Abstract

HOX genes are master regulators of organ morphogenesis and cell differentiation during embryonic development, and continue to be expressed throughout post-natal life. To test the hypothesis that HOX genes are dysregulated in head and neck squamous cell carcinoma (HNSCC) we defined their expression profile, and investigated the function, transcriptional regulation and clinical relevance of a subset of highly expressed HOXD genes. Two HOXD genes, D10 and D11, showed strikingly high levels in HNSCC cell lines, patient tumor samples and publicly available datasets. Knockdown of HOXD10 in HNSCC cells caused decreased proliferation and invasion, whereas knockdown of HOXD11 reduced only invasion. POU2F1 consensus sequences were identified in the 5' DNA of HOXD10 and D11. Knockdown of POU2F1 significantly reduced expression of HOXD10 and D11 and inhibited HNSCC proliferation. Luciferase reporter constructs of the HOXD10 and D11 promoters confirmed that POU2F1 consensus binding sites are required for optimal promoter activity. Utilizing patient tumor samples a significant association was found between immunohistochemical staining of HOXD10 and both the overall and the disease-specific survival, adding further support that HOXD10 is dysregulated in head and neck cancer. Additional studies are now warranted to fully evaluate HOXD10 as a prognostic tool in head and neck cancers.

Highlights

  • Head and Neck cancer encompasses a heterogeneous group of malignancies that can differ markedly in presentation, treatment and prognosis [1]

  • HOXD10 was 185-fold and HOXD11 was 275-fold higher in Head and neck squamous cell carcinoma (HNSCC) tissue compared to the patient-matched control tissue, but none of the other HOXD genes were significantly different (Fig 1B)

  • In the current study 25 of the 39 HOX genes were consistently more highly expressed in HNSCC cell lines than in normal oral keratinocytes (NOKs)

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Summary

Introduction

Head and Neck cancer encompasses a heterogeneous group of malignancies that can differ markedly in presentation, treatment and prognosis [1]. 95% of these cancers are squamous cell carcinomas that affect the oral cavity, oropharynx, hypopharynx, nasopharynx and larynx [2]. Head and neck squamous cell carcinoma (HNSCC) accounts for approximately 2% of all malignancies worldwide [3]. A better understanding of the pathogenesis of HNSCC may provide useful insights for the development of novel therapeutic strategies. Combinations of HOX genes specify the anterior-posterior axis and segment identity during early embryonic development, and postnatally HOX genes continue to execute critical regulatory roles in many processes such as apoptosis, receptor signaling, motility and angiogenesis (reviewed by Shah and Sukumar [5]). Numerous observations of dysregulated HOX gene www.impactjournals.com/oncotarget expression in solid tumors and leukemia [6] suggest that HOX genes are important for both oncogenesis and tumor suppression, but their functional role in cancer onset and maintenance requires further investigation

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