本院管坤良博士和赵斌博士2012年1月1日在Genes & Development杂志发表研究论文“Cell detachment activates the Hippo pathway via cytoskeleton reorganization to induce anoikis”其中赵斌博士为第一作者，管坤良博士为通讯作者。

失巢凋亡是指由细胞脱离细胞外基质而引起的细胞凋亡现象。它保障了从正常组织脱离的细胞被及时清除而不会附着到其它组织引起机体生理异常，因此该机制在维持生物体的正常发育和稳态上发挥着重要作用。失巢凋亡也被认为是癌细胞脱离原发肿瘤通过体液循环系统发生转移的重要障碍。本文从Hippo通路活性受细胞与细胞外基质粘附状态的调控这一现象出发，通过比较正常细胞与癌细胞，以及比较通过RNA干扰及病毒载体等手段人为改变Hippo通路活性的细胞在贴壁培养及悬浮培养条件下的细胞凋亡情况，阐明了该通路在细胞失巢凋亡现象中的重要功能。这一研究不仅发现了Hippo通路的新的细胞生物学功能，并且将细胞失巢凋亡的分子机制从传统的细胞膜表面分子介导的信号解脱出来，提出了细胞骨架及细胞形态起始的信号介导失巢凋亡的新模型。并且该研究通过临床样品的分析为Hippo通路在癌症转移中的特异性作用提供了初步的依据。

Abstract

Cell attachment to the extracellular matrix (ECM) is crucial to cell physiology such as polarity, motility, and proliferation. In normal cells, loss of attachment to the ECM induces a specific type of apoptosis, termed anoikis. Resistance to anoikis in cancer cells promotes their survival in circulation and dispersion to distant anatomic sites, leading to tumor metastasis. The Yes-associated protein (YAP) transcription coactivator is a human oncogene and a key regulator of organ size. The Hippo tumor suppressor pathway phosphorylates and inhibits YAP. However, little is known about the signals that regulate the Hippo pathway. Here we report that through cytoskeleton reorganization, cell detachment activates the Hippo pathway kinases Lats1/2 and leads to YAP phosphorylation and inhibition. The detachment-induced YAP inactivation is required for anoikis in nontransformed cells, whereas in cancer cells with deregulation of the Hippo pathway, knockdown of YAP and TAZ restores anoikis. Furthermore, we provided evidence that Lats1/2 expression level is indeed significantly down-regulated in metastatic prostate cancer. Our findings provide a novel connection between cell attachment and anoikis through the Hippo pathway and have important implications in cancer therapeutics.

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浙江大学生命科学研究院

2012年3月1日