Increased nuclear factor-kappa B activation is related to the tumor development of renal cell carcinoma.
Although an aggressive phenotype of renal cell carcinoma (RCC) is known to frequently be associated with inflammatory paraneoplastic syndrome including serum C-reactive protein (CRP) elevation, the molecular mechanism underlying this clinical phenomenon as well as what yields the malignant phenotype leading to the progression of RCC has yet to be elucidated. Based on the increased level of inflammatory cytokines such as interleukin-6 in advanced cases of RCC, a cytokine-inducible transcription factor, namely, nuclear factor-kappa B (NF-kappa B), may thus play a role in the progression of RCC. An electrophoretic mobility shift assay (EMSA) was carried out to determine the activity of NF-kappa B. Out of 45 cases of RCC, 15 cases (33%) showed a >200% increase in the NF-kappa B activity in comparison with that seen in normal renal tissue. In locally advanced cases (> or =pT3), 64% (9/14) showed an increased activity whereas it was only observed in 19% (6/31) of localized cases (< or =pT2). All three cases with metastases showed an increased NF-kappa B activity. The NF-kappa B activity determined by EMSA was further confirmed by an immunohistochemical analysis using an antibody recognizing the nuclear localization signal (NLS) in p65 subunit of NF-kappa B. The serum CRP elevation correlated with the increased NF-kappa B activation, and therefore NF-kappa B may be a causative transcription factor of inflammatory paraneoplastic syndrome. A high NF-kappa B activity was associated with an increased expression of both the p65 and p50 subunits of NF-kappa B and a concomitant decreased expression of I kappa B alpha. No functional mutations of the I kappa B alpha gene were detected. The NF-kappa B activity may therefore be a late event in carcinogenesis related to tumor development, thereby representing a possible molecular target in the treatment of RCC.
Oya
Mototsugu
M
Department of Urology and Department of Molecular Biology, Keio University School of Medicine, Shinjuku-ku, Tokyo 160-8582, Japan. moto-oya@sc.itc.keio.ac.jp
Takayanagi
Atsushi
A
Horiguchi
Akio
A
Mizuno
Ryuichi
R
Ohtsubo
Masafumi
M
Marumo
Ken
K
Shimizu
Nobuyoshi
N
Murai
Masaru
M
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001483:Base Sequence; D002292:Carcinoma, Renal Cell / Q000378:metabolism*; D017931:DNA Primers; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D007680:Kidney Neoplasms / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D016328:NF-kappa B / Q000378:metabolism*
D017931:DNA Primers; D016328:NF-kappa B