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

• Type of Material: Article
• Authors: Jeff J. Johnson, University of Notre Dame; Daniel L. Miller, University of Missouri; Rong Jiang, Emory University; Yueying Liu, University of Notre Dame; Zonggao Shi, University of Notre Dame; Laura Tarwater, University of Notre Dame; Russell Williams, Indiana University; Rashna Balsara, W. M. Keck Center for Transgene Research; Edward R. Sauter, University of Texas; M. Sharon Stack, University of Notre Dame
• Language: English
• Date: 2016-03-25
• Publisher: American Society for Biochemistry and Molecular Biology
• Publication Version: Final Published Version
• Copyright Statement: © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.
• Final Published Version (URL): http://dx.doi.org/10.1074/jbc.M115.692640
• Title of Journal or Parent Work: Journal of Biological Chemistry
• ISSN: 0021-9258
• Volume: 291
• Issue: 13
• Start Page: 6936
• End Page: 6945
• Grant/Funding Information: 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.).
• Keywords: LESIONS; Science & Technology; serine protease; microRNA (miRNA); protease-activated receptor; inflammation; Biochemistry & Molecular Biology; NF-B; UP-REGULATION; HEAD; kallikrein; Life Sciences & Biomedicine; METASTASIS; oral cancer; CANCER-RELATED INFLAMMATION; HUMAN KERATINOCYTES; EXPRESSION; KAPPA-B; protease; EPITHELIAL-MESENCHYMAL TRANSITION; NETHERTON-SYNDROME
• Research Categories: Chemistry, Biochemistry; Health Sciences, Pathology

Abstract

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.