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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

Expression of PA28γ related to carcinogenesis and prognosis in OSCC cells and human tissues. (a) Validation of PA28γ over-expression in six OSCC cells compared with normal oral keratinocyte by Western blot as described in material and methods. (b) Validation the role of PA28γ expression in OSCC prognosis in 118 clinical OSCC samples. IHC staining showed those cases with poorer prognosis exhibited stronger staining. Left: a moderate-differentiated OSCC sample with disease free survival. Middle: a well-differentiated OSCC sample with regional neck recurrence within 2 years postoperation. Right: a well-differentiated OSCC sample with cancer-related death with 4 year's postoperation. The scale bar represents 100 μm.
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f0030: Expression of PA28γ related to carcinogenesis and prognosis in OSCC cells and human tissues. (a) Validation of PA28γ over-expression in six OSCC cells compared with normal oral keratinocyte by Western blot as described in material and methods. (b) Validation the role of PA28γ expression in OSCC prognosis in 118 clinical OSCC samples. IHC staining showed those cases with poorer prognosis exhibited stronger staining. Left: a moderate-differentiated OSCC sample with disease free survival. Middle: a well-differentiated OSCC sample with regional neck recurrence within 2 years postoperation. Right: a well-differentiated OSCC sample with cancer-related death with 4 year's postoperation. The scale bar represents 100 μm.

Mentions: A total of 368 patients from three independent cohorts (118, 156, and 94 patients in CD-I cohort, CD-II cohort, and GZ cohort, respectively) were included in this study (Fig. 1). All patients were treated with curative intent. Some of these patients had been treated by radiotherapy and/or chemotherapy. The mean age and gender distribution were comparable across the three cohorts. The median durations of follow-up in the cohorts were 60, 52, and 51 months, respectively. IHC staining showed that PA28γ has a very clear nuclear positive in most tumor but not normal tissues (Fig. S1). High expression of PA28γ was observed on OSCC cell lines, and in 52.54%, 38.46%, and 60.64% of the patients in the CD-I cohort, CD-II cohort and GZ cohort, respectively (Table 1 and Fig. S2). This finding is consistent with the TCGA database analysis of PA28γ mRNA abundance in human primary oral cancers (Fig. S3a).


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)

Expression of PA28γ related to carcinogenesis and prognosis in OSCC cells and human tissues. (a) Validation of PA28γ over-expression in six OSCC cells compared with normal oral keratinocyte by Western blot as described in material and methods. (b) Validation the role of PA28γ expression in OSCC prognosis in 118 clinical OSCC samples. IHC staining showed those cases with poorer prognosis exhibited stronger staining. Left: a moderate-differentiated OSCC sample with disease free survival. Middle: a well-differentiated OSCC sample with regional neck recurrence within 2 years postoperation. Right: a well-differentiated OSCC sample with cancer-related death with 4 year's postoperation. The scale bar represents 100 μm.
© Copyright Policy - CC BY-NC-ND
Related In: Results  -  Collection

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

f0030: Expression of PA28γ related to carcinogenesis and prognosis in OSCC cells and human tissues. (a) Validation of PA28γ over-expression in six OSCC cells compared with normal oral keratinocyte by Western blot as described in material and methods. (b) Validation the role of PA28γ expression in OSCC prognosis in 118 clinical OSCC samples. IHC staining showed those cases with poorer prognosis exhibited stronger staining. Left: a moderate-differentiated OSCC sample with disease free survival. Middle: a well-differentiated OSCC sample with regional neck recurrence within 2 years postoperation. Right: a well-differentiated OSCC sample with cancer-related death with 4 year's postoperation. The scale bar represents 100 μm.
Mentions: A total of 368 patients from three independent cohorts (118, 156, and 94 patients in CD-I cohort, CD-II cohort, and GZ cohort, respectively) were included in this study (Fig. 1). All patients were treated with curative intent. Some of these patients had been treated by radiotherapy and/or chemotherapy. The mean age and gender distribution were comparable across the three cohorts. The median durations of follow-up in the cohorts were 60, 52, and 51 months, respectively. IHC staining showed that PA28γ has a very clear nuclear positive in most tumor but not normal tissues (Fig. S1). High expression of PA28γ was observed on OSCC cell lines, and in 52.54%, 38.46%, and 60.64% of the patients in the CD-I cohort, CD-II cohort and GZ cohort, respectively (Table 1 and Fig. S2). This finding is consistent with the TCGA database analysis of PA28γ mRNA abundance in human primary oral cancers (Fig. S3a).

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