title: Clinical significance of kallikrein-related peptidase-4 in oral cancer.
abstract: Kallikrein-related-peptidase-4 (KLK4), a serine protease originally discovered in developing tooth with broad target sequence specificity, serves vital functions in dental enamel formation. KLK4 is involved in degradation of extracellular matrix proteins and it is thought that this proteolytic activity could also promote tumor invasion and metastasis. Recent studies have associated KLK4 expression with tumor progression and clinical outcome, particularly in prostate and ovarian cancer. Very little is known in regard KLK4 involvement in oral squamous cell carcinomas (OSCCs). Our objective was to investigate KLK4 expression in OSCC pathogenesis and disease progression. KLK4 expression was evaluated by immunohistochemistry, western blots and zymograms in OSCC lines. Invasion assays using high versus low/undetectable KLK4-expressing OSCC cell lines were performed jointly with KLK4 siRNA inhibition. A large collection of OSCC specimens was evaluated for KLK4 expression and correlation with patients' characteristics and outcomes were determined. Our data indicate that KLK4 is differentially expressed in oral carcinomas. OSCC cell lines with high invasive and metastatic potential have the highest levels of KLK4 expression. KLK4 mRNA and protein expression correlated with enzyme activity detected by zymograms. Inhibition of KLK4 expression results in diminished invasive potential in OSCC cell lines. Consistently, KLK4 expression is stronger in primary tumors that later either recurred or developed metastases, suggesting that its preferential expression in OSCC might contribute to individual tumor biology. Therefore, this study provides supportive evidence in favor of a prognostic value for KLK4 in OSCC and suggests that KLK4 could serve as a potential therapeutic target in patients with oral cancer.
authors: Department of Pediatric Dentistry and Orthodontics, School of Dentistry, University of Michigan, Ann Arbor, MI, U.S.A. Department of Computational Medicine and Bioinformatics, Medical School, University of Michigan, Ann Arbor, MI, U.S.A.
authors: Petros
authors: P
authors: Papagerakis
authors: Department of Clinical and Experimental Medicine, Section of Anatomic Pathology, University of Foggia, Foggia, Italy.
authors: Giuseppe
authors: G
authors: Pannone
authors: Department of Pediatric Dentistry and Orthodontics, School of Dentistry, University of Michigan, Ann Arbor, MI, U.S.A. Department of Otolaryngology-Head & Neck Surgery, Medical School, University of Michigan, Ann Arbor, MI, U.S.A.
authors: L I
authors: LI
authors: Zheng
authors: Department of Pediatric Dentistry and Orthodontics, School of Dentistry, University of Michigan, Ann Arbor, MI, U.S.A. Department of Otolaryngology-Head & Neck Surgery, Medical School, University of Michigan, Ann Arbor, MI, U.S.A.
authors: Maria
authors: M
authors: Athanassiou-Papaefthymiou
authors: Department of Biomaterials Sciences, School of Dentistry, University of Michigan, Ann Arbor, MI, U.S.A.
authors: Yashuo
authors: Y
authors: Yamakoshi
authors: Department of Pathology, School of Medicine, University of Texas Health Science Center, San Antonio, TX, U.S.A.
authors: Howard Stan
authors: HS
authors: McGuff
authors: Department of Otolaryngology-Head & Neck Surgery, Medical School, University of Michigan, Ann Arbor, MI, U.S.A.
authors: Omar
authors: O
authors: Shkeir
authors: Department of Pediatric Dentistry and Orthodontics, School of Dentistry, University of Michigan, Ann Arbor, MI, U.S.A. Department of Otolaryngology-Head & Neck Surgery, Medical School, University of Michigan, Ann Arbor, MI, U.S.A.
authors: Konstantinos
authors: K
authors: Ghirtis
authors: Department of Otolaryngology-Head & Neck Surgery, Medical School, University of Michigan, Ann Arbor, MI, U.S.A. silvanap@umich.edu.
authors: Silvana
authors: S
authors: Papagerakis
mesh_terms: D014408:Biomarkers, Tumor / Q000096:biosynthesis / Q000235:genetics; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D018450:Disease Progression; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007610:Kallikreins / Q000096:biosynthesis / Q000235:genetics*; D008297:Male; D009062:Mouth Neoplasms / Q000235:genetics* / Q000473:pathology; D009362:Neoplasm Metastasis; D009364:Neoplasm Recurrence, Local / Q000235:genetics; D011379:Prognosis; D012333:RNA, Messenger / Q000235:genetics; D016896:Treatment Outcome
chemical_list: D014408:Biomarkers, Tumor; D012333:RNA, Messenger; D007610:Kallikreins; C120801:kallikrein 4
keywords: Kallikrein-related-peptidase-4 (KLK4); Oral squamous cell carcinoma (OSCC); cell lines; clinical outcome; invasion; metastasis