title: JNK1/2 expression and modulation of STAT3 signaling in oral cancer.
abstract: Mitogen-activated protein kinases (MAPKs) are a family of protein kinases that link extracellular stimuli with intracellular responses and participate in numerous cellular processes such as growth, proliferation, differentiation, inflammation and apoptosis. Persistent activation of signal transducer and activator of transcription 3 (STAT3), which is accompanied by increases in STAT3 tyrosine phosphorylation, is associated with cell proliferation, differentiation and apoptosis in oral squamous cell carcinoma (OSCC). The role and significance of the activation of MAPKs, particularly of c-Jun N-terminal kinase (JNK), on STAT3 signaling in OSCC have not been thoroughly investigated. The present study examines the effects of JNK1/2 modulation on STAT3 signaling and cellular activities in OSCC cells. The expression levels of STAT3 [total, tyrosine phosphorylated (p-Tyr) and serine phosphorylated (p-Ser)], JNK, c-Jun and cyclin D1 were assessed in the OSCC cell lines SCC25 and SCC9. Inhibition of JNK1/2 was achieved by pharmacological agents (SP600125) and by small interfering RNA (siRNA) silencing, while JNK1/2 was induced by active MAPK kinase 7. Cell proliferation and viability rates were also evaluated. Inhibition of JNK1/2 with either SP600125 treatment or specific siRNA silencing resulted in decreased levels of p-Ser STAT3 and increased levels of p-Tyr STAT3 and cyclin D1 in both cell lines. Furthermore, JNK1/2 inhibition resulted in a dose-dependent increase in cell growth and viability in both cell lines. Opposite results were observed with JNK1/2 induction in both cell lines. The present results are supportive of a potential tumor suppressive role of JNK1/2 signaling in OSCC, which may be mediated through negative crosstalk with the oncogenic STAT3 signaling pathway. The possible therapeutic implications of JNK1/2 inhibition for patients with OSCC require to be investigated.
authors.affiliation: Department of Oral Pathology and Medicine, Dental School, National and Kapodistrian University of Athens, 11527 Athens, Greece.
authors.forename: Ioannis
authors.initials: I
authors.lastname: Gkouveris
authors.affiliation: Department of Oral Pathology and Medicine, Dental School, National and Kapodistrian University of Athens, 11527 Athens, Greece.
authors.forename: Nikolaos
authors.initials: N
authors.lastname: Nikitakis
authors.affiliation: First Department of Pathology, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece.
authors.forename: Maria
authors.initials: M
authors.lastname: Karanikou
authors.affiliation: First Department of Pathology, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece.
authors.forename: George
authors.initials: G
authors.lastname: Rassidakis
authors.affiliation: Department of Oral Pathology and Medicine, Dental School, National and Kapodistrian University of Athens, 11527 Athens, Greece.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Sklavounou
keywords: JNK1/2; STAT3; crosstalk; oral; signaling; squamous carcinoma