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

Li J, Feng X, Sun C, Zeng X, Xie L, Xu H, Li T, Wang R, Xu X, Zhou X, Zhou M, Zhou Y, Dan H, Wang Z, Ji N, Deng P, Liao G, Geng N, Wang Y, Zhang D, Lin Y, Ye L, Liang X, Li L, Luo G, Jiang L, Wang Z, Chen Q - EBioMedicine (2015)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China.

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.

Findings: 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.

Interpretation: 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.

Research in context: 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.

No MeSH data available.


Related in: MedlinePlus

Overall Survival (OS) of OSCC patients with high and low expression of PA28γ in Three cohorts defined by the Kaplan–Meier survival curves. (a) Overall Survival in CD-I cohort. (b) Overall Survival in CD-II cohort. (c) Overall Survival in CD-I and -II cohorts. (d) Overall Survival in GZ cohort.
© Copyright Policy - CC BY-NC-ND
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4563126&req=5

f0010: Overall Survival (OS) of OSCC patients with high and low expression of PA28γ in Three cohorts defined by the Kaplan–Meier survival curves. (a) Overall Survival in CD-I cohort. (b) Overall Survival in CD-II cohort. (c) Overall Survival in CD-I and -II cohorts. (d) Overall Survival in GZ cohort.

Mentions: In all three cohorts, the results of univariate analysis showed that OS at five years was associated with PA28γ expression (Table 2). For the CD-I cohort, estimated 5-year OS values for patients in the low and high PA28γ expression groups were 84% (95% CI, 0.71–0.91) and 40% (95% CI, 0.28–0.52; Fig. 2a), respectively. For the CD-II cohort, the estimated 5-year OS values for patients in the low and high PA28γ expression groups were 67% (95% CI, 0.56–0.57) and 28% (95% CI, 0.18–0.40; Fig. 2b), respectively. For the joint CD-I and CD-II cohorts, the estimated 5-year OS for patients also showed that the risk increased associated with positive staining (P < 0.001; Fig. 2c). For the GD validation cohort, the estimated 5-year OS values for patients in the low and high PA28γ expression groups were 89% (95% CI, 0.74–0.96) and 57% (95% CI, 0.43–0.69; Fig. 2d), respectively. Consistent with an external validation cohort of 460 HNSCC patients from the TCGA database analysis in the US population, high PA28γ mRNA was associated with poor survival (P = 0.016, Fig. S3b). Furthermore, the association between PA28γ high expression with lower rates of 5-year Disease-Free Survival (DFS) was also statistically significant in those three independent cohorts (P < 0.001; CD-II: P < 0.001; joint CD-I and -II cohorts: P < 0.001; GD: P = 0.004; Table S2; Fig. S4). Several conventional prognostic factors, including lower cell differentiation, positive nodal stage, higher tumor stage, higher clinical TNM stage and radiotherapy or chemotherapy, were associated with a significantly increased risk of death. History of smoking and alcohol consumption were significantly related with survival (P < 0.005). Some of these factors were included in the multivariable Cox proportional-hazards model and fixed.


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

Li J, Feng X, Sun C, Zeng X, Xie L, Xu H, Li T, Wang R, Xu X, Zhou X, Zhou M, Zhou Y, Dan H, Wang Z, Ji N, Deng P, Liao G, Geng N, Wang Y, Zhang D, Lin Y, Ye L, Liang X, Li L, Luo G, Jiang L, Wang Z, Chen Q - EBioMedicine (2015)

Overall Survival (OS) of OSCC patients with high and low expression of PA28γ in Three cohorts defined by the Kaplan–Meier survival curves. (a) Overall Survival in CD-I cohort. (b) Overall Survival in CD-II cohort. (c) Overall Survival in CD-I and -II cohorts. (d) Overall Survival in GZ cohort.
© Copyright Policy - CC BY-NC-ND
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4563126&req=5

f0010: Overall Survival (OS) of OSCC patients with high and low expression of PA28γ in Three cohorts defined by the Kaplan–Meier survival curves. (a) Overall Survival in CD-I cohort. (b) Overall Survival in CD-II cohort. (c) Overall Survival in CD-I and -II cohorts. (d) Overall Survival in GZ cohort.
Mentions: In all three cohorts, the results of univariate analysis showed that OS at five years was associated with PA28γ expression (Table 2). For the CD-I cohort, estimated 5-year OS values for patients in the low and high PA28γ expression groups were 84% (95% CI, 0.71–0.91) and 40% (95% CI, 0.28–0.52; Fig. 2a), respectively. For the CD-II cohort, the estimated 5-year OS values for patients in the low and high PA28γ expression groups were 67% (95% CI, 0.56–0.57) and 28% (95% CI, 0.18–0.40; Fig. 2b), respectively. For the joint CD-I and CD-II cohorts, the estimated 5-year OS for patients also showed that the risk increased associated with positive staining (P < 0.001; Fig. 2c). For the GD validation cohort, the estimated 5-year OS values for patients in the low and high PA28γ expression groups were 89% (95% CI, 0.74–0.96) and 57% (95% CI, 0.43–0.69; Fig. 2d), respectively. Consistent with an external validation cohort of 460 HNSCC patients from the TCGA database analysis in the US population, high PA28γ mRNA was associated with poor survival (P = 0.016, Fig. S3b). Furthermore, the association between PA28γ high expression with lower rates of 5-year Disease-Free Survival (DFS) was also statistically significant in those three independent cohorts (P < 0.001; CD-II: P < 0.001; joint CD-I and -II cohorts: P < 0.001; GD: P = 0.004; Table S2; Fig. S4). Several conventional prognostic factors, including lower cell differentiation, positive nodal stage, higher tumor stage, higher clinical TNM stage and radiotherapy or chemotherapy, were associated with a significantly increased risk of death. History of smoking and alcohol consumption were significantly related with survival (P < 0.005). Some of these factors were included in the multivariable Cox proportional-hazards model and fixed.

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China.

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.

Findings: 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.

Interpretation: 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.

Research in context: 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.

No MeSH data available.


Related in: MedlinePlus