title: Secretory leukocyte protease inhibitor modulates urethane-induced lung carcinogenesis.
abstract: Secretory leukocyte protease inhibitor (SLPI), 11.7 kDa serine protease inhibitor, is produced primarily in the respiratory tract, but it is often elevated in lung, head/neck and ovarian cancers. SLPI expression in relation to cancer progression, metastasis and invasion has been studied extensively in non-small cell lung cancer. However, the role of SLPI during the early stages of carcinogenesis remains unknown. We hypothesized that SLPI is required from the initiation and promotion to the progression of lung carcinogenesis. A skin allograft model using SLPI-knockout (SLPI-KO) mice and short hairpin RNA-treated cells was used to demonstrate that SLPI expression in tumor cells is crucial for tumor formation. Moreover, lung tumorigenesis induced by urethane, a chemical lung carcinogen, was significantly suppressed in SLPI-KO mice in association with decreased nuclear factor-kappaB (NF-κB) activity. SLPI deficiency also resulted in decreased cell numbers and decreased production of inflammatory cytokines in bronchoalveolar lavage fluids. The suppression of NF-κB activation in SLPI-KO mice was associated with lower expression of NF-κB-related survival genes and DNA repair genes. Our findings demonstrate that SLPI plays an important role from the initial stages of lung carcinogenesis to the progression of lung cancer in an NF-κB-dependent manner.
authors.affiliation: Department of Respiratory Medicine, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan and.
authors.forename: Cezary
authors.initials: C
authors.lastname: Jan Treda
authors.forename: Tatsuro
authors.initials: T
authors.lastname: Fukuhara
authors.forename: Takuji
authors.initials: T
authors.lastname: Suzuki
authors.forename: Akira
authors.initials: A
authors.lastname: Nakamura
authors.forename: Jamal
authors.initials: J
authors.lastname: Zaini
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Kikuchi
authors.forename: Masahito
authors.initials: M
authors.lastname: Ebina
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Nukiwa
mesh_terms: D000230:Adenocarcinoma / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D000818:Animals; D001483:Base Sequence; D063646:Carcinogenesis; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D017931:DNA Primers; D006801:Humans; D008175:Lung Neoplasms / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D053481:Secretory Leukocyte Peptidase Inhibitor / Q000502:physiology*; D014520:Urethane / Q000633:toxicity*
chemical_list: D017931:DNA Primers; D016328:NF-kappa B; D053481:Secretory Leukocyte Peptidase Inhibitor; D014520:Urethane