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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

ROC curves for all-cause death of OSCC patients with or without PA28γ expression in three cohorts of two independent centers. (a) ROC curve for Model 3 in CD-I and -II Cohorts. (b) ROC curve for Model 3 in GZ cohort.
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f0015: ROC curves for all-cause death of OSCC patients with or without PA28γ expression in three cohorts of two independent centers. (a) ROC curve for Model 3 in CD-I and -II Cohorts. (b) ROC curve for Model 3 in GZ cohort.

Mentions: Multivariable models were constructed for the prediction of all-cause death in OSCC patients by using the combined CD cohort as the discovery cohort, and the GD cohort as a validation cohort. We assessed model discrimination using the C statistic for predictive value and compared the difference between basic models and models including PA28γ expression (Table S4). For the discovery of CD cohort, in Model 1, among the basic risk factors, the C statistic value of PA28γ was highest. The C statistic increased significantly when PA28γ was combined with those conventional risk factors in Models 2 to 4. In Models 3 and 4, when PA28γ was added, the C statistic was larger than 0.75, above which the prediction model is considered relatively good. Similar results were found in the validation GZ cohort. ROC curves were constructed for the mode Models 3 and 4, in which the area under the ROC curve indicates the C statistic (Fig. 3, Fig. S5).


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)

ROC curves for all-cause death of OSCC patients with or without PA28γ expression in three cohorts of two independent centers. (a) ROC curve for Model 3 in CD-I and -II Cohorts. (b) ROC curve for Model 3 in GZ cohort.
© Copyright Policy - CC BY-NC-ND
Related In: Results  -  Collection

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

f0015: ROC curves for all-cause death of OSCC patients with or without PA28γ expression in three cohorts of two independent centers. (a) ROC curve for Model 3 in CD-I and -II Cohorts. (b) ROC curve for Model 3 in GZ cohort.
Mentions: Multivariable models were constructed for the prediction of all-cause death in OSCC patients by using the combined CD cohort as the discovery cohort, and the GD cohort as a validation cohort. We assessed model discrimination using the C statistic for predictive value and compared the difference between basic models and models including PA28γ expression (Table S4). For the discovery of CD cohort, in Model 1, among the basic risk factors, the C statistic value of PA28γ was highest. The C statistic increased significantly when PA28γ was combined with those conventional risk factors in Models 2 to 4. In Models 3 and 4, when PA28γ was added, the C statistic was larger than 0.75, above which the prediction model is considered relatively good. Similar results were found in the validation GZ cohort. ROC curves were constructed for the mode Models 3 and 4, in which the area under the ROC curve indicates the C statistic (Fig. 3, Fig. S5).

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