Klotho endows hepatoma cells with resistance to anoikis via VEGFR2/PAK1 activation in hepatocellular carcinoma.
Klotho endows hepatoma cells with resistance to anoikis via VEGFR2/PAK1 activation in hepatocellular carcinoma.
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DOI：
10.1371/journal.pone.0058413
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Gu J
中科院分区：
文献类型：
--
作者：
Chen L;Liu H;Liu J;Zhu Y;Xu L;He H;Zhang H;Wang S;Wu Q;Liu W;Liu Y;Pan D;Ren S;Xu J;Gu J
Klotho最初被认为是一种衰老抑制基因，使Klotho缺陷小鼠易患早衰样综合征。尽管最近有报道称Klotho在各种恶性转化过程中表现出抑制肿瘤的特性，但对Klotho在肝癌发生中的功能作用和分子机制仍知之甚少。在我们的研究中，52例肝癌患者的临床随访中，免疫组织化学Klotho染色水平与肝硬化、肿瘤多样性和静脉侵袭有显著相关性。Klotho高表达的肝癌患者的总生存率明显低于Klotho低表达的肝癌患者。此外，Klotho过表达增加了肝癌细胞的细胞迁移、不依赖锚定生长和anoikis抗性。Klotho过表达上调p21活化激酶1 （PAK1）的表达，shrna介导的PAK1敲低和激酶活性抑制与激酶死亡突变体PAK1 K299R共表达或变抑抑制剂IPA3处理逆转了Klotho过表达的肝癌细胞的anoikis耐药。更重要的是，VEGFR2抑制剂阿西替尼和阻断抗体治疗肝癌细胞证实了Klotho表达介导的VEGFR2蛋白水平上调的关键意义。在klotho过表达的肝癌细胞中，组成型活性突变体PAK1 T423E共表达逆转了阿西替尼治疗致敏的anoikis。相反，Klotho的敲除降低了VEGFR2/PAK1依赖性的anoikis耐药，这可以通过PAK1 T423E逆转。这些结果揭示了Klotho通过激活VEGFR2/PAK1信号通路促进anoikis耐药的新功能，从而促进肝癌进展过程中肿瘤的迁移和侵袭，这可能为肿瘤转移提供了一种推测的分子机制。
Klotho was originally characterized as an aging suppressor gene that predisposed Klotho-deficient mice to premature aging-like syndrome. Although Klotho was recently reported to exhibit tumor suppressive properties during various malignant transformations, the functional role and molecular mechanism of Klotho in hepatocarcinogenesis remains poorly understood. In our present study, immunohistochemical Klotho staining levels in a clinical follow-up of 52 hepatoma patients were significantly associated with liver cirrhosis, tumor multiplicity and venous invasion. The overall survival rate of hepatoma patients with high Klotho expression was significantly lower than those patients with low Klotho expression. Moreover, Klotho overexpression increased cellular migration, anchorage-independent growth, and anoikis resistance in hepatoma cells. Klotho overexpression elevated p21-activated kinase 1 (PAK1) expression and shRNA-mediated PAK1 knockdown and kinase activity inhibition with kinase dead mutant PAK1 K299R coexpression or allosteric inhibitor IPA3 treatment reversed anoikis resistance in Klotho-overexpressed hepatoma cells. More importantly, the pivotal significance of upregulated VEGFR2 protein levels mediated by Klotho expression was confirmed by VEGFR2 inhibitor Axitinib and blocking antibody treatment in hepatoma cells. Axitinib treatment sensitized anoikis was reversed by constitutive active mutant PAK1 T423E coexpression in Klotho-overexpressed hepatoma cells. Conversely, knockdown of Klotho reduced VEGFR2/PAK1 dependent anoikis resistance, which could be reversed by PAK1 T423E. These results revealed a novel oncogenic function of Klotho in promoting anoikis resistance via activating VEGFR2/PAK1 signaling, thus facilitating tumor migration and invasion during hepatoma progression, which could provide a putative molecular mechanism for tumor metastasis.
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影响因子：
4.8
作者：
Cheng, Chunming;Kong, Xiangfei;Gu, Jianxin
通讯作者：
Gu, Jianxin
影响因子：
11.2
作者：
Liu, Haiou;Xu, Jiejie;Gu, Jianxin
通讯作者：
Gu, Jianxin
Klotho 抑制人肺癌细胞系 A549 生长并促进细胞凋亡
DOI：
10.1186/1756-9966-29-99
发表时间：
2010-07-19
期刊：
Journal of experimental & clinical cancer research : CR
影响因子：
--
作者：
Chen B;Wang X;Zhao W;Wu J
通讯作者：
Wu J
影响因子：
4.8
作者：
Kurosu, H;Ogawa, Y;Kuro-o, M
通讯作者：
Kuro-o, M
影响因子：
56.9
作者：
Kurosu, H;Yamamoto, M;Kuro-o, M
通讯作者：
Kuro-o, M