Associations between proteasomal activator PA28γ and outcome of oral squamous cell carcinoma: Evidence from cohort studies and functional analyses

• PA28γ protein over-expressed in a large subset of patients with OSCC
• PA28γ was a prognostic factor in OSCC based on the results of three cohorts in China
• The analysis of PA28γ mRNA abundance in a US/non-Chinese cohort from TCGA dataset consistent with Chinese-cohort study
• PA28γ silencing could affect the tumor biological behavior of OSCC both in vitro and vivo.

SummaryBackgroundPA28γ was suggested to play a role in malignant progression. This paper aimed to investigate the association between PA28γ and the prognosis of oral squamous cell carcinoma (OSCC) in cohort studies.MethodsThe PA28γ expression level was assessed by immunohistochemistry in a total of 368 OSCC patients from three independent cohorts. The Cox proportional hazards regression model was used to determine multivariate hazard ratios for Overall Survival (OS). Model discrimination was measured using C Statistic. Additionally, OS was analyzed in Head Neck Squamous Cell Carcinoma (HNSCC) patients from The Cancer Genome Atlas (TCGA) data set. Functional analyses were conducted both in-vitro and in-vivo.FindingsThe median follow-up times of patients in the three studies were 60, 52, and 51 months. High expression of PA28γ was identified in tumors from 179 of 368 patients (48.6%). Compared with low expression, high expression of PA28γ was strongly associated with worse OS, with relative risks of 5.14 (95% CI, 2.51–10.5; P < 0.001), 2.82 (95% CI, 1.73–4.61; P < 0.001), and 3.85 (95% CI, 1.59–9.37; P = 0.003). PA28γ expression was also associated with disease-free survival in all three cohorts (P < 0.005). These findings are consistent with TCGA HNSCC data (P < 0.006). The prediction of all-cause mortality was significantly improved when PA28γ was added to the traditional clinical factors (Model 3, C statistic value: 0.78 VS 0.73, P = 0.016). In functional analyses, we found that PA28γ silencing dramatically inhibited the growth, proliferation and mobility of OSCC cells in vitro and reduced tumor growth and angiogenesis in tumor-bearing mice.InterpretationPA28γ overexpression is associated with adverse prognosis in patients with OSCC. The aberrant expression of PA28γ may contribute to the pathogenesis and progression of OSCC.Research in contextOSCC is one of the most common HNSCC, which have a high lethally rate. However, few prognostic markers have been applied in the clinical practice. We found that PA28γ in OSCC tumor tissues were significantly high expression than those in normal tissues. As the results of the three cohorts from two independent research centers and from an additional validation cohort from a US population in the TCGA dataset, we demonstrate PA28γ is a good predictor of the risk of death in OSCC. Meanwhile, we demonstrate PA28γ have a potential role in OSCC tumorigenesis.