Toyoshima Masafumi, Tanaka Nobuyuki, Aoki Jun, Tanaka Yoshinori, Murata Kazuko, Kyuuma Masanao, Kobayashi Hideyuki, Ishii Naoto, Yaegashi Nobuo, Sugamura Kazuo
Department of Microbiology, Tohoku University Graduate School of Medicine, Sendai, Japan.
Cancer Res. 2007 Jun 1;67(11):5162-71. doi: 10.1158/0008-5472.CAN-06-2756.
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 E-cadherin.
受体酪氨酸激酶（RTK）的异常高信号与致癌作用相关，RTK失活受损也可能是癌症发生的一种机制。肝细胞生长因子调节的酪氨酸激酶底物（Hrs）是将活化受体分选至溶酶体并关闭其信号的主要调节因子之一。Hrs含有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-钙黏蛋白）的内体分选。在此，我们研究了Hrs在决定癌细胞恶性程度中的作用，发现用小干扰RNA靶向破坏Hrs可有效减弱HeLa细胞在体外和体内的增殖、非锚定依赖性生长、肿瘤发生及转移潜能。在从Hrs基因敲除小鼠建立的小鼠胚胎成纤维细胞系中，Hrs表达的恢复增加了细胞增殖和非锚定依赖性生长。进一步分析表明，Hrs缺失与E-钙黏蛋白上调及β-连环蛋白信号传导减少有关。E-钙黏蛋白的异常积累很可能是由于其在溶酶体中的降解受损所致。这些结果表明，Hrs可能通过调节E-钙黏蛋白的降解在决定癌细胞恶性程度中起关键作用。
