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Proc Natl Acad Sci U S A. 2017 Dec 12;114(50):13254-13259. doi: 10.1073/pnas.1711777114. Epub 2017 Nov 21.

ΔNp63-mediated regulation of hyaluronic acid metabolism and signaling supports HNSCC tumorigenesis.

Author information

1
Department of Experimental Medicine and Surgery, University of Rome "Tor Vergata", 00133 Rome, Italy.
2
Institute of Cell Biology and Neurobiology, National Research Council of Italy (CNR), 00015 Monterotondo (Rome), Italy.
3
Institute of Cancer Sciences, University of Glasgow, Glasgow, G61 1BD United Kingdom.
4
The Francis Crick Institute, London NW 1AT, United Kingdom.
5
Radboud Institute for Molecular Life Sciences, Department of Human Genetics 855, Radboud University Medical Centre, 6525 GA Nijmegen, The Netherlands.
6
Faculty of Science, Radboud Institute for Molecular Life Sciences, Department of Molecular Developmental Biology, Radboud University, 6525 GA Nijmegen, The Netherlands.
7
Department of Experimental Medicine and Surgery, University of Rome "Tor Vergata", 00133 Rome, Italy; melino@uniroma2.it angelo.peschiaroli@cnr.it.
8
Medical Research Council, Toxicology Unit, Leicester University, Leicester LE1 9HN, United Kingdom.
9
Institute of Cell Biology and Neurobiology, National Research Council of Italy (CNR), 00015 Monterotondo (Rome), Italy; melino@uniroma2.it angelo.peschiaroli@cnr.it.

Abstract

Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide, and several molecular pathways that underlie the molecular tumorigenesis of HNSCC have been identified. Among them, amplification or overexpression of ΔNp63 isoforms is observed in the majority of HNSCCs. Here, we unveiled a ΔNp63-dependent transcriptional program able to regulate the metabolism and the signaling of hyaluronic acid (HA), the major component of the extracellular matrix (ECM). We found that ∆Np63 is capable of sustaining the production of HA levels in cell culture and in vivo by regulating the expression of the HA synthase HAS3 and two hyaluronidase genes, HYAL-1 and HYAL-3. In addition, ∆Np63 directly regulates the expression of CD44, the major HA cell membrane receptor. By controlling this transcriptional program, ∆Np63 sustains the epithelial growth factor receptor (EGF-R) activation and the expression of ABCC1 multidrug transporter gene, thus contributing to tumor cell proliferation and chemoresistance. Importantly, p63 expression is positively correlated with CD44, HAS3, and ABCC1 expression in squamous cell carcinoma datasets and p63-HA pathway is a negative prognostic factor of HNSCC patient survival. Altogether, our data shed light on a ∆Np63-dependent pathway functionally important to the regulation of HNSCC progression.

KEYWORDS:

HNSCC; hyaluronic acid; p63

PMID:
29162693
PMCID:
PMC5740608
DOI:
10.1073/pnas.1711777114
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

The authors declare no conflict of interest.

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