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Inhibition of Tumor Growth and Metastasis by Depletion of Vesicular Sorting Protein Hrs: Its Regulatory Role on E-Cadherin and ß-Catenin

Departments of ¹ Microbiology and Immunology and ² Obstetrics and Gynecology, Tohoku University Graduate School of Medicine, Sendai, Japan and ³ Division of Immunology, Miyagi Cancer Center Research Institute, Miyagi, Japan

Requests for reprints: Nobuyuki Tanaka, Department of Microbiology and Immunology, Tohoku University Graduate School of Medicine, 2-1, Seiryo-machi, Aoba, Sendai 980-8575, Japan. Phone: 81-22-717-8096; Fax: 81-22-717-8097; E-mail: n-tanaka{at}mail.tains.tohoku.ac.jp.

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 ß-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. [Cancer Res 2007;67(11):5162–71]

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