Fusella Federica, Ferretti Roberta, Recupero Daniele, Rocca Stefania, Di Savino Augusta, Tornillo Giusy, Silengo Lorenzo, Turco Emilia, Cabodi Sara, Provero Paolo, Pandolfi Pier Paolo, Sapino Anna, Tarone Guido, Brancaccio Mara
Department of Biotechnology and Health Sciences, University of Torino, Torino, Italy.
J Pathol. 2014 Oct;234(2):152-63. doi: 10.1002/path.4341. Epub 2014 Aug 6.
Morgana/CHP-1 is a ubiquitously expressed protein able to inhibit ROCK II kinase activity. We have previously demonstrated that morgana haploinsufficiency leads to multiple centrosomes, genomic instability, and higher susceptibility to tumour development. While a large fraction of human cancers has shown morgana down-regulation, a small subset of tumours was shown to express high morgana levels. Here we demonstrate that high morgana expression in different breast cancer subtypes correlates with high tumour grade, mitosis number, and lymph node positivity. Moreover, morgana overexpression induces transformation in NIH-3T3 cells and strongly protects them from various apoptotic stimuli. From a mechanistic point of view, we demonstrate that morgana causes PTEN destabilization, by inhibiting ROCK activity, hence triggering the PI3K/AKT survival pathway. In turn, morgana down-regulation in breast cancer cells that express high morgana levels increases PTEN expression and leads to sensitization of cells to chemotherapy.
莫尔加娜/CHP-1是一种普遍表达的蛋白质，能够抑制ROCK II激酶活性。我们之前已经证明，莫尔加娜单倍体不足会导致多个中心体、基因组不稳定以及对肿瘤发生更高的易感性。虽然大部分人类癌症都表现出莫尔加娜下调，但一小部分肿瘤显示出高莫尔加娜水平的表达。在这里，我们证明不同乳腺癌亚型中高莫尔加娜表达与高肿瘤分级、有丝分裂数和淋巴结阳性相关。此外，莫尔加娜过表达诱导NIH-3T3细胞发生转化，并强烈保护它们免受各种凋亡刺激。从机制角度来看，我们证明莫尔加娜通过抑制ROCK活性导致PTEN不稳定，从而触发PI3K/AKT存活途径。反过来，在表达高莫尔加娜水平的乳腺癌细胞中下调莫尔加娜会增加PTEN表达，并导致细胞对化疗敏感。
