组织蛋白酶D在小鼠肺腺癌发生发展中的表达特点及其意义

张慧娟 郑晓伟 乔玲 常文静 卢锋* 贾彩云*

doi:10.16098/j.issn.0529-1356.2018.01.009

PDF(816 KB)

解剖学报 ›› 2018, Vol. 49 ›› Issue (1) : 56-62. DOI: 10.16098/j.issn.0529-1356.2018.01.009

肿瘤生物学

组织蛋白酶D在小鼠肺腺癌发生发展中的表达特点及其意义

张慧娟¹ 郑晓伟^1,2 乔玲¹常文静¹ 卢锋^1* 贾彩云^1*

作者信息 +

Expression characteristics and significance of cathepsin D in the initiation and progression of mouse lung adenocarcinoma

ZHANG Hui-juan¹ ZHENG Xiao-wei ^1,2 QIAO Ling¹ CHANG Wen-jing¹ LU Feng ^1* JIA Cai-yun ^1*

Author information +

文章历史 +

摘要

目的探索组织蛋白酶D（CTSD）在肺腺癌发生发展中的表达特点及其意义。方法使用氨基甲酸乙酯腹腔注射建立BALB/c小鼠肺腺癌模型；蛋白质组放射性核素相对标记和绝对定量（iTRAQ）分析筛选差异表达蛋白；免疫组织化学和Western blotting检测蛋白在肺腺癌不同病理时期的表达变化特点。结果 CTSD蛋白在肺腺癌早期表达较对照组明显增强；免疫组织化学和Western blotting检验分析发现，随着肺腺癌病程进展，CTD表达呈上升趋势，在肺腺癌晚期，实验组为对照组13.7倍；出现肝转移实验组小鼠肺组织CTSD呈现不同异构体。结论 CTSD是肺组织癌变过程中的重要蛋白，其异常表达和修饰可能在肺腺癌发生、发展和转移中起重要作用，可能成为肺腺癌早期诊断的分子指标。

Abstract

Objective To investigate the expression characteristics and significance of cathepsin D(CTSD) in the initiation and progression of mouse lung adenocarcinoma.Methods We used urethane intraperitoneal injection to establish lung adenocarcinoma model in the BALB/c mouse. Differentially expressed proteins were identified using isobaric tag for relative and absolute quantitation(iTRAQ)-based quantitative proteomic technology in tumor group compared with control group. Cathepsin D expression characteristics were detected in different time points by immunohistochemical and Western blotting analysis. Results The expression of cathepsin D was significantly increased in the early-stage lung adenocarcinoma tissue compared with the control group. Immonohistochemical and Western blotting analysis observed that following tumor progression, cathepsin D expression was up-regulated. At the late-stage of lung adenocarcinoma, cathepsin D expression was 13.7-fold significantly higher than that in the control group and showed different molecular weight isoform of cathepsin D in the lung tissue of mouse with liver metastasis. Conclusion Cathepsin D is a critical protein in lung carcinogenesis. Aberrant expression and modification of cathepsin D may play an important role in the occurrence, development and metastasis of lung adenocarcinoma. Cathepsin D may have the potential to become biomarkers for early diagnosis of lung adenocarcinoma.

导出引用

张慧娟郑晓伟乔玲常文静卢锋贾彩云. 组织蛋白酶D在小鼠肺腺癌发生发展中的表达特点及其意义[J]. 解剖学报. 2018, 49(1): 56-62 https://doi.org/10.16098/j.issn.0529-1356.2018.01.009

ZHANG Hui-juan ZHENG Xiao-wei QIAO Ling CHANG Wen-jing LU Feng JIA Cai-yun. Expression characteristics and significance of cathepsin D in the initiation and progression of mouse lung adenocarcinoma[J]. Acta Anatomica Sinica. 2018, 49(1): 56-62 https://doi.org/10.16098/j.issn.0529-1356.2018.01.009

参考文献

［1］Conner GE, Richo G. Isolation and characterization of a stable activation intermediate of the lysosomal aspartyl protease cathepsin D ［J］. Biochemistry, 1992, 31(4): 1142-1147.

