About this item:

220 Views | 227 Downloads

Author Notes:

To whom correspondence should be addressed: University of Notre Dame, 1234 Notre Dame Ave., A200E Harper Hall, South Bend, IN 46617., Tel.: 574-631-4100; E-mail: sstack@nd.edu

J. J. J. designed, performed, and analyzed the experiments shown in Figs. 1​1​​​–6 and drafted the paper.

D. L. M. contributed to data analysis and interpretation of data in Fig. 4.

R. J. generated the cell lines used in this study.

Y. L. provided technical assistance with data collection for Figs. 2 and ​and 4.

Z. S. provided pathology support and assistance with cell and tissue staining in Figs. 1, ​5, and ​6.

L. T. provided technical assistance with tissue-based studies in Figs. 1, 5, and 6.

R. W. assisted with experiments shown in Fig. 3.

R. B. performed and analyzed the experiments shown in Fig. 2.

E. R. S. contributed key reagents for the experiments in Fig. 1.

M. S. S. conceived and designed the study, supervised the study, assisted with development of methodology, provided data interpretation, and revised the paper.

All authors reviewed the results and approved the final version of the manuscript.

The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

The authors declare that they have no conflicts of interest with the contents of this article.


Research Funding:

This work was supported in part by National Institutes of Health NCI Research Grant RO1CA085870 (to M. S. S.) and NIDCR Grant F31DE021926 (to D. L. M.).


  • Science & Technology
  • Life Sciences & Biomedicine
  • Biochemistry & Molecular Biology
  • inflammation
  • kallikrein
  • microRNA (miRNA)
  • NF-B
  • protease
  • serine protease
  • oral cancer
  • protease-activated receptor
  • HEAD

Protease-activated Receptor-2 (PAR-2)-mediated Nf-B Activation Suppresses Inflammation-associated Tumor Suppressor MicroRNAs in Oral Squamous Cell Carcinoma


Journal Title:

Journal of Biological Chemistry


Volume 291, Number 13


, Pages 6936-6945

Type of Work:

Article | Final Publisher PDF


Oral cancer is the sixth most common cause of death from cancer with an estimated 400,000 deaths worldwide and a low (50%) 5-year survival rate. The most common form of oral cancer is oral squamous cell carcinoma (OSCC). OSCC is highly inflammatory and invasive, and the degree of inflammation correlates with tumor aggressiveness. The G protein-coupled receptor protease-activated receptor-2 (PAR-2) plays a key role in inflammation. PAR-2 is activated via proteolytic cleavage by trypsin-like serine proteases, including kallikrein-5 (KLK5), or by treatment with activating peptides. PAR-2 activation induces G protein-α-mediated signaling, mobilizing intracellular calcium and Nf-κBsignaling, leading to the increased expression of pro-inflammatory mRNAs. Little is known, however, about PAR-2 regulation of inflammation-related microRNAs. Here, we assess PAR-2 expression and function in OSCC cell lines and tissues. Stimulation of PAR-2 activates Nf-κB signaling, resulting in RelA nuclear translocation and enhanced expression of pro-inflammatory mRNAs. Concomitantly, suppression of the anti-inflammatory tumor suppressor microRNAs let-7d, miR-23b, and miR-200c was observed following PAR-2 stimulation. Analysis of orthotopic oral tumors generated by cells with reduced KLK5 expression showed smaller, less aggressive lesions with reduced inflammatory infiltrate relative to tumors generated by KLK5-expressing control cells. Together, these data support a model wherein KLK5-mediated PAR-2 activation regulates the expression of inflammation-associated mRNAs and microRNAs, thereby modulating progression of oral tumors.

Copyright information:

© 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

Export to EndNote