Increased expression of transcription factor EB (TFEB) is associated with autophagy, migratory phenotype and poor prognosis in non-small cell lung cancer
Giatromanolaki A., Kalamida D., Sivridis E., Karagounis IV., Gatter KC., Harris AL., Koukourakis MI.
© 2015 Elsevier Ireland Ltd. 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.