title: Protease-activated Receptor-2 (PAR-2)-mediated Nf-κB Activation Suppresses Inflammation-associated Tumor Suppressor MicroRNAs in Oral Squamous Cell Carcinoma.
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-κB signaling, 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.
authors.affiliation: From the Harper Cancer Research Institute and Department of Chemistry and Biochemistry, University of Notre Dame, South Bend, Indiana 46617.
authors.forename: Jeff J
authors.initials: JJ
authors.lastname: Johnson
authors.affiliation: the Department of Pathology and Anatomical Sciences, University of Missouri School of Medicine, Columbia, Missouri 65212.
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Miller
authors.affiliation: the Department of Human Genetics, Emory University, Atlanta, Georgia 75440.
authors.forename: Rong
authors.initials: R
authors.lastname: Jiang
authors.affiliation: From the Harper Cancer Research Institute and Department of Chemistry and Biochemistry, University of Notre Dame, South Bend, Indiana 46617.
authors.forename: Yueying
authors.initials: Y
authors.lastname: Liu
authors.affiliation: From the Harper Cancer Research Institute and Department of Chemistry and Biochemistry, University of Notre Dame, South Bend, Indiana 46617.
authors.forename: Zonggao
authors.initials: Z
authors.lastname: Shi
authors.affiliation: From the Harper Cancer Research Institute and.
authors.forename: Laura
authors.initials: L
authors.lastname: Tarwater
authors.affiliation: the Department of Biology, Indiana University South Bend, South Bend, Indiana 46634.
authors.forename: Russell
authors.initials: R
authors.lastname: Williams
authors.affiliation: the W. M. Keck Center for Transgene Research, South Bend, Indiana 46617, and.
authors.forename: Rashna
authors.initials: R
authors.lastname: Balsara
authors.affiliation: the Department of Surgery, University of Texas Health Science Center, Tyler, Texas 75799.
authors.forename: Edward R
authors.initials: ER
authors.lastname: Sauter
authors.affiliation: From the Harper Cancer Research Institute and Department of Chemistry and Biochemistry, University of Notre Dame, South Bend, Indiana 46617, sstack@nd.edu.
authors.forename: M Sharon
authors.initials: MS
authors.lastname: Stack
mesh_terms: D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007249:Inflammation; D007610:Kallikreins / Q000235:genetics / Q000378:metabolism; D015603:Keratinocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008819:Mice, Nude; D035683:MicroRNAs / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D009062:Mouth Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D016328:NF-kappa B / Q000819:agonists / Q000235:genetics* / Q000378:metabolism; D009368:Neoplasm Transplantation; D009842:Oligopeptides / Q000494:pharmacology; D011230:Precancerous Conditions / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D044464:Receptor, PAR-2 / Q000819:agonists / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D051996:Transcription Factor RelA / Q000235:genetics / Q000378:metabolism
chemical_list: C533896:MIRN200 microRNA, human; C552430:MIRN23a microRNA, human; D035683:MicroRNAs; D016328:NF-kappa B; D009842:Oligopeptides; C498143:RELA protein, human; D044464:Receptor, PAR-2; D051996:Transcription Factor RelA; C487931:mirnlet7 microRNA, human; C112356:seryl-leucyl-isoleucyl-glycyl--arginyl-leucinamide; C400147:KLK5 protein, human; D007610:Kallikreins
keywords: NF-κB; inflammation; kallikrein; microRNA (miRNA); oral cancer; protease; protease-activated receptor; serine protease
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