title: Associations between proteasomal activator PA28γ and outcome of oral squamous cell carcinoma: Evidence from cohort studies and functional analyses.
abstract: BACKGROUND
  PA28γ 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.
  
  
  METHODS
  The 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.
  
  
  RESULTS
  The 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.
  
  
  CONCLUSIONS
  PA28γ overexpression is associated with adverse prognosis in patients with OSCC. The aberrant expression of PA28γ may contribute to the pathogenesis and progression of OSCC.
  
  
  BACKGROUND
  OSCC 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.
authors.affiliation: State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Li
authors.affiliation: State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China.
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Feng
authors.affiliation: State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China.
authors.forename: Chongkun
authors.initials: C
authors.lastname: Sun
authors.affiliation: State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Zeng
authors.affiliation: State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China.
authors.forename: Liang
authors.initials: L
authors.lastname: Xie
authors.affiliation: State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China ; West China School of Public health, Sichuan University, Chengdu, China.
authors.forename: Hao
authors.initials: H
authors.lastname: Xu
authors.affiliation: State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China.
authors.forename: Taiwen
authors.initials: T
authors.lastname: Li
authors.affiliation: State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China.
authors.forename: Ruinan
authors.initials: R
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China.
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Xu
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu, China.
authors.forename: Xikun
authors.initials: X
authors.lastname: Zhou
authors.affiliation: State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China.
authors.forename: Min
authors.initials: M
authors.lastname: Zhou
authors.affiliation: State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China.
authors.forename: Hongxia
authors.initials: H
authors.lastname: Dan
authors.affiliation: State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China.
authors.forename: Zhiyong
authors.initials: Z
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China.
authors.forename: Ning
authors.initials: N
authors.lastname: Ji
authors.affiliation: State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China.
authors.forename: Peng
authors.initials: P
authors.lastname: Deng
authors.affiliation: State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China.
authors.forename: Ga
authors.initials: G
authors.lastname: Liao
authors.affiliation: State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China.
authors.forename: Ning
authors.initials: N
authors.lastname: Geng
authors.affiliation: State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China.
authors.forename: Yun
authors.initials: Y
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China.
authors.forename: Dunfang
authors.initials: D
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China.
authors.forename: Yunfeng
authors.initials: Y
authors.lastname: Lin
authors.affiliation: State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China.
authors.forename: Ling
authors.initials: L
authors.lastname: Ye
authors.affiliation: State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China.
authors.forename: Xinhua
authors.initials: X
authors.lastname: Liang
authors.affiliation: State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China.
authors.forename: Longjiang
authors.initials: L
authors.lastname: Li
authors.affiliation: Guangdong Provincial Stomatological Hospital & the Affiliated Stomatological Hospital of Southern Medical University, Guangzhou, China.
authors.forename: Gang
authors.initials: G
authors.lastname: Luo
authors.affiliation: State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China.
authors.forename: Lu
authors.initials: L
authors.lastname: Jiang
authors.affiliation: State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China.
authors.forename: Zhi
authors.initials: Z
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China.
authors.forename: Qianming
authors.initials: Q
authors.lastname: Chen
mesh_terms: D000368:Aged; D000818:Animals; D001324:Autoantigens / Q000096:biosynthesis*; D002294:Carcinoma, Squamous Cell / Q000201:enzymology / Q000401:mortality; D018572:Disease-Free Survival; D005260:Female; D005500:Follow-Up Studies; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D051379:Mice; D008875:Middle Aged; D008954:Models, Biological; D009062:Mouth Neoplasms / Q000201:enzymology / Q000401:mortality; D046988:Proteasome Endopeptidase Complex / Q000096:biosynthesis*; D015996:Survival Rate
chemical_list: D001324:Autoantigens; C099558:Ki antigen; D046988:Proteasome Endopeptidase Complex
keywords: Carcinogenesis; OSCC; PA28γ; Prognosis