Prefoldin overexpression associates with the risk of mortality and metastasis in lung cancer

Abstract

Purpose or Objective Prefoldin (PFDN) is a co-chaperone that contributes to both cytoplasmic and nuclear biological processes. Canonical PFDN has a heterohexameric jellyfish-like structure. Four ß-type subunits (PFDN1, 2, 4 and 6) form two dimers onto two subunits of the α type (PFDN3 and 5). PFDN2 and 6 are also components of the URI-prefoldin-like complex, which has been described to promote cancer. It has been shown that PFDN1 overexpresion promotes epithelial-mesenchymal transition (EMT) and lung cancer (LC) progression in different LC cell lines and murine models whereas cyclin A knockdown alone induces EMT and increases cell migration and invasion ability. We investigated whether this putative involvement of canonical PFDN in LC translates into the clinic. Material and Methods 58 non-small cell LC patients with available tumor tissue samples (59% squamous and 41% adenocarcinoma) were assessed. The stages were as follows: 24% I, 7% II, 61% III, and 8% IV. 90% of patients were primarily treated with surgery and 69% received chemotherapy. 86% underwent thoracic radiotherapy either primarily (41%) or after locorregional recurrence (45%). The levels of PFDN1, 3, 5 were examined by immunoblotting. Additionally, the mRNA expression of 518 LC cases from The Cancer Genome Atlas (TCGA) database was evaluated. To assess the risk of mortality and recurrences we used Kaplan-Meier and Cox proportional hazards analyses

Results PFDN1, 3, 5 and cyclin A overexpression (+++) were found in 22 (38%), 31 (53%), 24 (41%), and 14 (24%) tumor samples. After a follow up of 40 months, 39 (67%) patients were alive and 34 (58%) had experienced a recurrence (24 were distant metastasis). Body surface area and stage associated with overall survival (OS; p=0.01 and p=0.036, respectively), disease-free survival (DFS; p=0.033 and p=0.038, respectively), and distant metastasis-free survival (DMFS; p=0.002 and p=0.025, respectively) in the univariate analysis. In addition, the use of radiotherapy and chemotherapy also associated with DMFS (p=0.005 and p=0.015, respectively). PFDN1, 3 and 5 overexpression were associated with lower OS (p=0.002, p=0.015, and p=0.002, respectively), lower DFS (p=0.01, p=0.042, and p=0.055, respectively), and lower DMFS (p=0.011, p=0.036, and p=0.11, respectively). There was not any association with local recurrence. In the multivariate analysis, the PFDN5 retained significance for OS (HR 5.09; p=0.007) and the PFDN1 for DFS (HR 5.15; p=0.01) and DMFS (HR 5.45; p=0.05). In the TCGA adenocarcinoma cohort, there was a high correlation between PFDN1 and 5 (Pearson coefficient: 0.53; p <0.0001), a high mRNA expression of PFDN3 in the tumor compare with the normal tissue (p <0.0001), and PFDN1 overexpression showed lower OS (p=0.034). Conclusion Overexpression of canonical PFDN associates with the risk of mortality and metastasis in non-small cell LC. These response markers may be usefull biomarkers for guiding therapy intensity in an individualized therapy.