The Wnt/β-catenin Signaling Circuitry in Head and Neck Cancer

  • Rogerio M. CastilhoEmail author
  • J. Silvio Gutkind
Part of the Current Cancer Research book series (CUCR)


We have recently gained an unprecedented knowledge of the most frequent genetic alterations in head and neck squamous cell carcinoma (HNSCC). We have also learned that the aberrant function of multiple signaling networks contributes to HNSCC initiation and progression, including the persistent activation of the PI3K/Akt/mTOR, NFκB, and STAT3 signaling pathways and decreased antiproliferative responses to Notch and TGF-β. Emerging evidence suggests that many regulatory components of the Wnt signaling pathway are also dysfunctional in HNSCC, leading to increased nuclear β-catenin levels. This includes increased expression of Wnt family members and their coreceptor, Frizzled, loss of heterozygosity of the adenomatosis polyposis coli (APC) tumor suppressor gene, and epigenetic events leading to decreased expression of APC and the Wnt antagonists the secreted Frizzled-related proteins (SFRPs), Wnt inhibitory factors (WIFs) and Dickkopf family members (DKKs), primarily by promoter hypermethylation. Wnt/β-catenin controls cell fate decisions in normal epithelial stem cells, but persistent β-catenin signaling contributes to increased growth, metastatic potential and resistance to chemotherapy in HNSCC and their tumor-initiating cells. While the role of Wnt/β-catenin in HNSCC is not as well defined as in other cancers, the development of small molecule inhibitors of the Wnt/β-catenin pathway for other cancer types may soon afford novel targeted options for the treatment of HNSCC lesions displaying aberrant Wnt signaling.


Wnt Squamous carcinoma Oral cancer HPV β-catenin Epigenetics Signal transduction Oncogenome Cancer stem cells 


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Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  1. 1.Laboratory of Epithelial Biology, Department of Periodontics and Oral MedicineUniversity of Michigan School of DentistryAnn ArborUSA
  2. 2.Oral and Pharyngeal Cancer BranchNational Institute of Dental and Craniofacial Research, National Institutes of HealthBethesdaUSA

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