤细胞的成长。（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.
