文献分享| Revolve正倒置一体显微镜在Akt信号通路研究中的应用

在2017年5月22日，由Sali Liu和Chonghui Cheng两位作者发表一篇了《Akt signaling is sustained by a CD44 spl ice isoform-mediated positive feedback loop》的文章。

使用Echo Laboratories-Revolve正倒置显微对样本玻片进行成像。

中文摘要：

肿瘤细胞几乎总是将持续的PI3K / Akt信号传导作为避免凋亡和维持生存的有效手段。然而，对于没有获得PI3K / Akt突变的那些肿瘤细胞来实现这一目的，潜在的机制仍然是模糊的。在这里，我们描述了在乳腺癌中维持PI3K / Akt信号传导所必需的剪接异构体依赖性阳性反馈环的发现。接头同种型CD44s通过激活Akt信号级联来促进透明质酸合酶HAS2的表达。 HAS2产品透明质酸（HA）进一步刺激了CD44s介导的Akt信号，创建了促进肿瘤细胞存活的前馈信号电路。在机制上，我们将FOXO1鉴定为HAS2的真正转录阻遏物。 FOXO1的Akt介导的磷酸化缓解了HAS2转录的抑制，FOXO1磷酸化状态通过正反馈循环的操作保持。在乳腺癌临床标本中，我们确定CD44s和HAS2的表达呈正相关。我们的结果建立了一个积极的反馈机制，在肿瘤细胞中维持PI3K / Akt信号，进一步揭示了该途径在癌细胞存活中几乎普遍的作用。

英文摘要： 

Tumor cells nearly invariably evolve sustained PI3K/Akt signaling as an effective means to circumvent apoptosis and maintain survival. However, for those tumor cells that do not acquire PI3K/Akt mutations to achieve this end the underlying mechanisms have remained obscure. Here we describe the discovery of a splice isoform-dependent positive feedback loop that is essential to sustain PI3K/Akt signaling in breast cancer. Splice isoform CD44s promoted expression of the hyaluronan synthase HAS2 by activating the Akt signaling cascade. The HAS2 product hyaluronan (HA) further stimulated CD44s-mediated Akt signaling, creating a feed- forward signaling circuit that promoted tumor cell survival. Mechanistically, we identified FOXO1 as a bona fide transcriptional repressor of HAS2. Akt-mediated phosphorylation of FOXO1 relieved its suppression of HAS2 transcription, with FOXO1 phosphorylation status maintained by operation of the positive feedback loop. In clinical specimens of breast cancer, we established that the expression of CD44s and HAS2 were positively correlated. Our results establish a positive feedback mechanism that sustains PI3K/Akt signaling in tumor cells, further illuminating the nearly universal role of this pathway in cancer cell survival.

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