Increased nuclear factor-κB activation is related to the tumor development of renal cell carcinoma
Increased nuclear factor-κB activation is related to the tumor development of renal cell carcinoma
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DOI：
10.1093/carcin/24.3.377
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发表时间：
2003-03-01
期刊：
影响因子：
4.7
通讯作者：
Murai, M
中科院分区：
文献类型：
--
作者：
Oya, M;Takayanagi, A;Murai, M
虽然已知肾细胞癌（RCC）的侵袭性表型经常与炎性副肿瘤综合征（包括血清c反应蛋白（CRP）升高）相关，但这种临床现象的分子机制以及导致RCC进展的恶性表型的产生尚未阐明。基于晚期RCC患者炎症因子如白细胞介素-6水平的升高，一种细胞因子诱导的转录因子，即核因子- kappab （NF-kappaB）可能在RCC的进展中发挥作用。电泳迁移率转移法（EMSA）测定NF-kappaB的活性。在45例RCC中，15例（33%）显示NF-kappaB活性比正常肾组织增加了约200%。在局部晚期病例（大于或等于topT3）中，64%（9/14）显示活性增加，而在局部病例（小于或等于topT2）中仅观察到19%（6/31）的活性增加。所有3例转移病例均显示NF-kappaB活性增加。利用识别NF-kappaB p65亚基核定位信号（NLS）的抗体进行免疫组化分析，进一步证实了EMSA测定的NF-kappaB活性。血清CRP升高与NF-kappaB活化增加相关，因此NF-kappaB可能是炎性副肿瘤综合征的致病转录因子。高NF-kappaB活性与NF-kappaB p65和p50亚基的表达增加以及IkappaBalpha的表达减少有关。未检测到ikappabα基因的功能性突变。因此，NF-kappaB活性可能是与肿瘤发展相关的癌变的晚期事件，因此代表了RCC治疗中可能的分子靶点。
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-kappaB (NF-kappaB), 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-kappaB. Out of 45 cases of RCC, 15 cases (33%) showed a >200% increase in the NF-kappaB activity in comparison with that seen in normal renal tissue. In locally advanced cases (greater than or equal topT3), 64% (9/14) showed an increased activity whereas it was only observed in 19% (6/31) of localized cases (less than or equal topT2). All three cases with metastases showed an increased NF-kappaB activity. The NF-kappaB 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-kappaB. The serum CRP elevation correlated with the increased NF-kappaB activation, and therefore NF-kappaB may be a causative transcription factor of inflammatory paraneoplastic syndrome. A high NF-kappaB activity was associated with an increased expression of both the p65 and p50 subunits of NF-kappaB and a concomitant decreased expression of IkappaBalpha. No functional mutations of the IkappaBalpha gene were detected. The NF-kappaB activity may therefore be a late event in carcinogenesis related to tumor development, thereby representing a possible molecular target in the treatment of RCC.