Ho Chao-Chi, Huang Pei-Hsin, Huang Hsin-Yi, Chen Yen-Ho, Yang Pan-Chyr, Hsu Su-Ming
Department of Pathology, National Taiwan University Hospital, and National Taiwan University College of Medicine, Taipei, Taiwan.
Am J Pathol. 2002 Nov;161(5):1647-56. doi: 10.1016/S0002-9440(10)64442-2.
Caveolin-1, a 21- to 24-kd integral membrane protein, is primarily implicated as a tumor suppressor gene. Transformed cells normally contain reduced or no caveolin-1. Re-expression of caveolin-1 is found in advanced human and mouse prostate adenocarcinomas. To explore its potential role in tumorigenesis and tumor progression of human lung cancers, we used the well-characterized cell line (CL) series of lung adenocarcinoma cells with increasing cellular invasiveness to show that expression of caveolin-1 mRNA and protein was up-regulated with enhanced invasion/metastatic capability of CL cells. Reintroducing the caveolin-1 gene into the less invasive, caveolin-1-negative CL cells enhanced their invasive capability at least by twofold, as revealed by an in vitro chamber invasion assay. Thus, a correlation exists for both constitutive and induced expression of caveolin-1 in CL cells. Immunohistochemical examination of caveolin-1 was performed in 95 specimens obtained retrospectively from patients who had lung adenocarcinoma either with (35 patients) or without (60 patients) ipsilateral hilar/peribronchial tumor-metastasized lymph nodes. Caveolin-1 immunoreactivity was either totally absent or just barely detectable in a few lung adenocarcinoma cells from cases diagnosed as lung adenocarcinoma without regional lymph node metastasis. In contrast, increased caveolin-1 immunoreactivity both in number and intensity was detected in primary lung adenocarcinoma cells as well as in cancer cells that metastasized to regional lymph nodes from the cases diagnosed as advanced lung adenocarcinoma with nodal metastases. Multivariate analysis considering caveolin-1 immunoreactivity in addition to the established prognostic parameters such as pT stage, pN in these patients confirmed that caveolin-1 is an independent functional predictor of poor survival. We further revealed that up-regulated caveolin-1 in CL cells is necessary for mediating filopodia formation, which may enhance the invasive ability of lung adenocarcinoma cells.
小窝蛋白-1是一种21至24千道尔顿的整合膜蛋白，主要被认为是一种肿瘤抑制基因。转化细胞通常含有减少的小窝蛋白-1或根本没有。在晚期人类和小鼠前列腺腺癌中发现了小窝蛋白-1的重新表达。为了探索其在人类肺癌发生和肿瘤进展中的潜在作用，我们使用了具有特征明确的、侵袭性不断增加的肺腺癌细胞系（CL）系列，以表明小窝蛋白-1 mRNA和蛋白的表达随着CL细胞侵袭/转移能力的增强而上调。通过体外小室侵袭试验发现，将小窝蛋白-1基因重新导入侵袭性较小的、小窝蛋白-1阴性的CL细胞中，可使其侵袭能力至少提高两倍。因此，CL细胞中小窝蛋白-1的组成性表达和诱导性表达之间存在相关性。对95例标本进行了小窝蛋白-1的免疫组织化学检查，这些标本是从患有肺腺癌且有（35例患者）或无（60例患者）同侧肺门/支气管周围肿瘤转移淋巴结的患者中回顾性获取的。在诊断为无区域淋巴结转移的肺腺癌病例的一些肺腺癌细胞中，小窝蛋白-1免疫反应性要么完全缺失，要么仅勉强可检测到。相比之下，在诊断为有淋巴结转移的晚期肺腺癌病例的原发性肺腺癌细胞以及转移至区域淋巴结的癌细胞中，均检测到小窝蛋白-1免疫反应性在数量和强度上均增加。在这些患者中，除了既定的预后参数如pT分期、pN外，考虑小窝蛋白-1免疫反应性的多变量分析证实，小窝蛋白-1是生存不良的独立功能预测指标。我们进一步揭示，CL细胞中小窝蛋白-1的上调对于介导丝状伪足的形成是必要的，这可能增强肺腺癌细胞的侵袭能力。
