Nuclear factor-κB is constitutively activated in prostate cancer in vitro and is overexpressed in prostatic intraepithelial neoplasia and adenocarcinoma of the prostate
Nuclear factor-κB is constitutively activated in prostate cancer in vitro and is overexpressed in prostatic intraepithelial neoplasia and adenocarcinoma of the prostate
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DOI：
10.1158/1078-0432.ccr-0571-03
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发表时间：
2004-08-15
影响因子：
11.5
通讯作者：
Cheng, L
中科院分区：
文献类型：
--
作者：
Sweeney, C;Li, L;Cheng, L
目的：转录因子核因子-kappaB（NF-κ B）促进生产的血管生成，抗凋亡，并参与carcinogenes.Experimental设计：电迁移率凝胶位移分析，以评估NF-κ B DNA结合在体外的促转移因子。通过cDNA阵列分析和前列腺癌细胞的增殖试验，评估NF-κ B DNA结合的功能相关性，并与NF-κ B抑制剂parthenoclavin接触。采用免疫组化法检测97例乳腺癌切除标本中p65 NF-κ B亚单位的表达。结果：电迁移率凝胶位移测定证实了NF κ B DNA结合的存在下，在所有四个前列腺癌细胞系测试。该结合被孤雌菊抑制，并且该药剂还减少NF-κ B控制下的多个基因转录，并抑制前列腺癌细胞的增殖。染色结果显示，与良性上皮相比，p65在前列腺上皮内瘤变和癌中过度表达。具体而言，在良性上皮中1+和2+染色占优势，没有3+染色，而在癌性区域中仅2+和3+染色（分别为30%和70%）。这些差异具有统计学差异。结论：NF-κ B在前列腺癌中被组成性激活，并且在体外具有功能相关性。人前列腺切除标本的免疫组化显示NF-κ B活性亚单位p65的过表达，并且这发生在前列腺癌发生的早期阶段。这项工作支持靶向NF-κ B用于预防和/或治疗前列腺癌的基本原理。
Purpose: The transcription factor nuclear factor-kappaB (NF-kappaB) promotes the production of angiogenic, antiapoptotic, and prometastatic factors that are involved in carcinogenesis.Experimental Design: Electromobility gel shift assays were used to evaluate NF-kappaB DNA binding in vitro. The functional relevance of NF-kappaB DNA binding was assessed by both cDNA array analyses and proliferation assays of prostate cancer cells with and without exposure to an NF-kappaB inhibitor, parthenolide. Immunohistochemistry staining for the p65 NF-kappaB subunit was used to determine the frequency and location of NF-kappaB in 97 prostatectomy specimens. The amount of staining was quantified on a 0-3+ scale.Results: An electromobility gel shift assay confirmed the presence of NFkappaB DNA binding in all four prostate cancer cell lines tested. The binding was inhibited by parthenolide, and this agent also decreased multiple gene transcripts under the control of NF-kappaB and inhibited proliferation of prostate cancer cells. The staining results revealed overexpression of p65 in the prostatic intraepithelial neoplasia and cancer compared with the benign epithelium. Specifically, there was a predominance of 1+ and 2+ with no 3+ staining in benign epithelium, whereas there was only 2+ and 3+ staining (30 and 70%, respectively) in the cancerous areas. These differences were statistically different. There was no correlation with tumor grade or stage.Conclusions: NF-kappaB is constitutively activated in prostate cancer and functionally relevant in vitro. Immunohistochemistry of human prostatectomy specimens demonstrated overexpression of the active subunit of NF-kappaB, p65, and that this occurs at an early stage in the genesis of prostate cancer. This work supports the rationale for targeting NF-kappaB for the prevention and/or treatment of prostate cancer.