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OBJECTIVES: We investigated the role of lysosomal biogenesis and hydrolase activity in the clinical behavior and postoperative outcome of lung cancer. MATERIALS AND METHODS: Using immunohistochemistry we investigated the expression of the transcription factor EB (TFEB) which orchestrates lysosomal biogenesis, the lysosome membrane protein LAMP2a and of the lysosomal hydrolase cathepsin D in a series of 98 non-small cell lung carcinomas (NSCLC) treated with surgery alone. In vitro experiments with the A549 and H1299 lung cancer cell lines were also performed. RESULTS: Overexpression of TFEB, LAMP2a and Cathepsin D was noted in 47/98 (47.9%), 43/98 (43.9%) and 39/98 (39.8%) cases, respectively, and were significantly correlated with each other and with adenocarcinomas. High LAMP2a was related to high histology grade. Linear regression analysis confirmed significant association of TFEB with BNIP3 (p=0.0003, r=0.35) and LC3A with LAMP2a expression (p=0.0002, r=0.37). An inverse association of Cathepsin D expression with stone-like structures (SLS) was recorded (p=0.02, r=0.22). On univariate analysis all three lyososomal variables were associated with poor prognosis (p=0.05, 0.04 and 0.01, for TFEB, Cathepsin D and LAMP2a, respectively). Multivariate analysis showed that the SLS number (p=0.0001, HR5.37), Cathepsin D expression (p=0.01, HR=2.2) and stage (p=0.01, HR=1.5) were independent prognostic variables. Silencing of TFEB with siRNAs in the A549 and H1299 lung cancer cell lines did not affect proliferation but resulted in reduced migration ability. CONCLUSION: Lysosomal biogenesis is linked to autophagosomal protein expression in NSCLC and characterizes subgroups of high risk patients after complete surgical lung tumor resection.

Original publication

DOI

10.1016/j.lungcan.2015.07.008

Type

Journal article

Journal

Lung Cancer

Publication Date

10/2015

Volume

90

Pages

98 - 105

Keywords

Autophagy, Cathepsin D, LAMP2a, Lung cancer, Lysosomes, TFEB, Adult, Aged, Aged, 80 and over, Autophagy, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors, Carcinoma, Non-Small-Cell Lung, Cathepsin D, Cell Line, Tumor, Cell Movement, Female, Humans, Immunohistochemistry, Lung Neoplasms, Lysosomal-Associated Membrane Protein 2, Lysosomes, Male, Middle Aged, Neoplasm Staging, Phenotype, Prognosis, Treatment Outcome