Tichelaar Jay W, Zhang Yu, leRiche Jean C, Biddinger Paul W, Lam Stephen, Anderson Marshall W
Department of Environmental Health, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA.
BMC Cancer. 2005 Dec 6;5:155. doi: 10.1186/1471-2407-5-155.
The development of non-small cell lung carcinoma proceeds through a series of well-defined pathological steps before the appearance of invasive lung carcinoma. The molecular changes that correspond with pathology changes are not well defined and identification of the molecular events may provide clues on the progression of intraepithelial neoplasia in the lung, as well as suggest potential targets for chemoprevention. The acquisition of anti-apoptotic signals is critical for the survival of cancer cells but the pathways involved are incompletely characterized in developing intra-epithelial neoplasia (IEN).
We used immunohistochemistry to determine the presence, relative levels, and localization of proteins that mediate anti-apoptotic pathways in developing human bronchial neoplasia.
Bronchial epithelial protein levels of the phosphorylated (active) form of AKT kinase and the caspase inhibitor cIAP-2 were increased in more advanced grades of bronchial IEN lesions than in normal bronchial epithelium. Additionally, the percentage of biopsies with nuclear localization of p65/RELA in epithelial cells increased with advancing pathology grade, suggesting that NF-kappaB transcriptional activity was induced more frequently in advanced IEN lesions.
Our results indicate that anti-apoptotic pathways are elevated in bronchial IEN lesions prior to the onset of invasive carcinoma and that targeting these pathways therapeutically may offer promise in prevention of non-small cell lung carcinoma.
在浸润性肺癌出现之前，非小细胞肺癌的发展会经历一系列明确的病理阶段。与病理变化相对应的分子变化尚未明确界定，而分子事件的识别可能为肺上皮内瘤变的进展提供线索，并提示化学预防的潜在靶点。获得抗凋亡信号对癌细胞的存活至关重要，但在发展中的上皮内瘤变（IEN）中，所涉及的途径尚未完全明确。
我们使用免疫组织化学来确定在发展中的人类支气管瘤变中介导抗凋亡途径的蛋白质的存在、相对水平和定位。
与正常支气管上皮相比，在更高级别的支气管IEN病变中，AKT激酶的磷酸化（活性）形式和半胱天冬酶抑制剂cIAP-2的支气管上皮蛋白水平升高。此外，上皮细胞中p65/RELA核定位的活检百分比随着病理分级的推进而增加，这表明在晚期IEN病变中，NF-κB转录活性更频繁地被诱导。
我们的结果表明，在浸润性癌发生之前，支气管IEN病变中的抗凋亡途径升高，并且针对这些途径进行治疗可能为预防非小细胞肺癌带来希望。
