RASAL2, a RAS GTPase-activating protein, inhibits stemness and epithelial-mesenchymal transition via MAPK/SOX2 pathway in bladder cancer.
RASAL2, a RAS GTPase-activating protein, inhibits stemness and epithelial-mesenchymal transition via MAPK/SOX2 pathway in bladder cancer.
复制标题
RASAL2 是一种 RAS GTP 酶激活蛋白，通过 MAPK/SOX2 通路抑制膀胱癌的干细胞性和上皮间质转化。
DOI：
10.1038/cddis.2017.9
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发表时间：
2017-02-09
影响因子：
9
通讯作者：
Wu K
中科院分区：
文献类型：
--
作者：
Hui K;Gao Y;Huang J;Xu S;Wang B;Zeng J;Fan J;Wang X;Yue Y;Wu S;Hsieh JT;He D;Wu K
肌肉浸润性或转移性膀胱癌（BCa）与非常差的预后相关，其潜在机制仍知之甚少。在这项研究中，我们证明RASAL 2，一种RAS GTP酶激活蛋白（RAS GAP），在BCa中作为肿瘤抑制因子。首先，RASAL 2在BCa标本中下调，并与病理分级和临床分期呈负相关。此外，基于我们的功能获得和功能丧失实验，我们观察到RASAL 2可以抑制BCa干性和上皮-间质转化（EMT）。从机制上讲，我们发现丝裂原活化蛋白激酶/SOX 2信号传导对于维持RASAL 2缺陷BCa细胞的干细胞性和间充质性质具有关键作用，因为ERK活性的抑制或SOX 2的敲低可以逆转这些表型。RASAL 2在体内可抑制BCa肿瘤的发生和远处转移。此外，在皮下异种移植物和人BCa标本中，RASAL 2表达与干性/EMT状态之间呈负相关。综上所述，我们的数据表明RASAL 2是BCa中的肿瘤抑制因子，并且调节癌症干性和EMT以用于BCa复发和转移。
Muscle-invasive or metastatic bladder cancer (BCa) is associated with a very poor prognosis, and the underlying mechanism remains poorly understood. In this study, we demonstrate RASAL2, a RAS GTPase-activating protein (RAS GAP), acts as a tumor suppressor in BCa. First, RASAL2 was downregulated in BCa specimens and inversely correlated with pathological grades and clinical stages. Furthermore, we observed that RASAL2 could inhibit BCa stemness and epithelial–mesenchymal transition (EMT) based on our gain-of-function and loss-of-function experiments. Mechanistically, we found that mitogen-activated protein kinase/SOX2 signaling had a critical role for maintaining the stemness and mesenchymal properties of RASAL2-deficient BCa cells because inhibition of ERK activity or knockdown of SOX2 could reverse these phenotypes. Also, RASAL2 could inhibit BCa tumorigenesis and distant metastasis in vivo. Moreover, there was an inverse correlation between RASAL2 expression and the stemness/EMT status in subcutaneous xenograft and human BCa specimens. Taken together, our data indicate that RASAL2 is a tumor suppressor in BCa, and modulates cancer stemness and EMT for BCa recurrence and metastasis.