Inhibition of tumor growth and metastasis by depletion of vesicular sorting protein Hrs: Its regulatory role on E-cadherin and β-catenin

Masafumi Toyoshima, Nobuyuki Tanaka, Jun Aoki, Yoshinori Tanaka, Kazuko Murata, Masanao Kyuuma, Hideyuki Kobayashi, Naoto Ishii, Nobuo Yaegashi, Kazuo Sugamura

Research output: Contribution to journalArticle

47 Citations (Scopus)

Abstract

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 β-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.

Original languageEnglish
Pages (from-to)5162-5171
Number of pages10
JournalCancer Research
Volume67
Issue number11
DOIs
Publication statusPublished - 2007 Jun 1

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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