Inhibition of tumor growth and metastasis by depletion of vesicular sorting protein Hrs:: Its regulatory role on E-cadherin and β-catenin
Inhibition of tumor growth and metastasis by depletion of vesicular sorting protein Hrs:: Its regulatory role on E-cadherin and β-catenin
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DOI：
10.1158/0008-5472.can-06-2756
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发表时间：
2007-06-01
期刊：
影响因子：
11.2
通讯作者：
Sugamura, Kazuo
中科院分区：
文献类型：
--
作者：
Toyoshima, Masafumi;Tanaka, Nobuyuki;Sugamura, Kazuo
受体酪氨酸激酶（RTK）的异常高信号与癌症发生有关，RTK失活受损也可能是癌症的一种机制。肝细胞生长因子调节的酪氨酸激酶底物（Hrs）是将激活的受体分选到溶酶体并关闭其信号的主要调节因子之一。Hrs包含一个泛素相互作用基序，并参与单泛素化膜蛋白（如生长因子受体和E-钙粘蛋白）的内体分选。在这里，我们研究了Hrs在确定癌细胞的恶性程度中的作用，并发现小干扰RNA对Hrs的靶向破坏有效地减弱了HeLa细胞在体外和体内的增殖、锚定非依赖性生长、肿瘤发生和转移潜力。Hrs表达的恢复增加了从Hrs敲除小鼠建立的小鼠胚胎成纤维细胞系中的细胞增殖和锚定非依赖性生长。进一步的分析显示，Hrs缺失与E-钙粘蛋白的上调和β-连环蛋白信号转导的减少有关。E-cadherin的异常蓄积最可能是由于溶酶体中E-cadherin降解受损所致。这些结果表明，Hrs可能通过调节F-cadherin的降解在决定癌细胞的恶性程度中起关键作用。
Abnormally high signals from receptor tyrosine kinases (RTK) are associated with carcinogenesis, and impaired deactivation of RTKs may also be a mechanism in cancer. Hepatocyte growth factor-regulated tyrosine kinase substrate (Hrs) is one of the master regulators that sort activated receptors toward lysosomes and shut down their signals. Hrs contains a ubiquitin-interacting motif and is involved in the endosomal sorting of monoubiquitinated membrane proteins, such as growth factor receptor and E-cadherin. Here, we investigated the role of Hrs in determining the malignancy of cancer cells and discovered that the targeted disruption of Hrs by small interfering RNA effectively attenuated the proliferation, anchorage-independent growth, tumorigenesis, and metastatic potential of HeLa cells in vitro and in vivo. The restoration of Hrs expression increased cell proliferation and anchorage-independent growth in a mouse embryonic fibroblast line established from a Hrs knockout mouse. Further analysis revealed that Hrs depletion was associated with the up-regulation of E-cadherin and reduced beta-catenin signaling. The aberrant accumulation of E-cadherin most likely resulted from impaired E-cadherin degradation in lysosomes. These results suggest that Hrs may play a critical role in determining the malignancy of cancer cells by regulating the degradation of F-cadherin.