Glioblastoma (GBM) is the most common and malignant brain tumor in adults. Recently, programmed death‐1/programmed death‐ligand 1 (PD‐1/PD‐L1) checkpoint blockades have been applied for GBM treatment. However, the mechanism of PD‐L1 upregulation in GBM is still unclear. COP9 signalosome 6 (CSN6) is crucial for maintaining the protein stabilization in cancer cells. In this study, we applied human GBM specimens and cell lines to investigate whether the EGFR‐ERK pathway regulates CSN6 for PD‐L1 upregulation. Data from The Cancer Genome Atlas dataset showed that high expression of EGFR, CSN6, and PD‐L1 in patients with glioma was associated with poor prognosis. In 47 human GBM specimens, high expression of PD‐L1 was associated with low amount of CD8+ T cell infiltration as well as the poor prognosis of patients. CSN6 was positively correlated with EGFR and PD‐L1 expression in human GBM specimens. We treated two GBM cell lines (U87 and U251) with epidermal growth factor (EGF) in vitro, and found EGF‐upregulated p‐EGFR, p‐ERK, CSN6, and PD‐L1 expression in GBM cells. PD98059, the ERK blocker, inhibited upregulations of CSN6 and PD‐L1 in EGF‐treated cells. Inhibition of CSN6 by small interfering RNA decreased PD‐L1 expression but also increased CHIP expression in GBM cells. When the cells were treated with EGF and cycloheximide (CHX), a protein synthesis inhibitor, EGF‐reduced CHX‐induced CSN6 and PD‐L1 turnover in GBM cells. Furthermore, CSN6‐mediated downregulation of PD‐L1 was inhibited by MG132, a proteasome inhibitor in U87 cells. Thus, these results suggest that the EGFR‐ERK pathway may upregulate CSN6, which may inhibit PD‐L1 degradation and subsequently maintain PD‐L1 stability in GBM.
Centrosomal protein 55 (CEP55) is a member of the centrosomal-associated protein family and participates in the regulation of cytokinesis during cell mitosis. However, aberrant CEP55 protein expression has been observed in human tumors. In addition, CEP55 regulates the biological functions of tumors by inducing the Akt pathway and upregulating forkhead box protein M1 (FoxM1) and matrix metalloproteinase-2 (MMP-2). In the present study, the levels, clinicopathological features and prognostic potential of CEP55, phosphorylated Akt (p-Akt), FoxM1 and MMP-2 in astrocytoma were evaluated. CEP55, p-Akt, FoxM1 and MMP-2 levels were examined in 27 normal brain tissues and 262 astrocytoma tissues by using immunohistochemistry. Furthermore, Kaplan-Meier analysis and Cox proportional hazards models were applied to predict the prognosis of patients with astrocytoma. The results indicated that expression levels of CEP55 and other proteins were elevated in human astrocytoma compared with those in normal brain tissue. The levels of the selected proteins were increased as the tumor grade increased. Furthermore, CEP55 expression was positively correlated with p-Akt, FoxM1 and MMP-2 levels in astrocytoma. Overall survival analysis revealed that patient prognosis was associated with CEP55, p-Akt, FoxM1 and MMP-2 levels, as well as with the tumor grade and patient age. Furthermore, CEP55, FoxM1, tumor grade and patient age were independent prognostic factors in astrocytoma according to multivariate analysis. Taken together, the present results suggested that CEP55, p-Akt, FoxM1 and MMP-2 have crucial roles in the progression and prognosis of human astrocytoma and that CEP55 and FoxM1 may be potential therapeutic targets.
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