J Cancer 2014; 5(8):646-654. doi:10.7150/jca.9955

Research Paper

Gene Expression Analysis of the 26S Proteasome Subunit PSMB4 Reveals Significant Upregulation, Different Expression and Association with Proliferation in Human Pulmonary Neuroendocrine Tumours

Fabian Dominik Mairinger*1, Robert Fred Henry Walter*1,2, Dirk Theegarten1, Thomas Hager1, Claudia Vollbrecht3, Daniel Christian Christoph4, Karl Worm1, Saskia Ting1, Robert Werner1, Georgios Stamatis5, Thomas Mairinger6, Hideo Baba1, Konstantinos Zarogoulidis7, Haidong Huang8, Qiang Li8, Kosmas Tsakiridis9, Paul Zarogoulidis7✉, Kurt Werner Schmid1, Jeremias Wohlschlaeger1

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.

Abstract

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.

This is an open access article distributed under the terms of the Creative Commons Attribution (CC BY-NC) License. See http://ivyspring.com/terms for full terms and conditions.
How to cite this article:
Mairinger FD, Walter RFH, Theegarten D, Hager T, Vollbrecht C, Christoph DC, Worm K, Ting S, Werner R, Stamatis G, Mairinger T, Baba H, Zarogoulidis K, Huang H, Li Q, Tsakiridis K, Zarogoulidis P, Schmid KW, Wohlschlaeger J. Gene Expression Analysis of the 26S Proteasome Subunit PSMB4 Reveals Significant Upregulation, Different Expression and Association with Proliferation in Human Pulmonary Neuroendocrine Tumours. J Cancer 2014; 5(8):646-654. doi:10.7150/jca.9955. Available from http://www.jcancer.org/v05p0646.htm