［2］Gemoo T, Epping F, Heinrich L, et al. Increased cathepsin D protein expression is a biomarker for osteosarcomas, pulmonary metastases and other bone malignancies［J］. Oncotarget, 2015, 6(18):16517-16526.

［3］Pigac B, Dmitrovic B, Maric S, et al. Cathepsin D and its prognostic value in neuroepithelial brain tumors ［J］. Coll Antropol, 2012, 36(1):227-233.

［4] Hara I, Miyake H, Yamanaka K, et al. Serum cathepsin D and its density in men with prostate cancer as new predictors of disease progression ［J］. Oncol, 2002, 9(6): 1379-1383.

［5］Arao J, Fukui H, Ono Y, et al. Immunohistochemical localization of cathepsin D in colorectal tumors ［J］. Dis Colon Rectum, 2000, 43(3):396-401.

［6］Pruitt FL, He Y, Franco OE, et al. Cathepsin D acts as an essential mediator to promote malignancy of benign prostatic epithelium ［J］. Prostate, 2012, 10(1002):22589-22601.

［7］Bach AS, Deroca D, LaurentMatha V, et al. Nuclear cathepsin D enhances TRPS1 transcriptional repressor function to regulate cell cycle progression and transformation in human breast cancer cells ［J］. Oncotarge, 2015, 6(29):28084-28103.

［8］Luo X, Lu F, Wang HL, et al. Comparative autoantibody profiling before and after the appearance of malignancy: Identification of anti-cathepsin D autoantibody as a promising diagnostic marker for lung cancer ［J］. Biochem Biophys Res Commun, 2012, 420(4):704-709.

［9］Kreisel D, Gelman AE, Higashikub R, et al. Strain-specific variation in murine natural killer gene complexcontributes to differentces in immosurveillance for urethane-induced lung cancer ［J］. Cancer Res, 2012, 72(17):4311-4317.

［10］Pandey M, Gupta KP. Involvement of STAT3, NF-κB and associated downstream molecules before and after the onset of urethane induced lung tumors in mouse ［J］. Environ Toxicol Pharmacol, 2012, 34(2):502-511.

［11］Connelly L, Robinson-Benion C, Chont M, et al. A transgenic model reveals important roles for the NF-kappa B alternative pathway［J］. J Biol Chem, 2007, 282(13): 10028-10035.

［12］Lawson WE, Polosukhin W, Stathopoulos GT, et al. Increased and prolonged pulmonary fibrosis in surfactant protein C-deficient mice following intratracheal bleomycin ［J］. Am J Pathol, 2005, 167(5):1267-1277.

［13］Lu F, Taghalout A. Membrane association via an amino-terminal amphipathic helic is required for the cellular organization and function of RNase Ⅱ ［J］. J Biol Chem, 2013, 288(10):7241-7251

［14］Downs LS, Lima PH, Bliss RL, et al. Cathepsins B and D activity and activity ratios in normal ovaries, benign ovarian neoplasms, and epithelial ovarian cancer ［J］. J Soc Gynecol Investig, 2005, 12(7):539-544.

［15］Berchem G, Glondu M, Gleizes M, et al. Cathepsis D affects multiple tumor progression steps in vivo: proliferation, angiogenesis and apoptosisv ［J］. Oncogene, 2002, 21(38):5951-5955.

［16］Mimae T, Tsuta K, Maeshima AM, et al. Cathepsin D as a potential prognostic marker for lung adenocarcinoma ［J］. Pathol Res Pract, 2012, 208(9):534-540.

［17］Yi W, Clark PM, Mason DE, et al. Phosphofructokinase 1 glycosylation regulates cell growth and metabolism ［J］. Science, 2012, 337(6097):975-980.

［18］Zhao Y, Takahashi M, Gu J, et al. Functional roles of N-glycans in cell signaling and cell adhesion in cancer ［J］. Cancer Sci, 2008, 99(7):1304-1310.