Proteasomal non‐catalytic subunit PSMD2 as a potential therapeutic target in association with various clinicopathologic features in lung adenocarcinomas

Abstract

We previously identified PSMD2, a subunit of the 19S regulatory complex of proteasomes, as a constituent of a signature associated with the acquisition of metastatic phenotype and poor prognosis in lung cancers. In the present study, we found that knockdown of PSMD2 decreased proteasome activity, and induced growth inhibition and apoptosis in lung cancer cell lines. These effects of siRNA-mediated PSMD2 inhibition were associated with changes in the balance between phosphorylated AKT and p38, as well as with induction of p21. In addition, patients with higher PSMD2 expression had poorer prognosis and a small fraction of lung cancer specimens carried increased copies of PSMD2. Notably, our findings clearly illustrate that lung adenocarcinomas can be divided into two groups; those with and without general upregulation of proteasome pathway genes including PSMD2. This general upregulation was significantly more prevalent in the non-terminal respiratory unit (non-TRU)-type, a recently proposed genetically and clinicopathologically relevant expression profile-defined classification of adenocarcinomas (P < 0.001 by Fisher's exact test). Patients with adenocarcinomas with general upregulation had significantly shorter survival after potentially curative resection (P = 0.0001 by log-rank test) independent of disease stage, as shown by multivariate Cox regression analysis. Our results suggest that PSMD2 may be a good molecular target candidate and that other co-regulated proteasome pathway genes and/or their common regulator(s) might also be potential targets, warranting future study including elucidation of the underlying common regulatory mechanism.

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

“…This study also demonstrated that genes encoding components of the 26S proteasome and those involved in proteasome assembly are co-regulated in lung adenocarcinomas and a high expression of these genes is associated with shortened survival. The authors conclude that such co-regulated upregulation may confer greater advantage to cancer cell growth during cancer development 43.…”

ADAM9 Promotes Lung Cancer Metastases to Brain by a Plasminogen Activator-Based Pathway

“…17) and GSE11969 (90 patients in Japan; ref. 18), and the third dataset, composed entirely of lung adenocarcinoma patients, was obtained from the Shedden and colleagues study (469 patients in the United States; ref. 19).…”

The transcription levels and prognostic values of seven proteasome alpha subunits in human cancers

“…Emerging evidence has indicated that multiple subunits of proteasome were strongly implicated in regulating the biological progression of cancer cells such as proliferation, apoptosis, cell cycle, DNA repair, invasion and metastasis [4–7]. Aberration and abnormal expression of proteasome subunits have been demonstrated in many tumors including breast cancer [8], lung cancer [5, 7], hepatocellular carcinoma [9] and colorectal cancer [10]. For instance, PSMB4, a subunit of the 20S core complex, has been shown to be upregulated in epithelial ovarian cancer, and overexpression of PSMB4 was significantly related to clinicopathological characteristics and worse prognosis in epithelial ovarian cancer patients [11].…”