1. Institute of Pathology, University Hospital Essen, University of Duisburg-Essen, Germany.
2. Ruhrlandklinik, West German Lung Centre, University Hospital Essen, University of Duisburg-Essen, Germany.
3. Institute of Pathology, University Hospital Cologne, University of Cologne, Germany.
4. Department of Medical Oncology, University Hospital Essen, University of Duisburg-Essen, Germany.
5. Department of Thoracic Surgery, Ruhrlandklinik, West German Lung Centre, University Hospital Essen, University of Duisburg-Essen, Germany.
6. Department of Pathology, Helios Klinikum Emil von Behring, Berlin, Germany.
7. Pulmonary-Oncology, ``G. Papanikolaou`` General Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece.
8. Department of Respiratory Diseases, Changhai Hospital/First Affiliated Hospital of the Second Military Medical University, Shanghai, People's Republic of China, China.
9. Thoracic Surgery Department, ``Saint Luke`` Private Clinic, Thessaloniki, Panorama, Greece.
* Authors equally contributed.
Background: Proteasomal subunit PSMB4 was suggested to be a survival gene in an animal model of hepatocellular carcinoma and in glioblastoma cell lines. In pulmonary adenocarcinoma, a high expression of these genes was found to be associated with poor differentiation and survival. This study investigates the gene expression levels of 26S proteasome subunits in human pulmonary neuroendocrine tumours including typical (TC) and atypical (AC) carcinoid tumours as well as small cell (SCLC) and large cell (LCNEC) neuroendocrine carcinomas.
Material and methods: Gene expression levels of proteasomal subunits (PSMA1, PSMA5, PSMB4, PSMB5 and PSMD1) were investigated in 80 neuroendocrine pulmonary tumours (each 20 TC, AC, LCNLC and SCLC) and compared to controls. mRNA levels were determined by using TaqMan assays. Immunohistochemistry on tissue microarrays (TMA) was performed to determine the expression of ki67, cleaved caspase 3 and PSMB4.
Results: All proteasomal subunit gene expressions were significantly upregulated in TC, AC, SCLC and LCNEC compared to controls. PSMB4 mRNA is differently expressed between all neuroendocrine tumour subtypes demonstrating the highest expression and greatest range in LCNEC (p=0.043), and is significantly associated with proliferative activity (p=0.039).
Conclusion: In line with other 26S proteasomal subunits PSMB4 is significantly increased, but differently expressed between pulmonary neuroendocrine tumours and is associated with the proliferative activity. Unlike in pulmonary adenocarcinomas, no association with biological behaviour was observed, suggesting that increased proteasomal subunit gene expression is a common and probably early event in the tumorigenesis of pulmonary neuroendocrine tumours regardless of their differentiation.
Keywords: 26S Proteasome, TaqMan qPCR, neuroendocrine lung tumours, carcinoid tumours, neuroendocrine lung carcinoma.