Nuclear factor‐κB (NF‐κB), a key transcription factor thought to play a major role in carcinogenesis, regulates many important signaling pathways involved in tumor promotion. Although NF‐κB can be activated in lung cancer cell lines by tobacco exposure, there have been no studies of the expression of NF‐κB in lung cancer pathogenesis.

The immunohistochemical expression of NF‐κB p65 was investigated in 394 lung cancers (370 nonsmall cell lung carcinomas [NSCLC]; and 24 small cell lung carcinomas [SCLC]) and 269 lung normal epithelium and preneoplastic lesions, including hyperplasias, squamous metaplasias, dysplasias, and atypical adenomatous hyperplasias.

High levels of nuclear immunohistochemical expression of NF‐κB p65 were detected in the lung cancers, with significantly higher levels in SCLCs compared with NSCLCs (P<.0001). In adenocarcinomas the NF‐κB p65 expression level was significantly higher in advanced TNM stages (III‐IV) than in earlier stages (I‐II) (P<.0001), and when NF‐κB p65 is dichotomized using 50% as the cutoff point (high vs low), a higher NF‐κB p65 expression level was detected in tumors having either K‐RAS (P = .02) or EGFR (P = .009) mutations compared with wildtype tumors. A relatively high level of nuclear NF‐κB p65 expression was detected in normal and mildly abnormal epithelium, and a progression with increasing histology severity was detected in preneoplastic lesions.

NF‐κB p65 nuclear expression is an early and frequent phenomenon in the pathogenesis of lung cancer. The findings indicate that NF‐κB activation plays an important role in lung cancer pathogenesis and is a suitable target for the development of new lung cancer therapies and chemoprevention strategies. Cancer 2006. © 2006 American Cancer Society.