Clinicopathological significance of cathepsin D expression in non-small cell lung cancer is conditional on apoptosis-associated protein phenotype: an immunohistochemistry study
Clinicopathological significance of cathepsin D expression in non-small cell lung cancer is conditional on apoptosis-associated protein phenotype: an immunohistochemistry study
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非小细胞肺癌中组织蛋白酶 D 表达的临床病理学意义取决于凋亡相关蛋白表型：一项免疫组织化学研究
DOI：
10.1007/s13277-012-0338-y
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发表时间：
2012-08-01
期刊：
影响因子：
--
通讯作者：
Wang, Enhua
中科院分区：
文献类型：
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作者：
Fan, Chuifeng;Lin, Xuyong;Wang, Enhua
组织蛋白酶D是一种众所周知的肽酶，属于天冬氨酸肽酶家族。已发现其在许多恶性肿瘤中过表达，并与癌症转移和临床结果相关。然而，它在癌症中的作用仍然存在争议。近年来，越来越多的证据表明组织蛋白酶D可能在细胞凋亡中发挥重要作用。在本研究中，我们检测了组织蛋白酶D和一组凋亡相关蛋白，包括bcl-2，caspase 3，Fas，fasL，p53和生存素在非小细胞肺癌（NSCLC）组织中的表达，以探讨组织蛋白酶D和这些凋亡相关蛋白之间的可能联系和临床病理特征，使用免疫组织化学。组织蛋白酶D在癌组织中的表达阳性率为64.5%（49/76），在间质中的表达阳性率为64.5%（49/76），间质包括白细胞、成纤维细胞、毛细血管内皮细胞和基质。组织蛋白酶D在癌细胞中的表达与相应的非肿瘤部位（支气管上皮和粘膜下腺体）的表达无显著性差异（阳性率53.3%（8/15））（p> 0.05）。对福尔马林固定的石蜡包埋标本的免疫荧光研究证实了癌细胞和非肿瘤部分中组织蛋白酶D的胞质表达。Western blot检测到组织蛋白酶D在肺组织和NSCLC组织中的成熟型和未成熟型表达，但两者表达水平差异无统计学意义（p> 0.05）。组织蛋白酶D的表达与癌细胞中Fas的表达呈正相关（p< 0.01），而与其它凋亡相关蛋白的表达无相关性（p> 0.05）。单独的组织蛋白酶D表达与任何临床病理学特征无关（p> 0.05），而多标记分析显示，基于组织蛋白酶D和一种凋亡相关蛋白表达的两种免疫染色表型，即组织蛋白酶D+/caspase 3−和组织蛋白酶D+/p53+，显示出临床病理学意义。组织蛋白酶D+/caspase 3−组与晚期肿瘤淋巴结转移阶段（III和IV）相关（p< 0.05），而组织蛋白酶D+/p53+组与淋巴结转移相关（p< 0.05）。目前的研究结果表明，组织蛋白酶D在非小细胞肺癌中的表达可能有助于癌症的发展，这是有条件的凋亡相关蛋白表型。
Cathepsin D is a well-known peptidase which belongs to the family of aspartic peptidases. It has been found to be overexpressed in many malignant tumors and associated with cancer metastasis and clinical outcome. However, its function in cancers remains controversial. Recently, increasing evidence shows that cathepsin D may play important roles in cell apoptosis. In the current study, we examined the expression of cathepsin D and a group of apoptosis-associated proteins including bcl-2, caspase 3, fas, fasL, p53, and survivin in non-small cell lung cancer (NSCLC) tissues to investigate the possible association between cathepsin D and these apoptosis-associated proteins and the clinicopathological features using immunohistochemistry. Cathepsin D expression was detected in cancer tissues including cancer cells (positive rate 64.5% (49/76)) and stromal parts including leukocytes, fibroblasts, capillary endothelial cells, and the matrix. No significant difference was found between the expression of cathepsin D in cancer cells and the corresponding non-tumor portions including bronchial epithelia and submucosal glands (positive rate 53.3% (8/15)) (p> 0.05). Immunofluorescence study on formalin-fixed, paraffin-embedded specimens confirmed the cytoplasmic expression of cathepsin D in cancer cells and non-tumor portions. Western blot study detected both mature and immature forms of cathepsin D in lung and NSCLC tissues, while the expression level of neither form showed a significant difference between these tissues (p> 0.05). Positive association was found between cathepsin D expression and fas status (p< 0.01) but not with the other apoptosis-associated proteins (p> 0.05) in cancer cells. Cathepsin D expression alone was not associated with any of the clinicopathological features (p> 0.05), while multiple-marker analysis revealed that two immunostaining phenotypes based on the expression of cathepsin D and one of the apoptosis-associated proteins, namely, cathepsin D+/caspase 3− and cathepsin D+/p53+ showed clinicopathological significance. The cathepsin D+/caspase 3− group was associated with advanced tumor node metastasis stages (III and IV) (p< 0.05), while the cathepsin D+/p53+ group was associated with lymph node metastasis (p< 0.05). The present findings indicate that the expression of cathepsin D in non-small cell lung cancer may have possible contributions to cancer development which is conditional on apoptosis-associated protein phenotype.