Increased expression of transcription factor EB (TFEB) is associated with autophagy, migratory phenotype and poor prognosis in non-small cell lung cancer.
OBJECTIVE
We investigated the role of lysosomal biogenesis and hydrolase activity in the clinical behavior and postoperative outcome of lung cancer.


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.


CONCLUSIONS
Lysosomal biogenesis is linked to autophagosomal protein expression in NSCLC and characterizes subgroups of high risk patients after complete surgical lung tumor resection.
Department of Pathology, Democritus University of Thrace, and University General Hospital of Alexandroupolis, Alexandroupolis 68100, Greece.
Alexandra
A
Giatromanolaki
Department of Radiotherapy/Oncology, Democritus University of Thrace, and University General Hospital of Alexandroupolis, Alexandroupolis 68100, Greece.
Dimitra
D
Kalamida
Department of Pathology, Democritus University of Thrace, and University General Hospital of Alexandroupolis, Alexandroupolis 68100, Greece.
Efthimios
E
Sivridis
Department of Radiotherapy/Oncology, Democritus University of Thrace, and University General Hospital of Alexandroupolis, Alexandroupolis 68100, Greece.
Ilias V
IV
Karagounis
Radcliffe Department of Medicine, Weatherall Institute of Molecular Medicine, University of Oxford, Headington, Oxford, UK.
Kevin C
KC
Gatter
CR UK Molecular Oncology Laboratories, Weatherall Institute of Molecular Medicine, University of Oxford, Headington, Oxford, UK. Electronic address: aharris.lab@cancer.org.uk.
Adrian L
AL
Harris
Department of Radiotherapy/Oncology, Democritus University of Thrace, and University General Hospital of Alexandroupolis, Alexandroupolis 68100, Greece. Electronic address: targ@her.forthnet.gr.
Michael I
MI
Koukourakis
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001343:Autophagy / Q000502:physiology; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000096:biosynthesis* / Q000235:genetics; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics / Q000378:metabolism* / Q000473:pathology* / Q000601:surgery; D002402:Cathepsin D / Q000096:biosynthesis / Q000235:genetics; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology* / Q000601:surgery; D052119:Lysosomal-Associated Membrane Protein 2 / Q000096:biosynthesis / Q000235:genetics; D008247:Lysosomes / Q000201:enzymology / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D010641:Phenotype; D011379:Prognosis; D016896:Treatment Outcome
D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; C497811:LAMP2 protein, human; D052119:Lysosomal-Associated Membrane Protein 2; C064972:TFEB protein, human; C533922:CTSD protein, human; D002402:Cathepsin D
Autophagy; Cathepsin D; LAMP2a; Lung cancer; Lysosomes; TFEB