Truncated neurokinin-1 receptor is increased in colonic epithelial cells from patients with colitis-associated cancer
Truncated neurokinin-1 receptor is increased in colonic epithelial cells from patients with colitis-associated cancer
复制标题
DOI：
10.1073/pnas.1114275108
复制
发表时间：
2011-10-18
影响因子：
11.1
通讯作者：
Becker, James M.
中科院分区：
文献类型：
--
作者：
Gillespie, Earl;Leeman, Susan E.;Becker, James M.
慢性溃疡性结肠炎（UC）患者患结直肠癌的风险很高。在这项研究中，我们检测了发生癌（CA）或高度发育不良（HGD）的UC患者的档案福尔马林固定石蜡包埋结肠组织中促炎和有丝分裂性神经激肽-1受体（NK-1R）的表达变化。使用激光捕获显微镜对结肠区域的上皮进行显微解剖，这些区域的组织学证据显示CA， HGD和未发育不良或癌性的上皮，但确实包含先前炎症（静止性结肠炎）的证据。从解剖组织中提取mRNA，对提取的mRNA进行PCR阵列分析。通过免疫组织化学分别估计截断（tr-NK-1R）和全长（fl-NK-1R）受体的蛋白水平需要两种抗体。与HGD组和CA组相比，tr-NK-1R mRNA表达量增加了14倍（P = 0.02）。相比之下，fl-NK-1R转录本在组间无显著差异。与静止性结肠炎相比，HGD患者总NK-1R蛋白水平升高40% (P = 0.02)， CA患者总NK-1R蛋白水平升高80% （P = 0.0007）。fl-NK-1R蛋白水平无明显变化。我们得出结论，HGD和CA中总NK-1R蛋白的增加可归因于tr-NK-1R的增加，这表明tr-NK-1R可能在结肠炎相关癌症的恶性转化中起功能作用。tr-NK-1R可能被证明是一种有用的诊断标记物，可以识别有肿瘤风险的患者，并可能作为治疗结肠炎相关癌症的有用治疗靶点。
Patients with chronic ulcerative colitis (UC) are at high risk for developing colorectal cancer. In this study, archival formalin-fixed paraffin-embedded colonic tissue from patients with UC who developed carcinoma (CA) or high-grade dysplasia (HGD) was examined for changes in expression of the proinflammatory and mitogenic neurokinin-1 receptor (NK-1R). Laser capture microscopy was used to microdissect epithelia from areas of colons that showed histologic evidence of CA, HGD, and epithelia that were not dysplastic or cancerous but did contain evidence of prior inflammation (quiescent colitis). mRNA was extracted from the dissected tissue, and PCR array analysis was performed on extracted mRNA. Two antibodies were necessary to separately estimate the protein levels of the truncated (tr-NK-1R) and full-length (fl-NK-1R) receptors by immunohistochemistry. mRNA expression of tr-NK-1R increased 14-fold (P = 0.02) when comparing the HGD and CA groups. In contrast, the fl-NK-1R transcript showed no significant differences among groups. The protein levels of the total NK-1R increased by 40% (P = 0.02) in HGD and 80% (P = 0.0007) in CA compared with quiescent colitis. There were no significant changes in protein levels of the fl-NK-1R. We conclude that the increase in total NK-1R protein in HGD and CA is attributable to an increase in tr-NK-1R, suggesting there may be a functional role for tr-NK-1R in malignant transformation in colitis-associated cancer. The tr-NK-1R could prove useful as a diagnostic marker to identify patients at risk for neoplasia and may serve as a useful therapeutic target in the treatment of colitis-associated cancer.