A critical role of c-Cbl-interacting protein of 85 kDa in the development and progression of head and neck squamous cell carcinomas through the Ras-ERK pathway

Takahiro Wakasaki, Muneyuki Masuda, Hiroaki Niiro, Siamak Jabbarzadeh-Tabrizi, Kumiko Noda, Tadayoshi Taniyama, Shizuo Komune, Koichi Akashi

Research output: Contribution to journalArticlepeer-review

19 Citations (Scopus)

Abstract

Activation of the transforming growth factor (TGF) α/epidermal growth factor receptor (EGFR)-mediated signaling pathway is a common mechanism for dysregulated growth of head and neck squamous cell carcinoma (HNSCC). c-Cbl-interacting protein of 85 kDa (CIN85) is an adaptor protein that facilitates EGFR internalization. Little is known, however, about a role of CIN85 in EGFR signaling as well as its relevance to tumor development and progression of HNSCC. Here, we demonstrate that CIN85 is highly expressed in HNSCC tumor samples compared with adjacent normal tissues, and this overexpression is significantly correlated with advanced clinical stage. The experiments using CIN85-overexpressing and knockdown HNSCC cell lines showed that CIN85 promotes HNSCC growth and facilitates EGFR internalization without apparently affecting phosphorylation of EGFR. Moreover, CIN85 promoted TGF-α-induced activation of Ras and phosphorylation of downstream molecules such as c-Raf, MEK, and extracellular signal-regulated kinase, leading to expression of c-Myc that is critical for sustained proliferation of HNSCC. Taken together, these findings suggest that CIN85 not only controls EGFR internalization but also promotes the EGFRmediated tumor development and progression, and thus, CIN85 may serve as a potential therapeutic target in a subset of HNSCC.

Original languageEnglish
Pages (from-to)789-796
Number of pages8
JournalNeoplasia
Volume12
Issue number10
DOIs
Publication statusPublished - Oct 2010

All Science Journal Classification (ASJC) codes

  • Cancer Research

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