Pro-inflammatory genes as biomarkers and therapeutic targets in oral squamous cell carcinoma.
Oral squamous cell carcinoma (OSCC) is a major health problem worldwide, and patients have a particularly poor 5-year survival rate. Thus, identification of the molecular targets in OSCC and subsequent innovative therapies are greatly needed. Prolonged exposure to alcohol, tobacco, and pathogenic agents are known risk factors and have suggested that chronic inflammation may represent a potential common denominator in the development of OSCC. Microarray analysis of gene expression in OSCC cell lines with high basal NF-κB activity and OSCC patient samples identified dysregulation of many genes involved in inflammation, wound healing, angiogenesis, and growth regulation. In particular IL-8, CCL5, STAT1, and VEGF gene expression was up-regulated in OSCC. Moreover, IL-8 protein levels were significantly higher in OSCC cell lines as compared with normal human oral keratinocytes. Targeting IL-8 expression by siRNA significantly reduced the survival of OSCC cells, indicating that it plays an important role in OSCC development and/or progression. Inhibiting the inflammatory pathway by aspirin and the proteasome/NF-κB pathway by bortezomib resulted in marked reduction in cell viability in OSCC lines. Taken together our studies indicate a strong link between inflammation and OSCC development and reveal IL-8 as a potential mediator. Treatment based on prevention of general inflammation and/or the NF-κB pathway shows promise in OSCCs.
Rao
Shailaja K
SK
Department of Bioscience Research, University of Tennessee Health Science Center, Memphis, Tennessee 38163, USA.
Pavicevic
Zoran
Z
Du
Ziyun
Z
Kim
Jong-Gwan
JG
Fan
Meiyun
M
Jiao
Yan
Y
Rosebush
Molly
M
Samant
Sandeep
S
Gu
Weikuan
W
Pfeffer
Lawrence M
LM
Nosrat
Christopher A
CA
D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000627:therapeutic use; D001241:Aspirin / Q000627:therapeutic use; D015415:Biomarkers / Q000378:metabolism*; D001897:Boronic Acids / Q000627:therapeutic use; D000069286:Bortezomib; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000235:genetics / Q000276:immunology; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D020869:Gene Expression Profiling; D006801:Humans; D007249:Inflammation / Q000235:genetics*; D016209:Interleukin-8 / Q000235:genetics / Q000276:immunology; D046228:Microarray Analysis; D009062:Mouth Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000276:immunology; D016328:NF-kappa B / Q000378:metabolism; D011719:Pyrazines / Q000627:therapeutic use; D034741:RNA, Small Interfering / Q000378:metabolism
D000894:Anti-Inflammatory Agents, Non-Steroidal; D000970:Antineoplastic Agents; D015415:Biomarkers; D001897:Boronic Acids; D016209:Interleukin-8; D016328:NF-kappa B; D011719:Pyrazines; D034741:RNA, Small Interfering; D000069286:Bortezomib; D001241:Aspirin