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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

Functional role of PA28γ on the tumor growth. (a) Colony formation assay. PA28γ silencing led to colony formation inhibition in two OSCC cell lines (HSC-3 and CAL-27), after 10 days transfection with siRNA. All data are presented as the mean ± SD of three independent experiments (*P < 0.05). (b) PA28γ silencing induced the apoptosis in OSCC cells, determined by Flow Cytometry assay, after 48 h transfection with siRNA. All data are presented as the mean ± SD of three independent experiments (*P < 0.05). (c) Chemically-modified PA28γ-si could inhibit PA28γ gene expression in HSC-3, illustrated by qPCR, 48 h. All data are presented as the mean ± SD of three independent experiments (*P < 0.05) (d ande) The tumor volumes (mean ± SD) of PA28γ-si group were significantly smaller compared to the other two groups, 30 days after injecting transfected cells. (n = 5, *P < 0.05).
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f0020: Functional role of PA28γ on the tumor growth. (a) Colony formation assay. PA28γ silencing led to colony formation inhibition in two OSCC cell lines (HSC-3 and CAL-27), after 10 days transfection with siRNA. All data are presented as the mean ± SD of three independent experiments (*P < 0.05). (b) PA28γ silencing induced the apoptosis in OSCC cells, determined by Flow Cytometry assay, after 48 h transfection with siRNA. All data are presented as the mean ± SD of three independent experiments (*P < 0.05). (c) Chemically-modified PA28γ-si could inhibit PA28γ gene expression in HSC-3, illustrated by qPCR, 48 h. All data are presented as the mean ± SD of three independent experiments (*P < 0.05) (d ande) The tumor volumes (mean ± SD) of PA28γ-si group were significantly smaller compared to the other two groups, 30 days after injecting transfected cells. (n = 5, *P < 0.05).

Mentions: On the basis of the clinical findings described above, we evaluated the effect of PA28γ on OSCC cell lines and xenograft models. We hypothesized that PA28γ might act as a tumor promoter. If so, PA28γ silencing should reverse some of the early processes of tumorigenesis. PA28γ silencing in both OSCC cell lines caused decreased cell viability and colony growth (Fig. S6, Fig. 4a). However, this silencing had no such effect on HOK cells. A significant induction of apoptosis was observed after treatment of cells with PA28γ-specific siRNA (Fig. 4b). Similar results were also observed in the TUNEL assay (Fig. S7). These results suggest that PA28γ silencing can inhibit cell proliferation via induction of apoptosis in OSCC cells. Moreover, our data suggested that PA28γ silencing could inhibit the migration and invasion of OSCC cells in vitro (Fig. S8).


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)

Functional role of PA28γ on the tumor growth. (a) Colony formation assay. PA28γ silencing led to colony formation inhibition in two OSCC cell lines (HSC-3 and CAL-27), after 10 days transfection with siRNA. All data are presented as the mean ± SD of three independent experiments (*P < 0.05). (b) PA28γ silencing induced the apoptosis in OSCC cells, determined by Flow Cytometry assay, after 48 h transfection with siRNA. All data are presented as the mean ± SD of three independent experiments (*P < 0.05). (c) Chemically-modified PA28γ-si could inhibit PA28γ gene expression in HSC-3, illustrated by qPCR, 48 h. All data are presented as the mean ± SD of three independent experiments (*P < 0.05) (d ande) The tumor volumes (mean ± SD) of PA28γ-si group were significantly smaller compared to the other two groups, 30 days after injecting transfected cells. (n = 5, *P < 0.05).
© Copyright Policy - CC BY-NC-ND
Related In: Results  -  Collection

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

f0020: Functional role of PA28γ on the tumor growth. (a) Colony formation assay. PA28γ silencing led to colony formation inhibition in two OSCC cell lines (HSC-3 and CAL-27), after 10 days transfection with siRNA. All data are presented as the mean ± SD of three independent experiments (*P < 0.05). (b) PA28γ silencing induced the apoptosis in OSCC cells, determined by Flow Cytometry assay, after 48 h transfection with siRNA. All data are presented as the mean ± SD of three independent experiments (*P < 0.05). (c) Chemically-modified PA28γ-si could inhibit PA28γ gene expression in HSC-3, illustrated by qPCR, 48 h. All data are presented as the mean ± SD of three independent experiments (*P < 0.05) (d ande) The tumor volumes (mean ± SD) of PA28γ-si group were significantly smaller compared to the other two groups, 30 days after injecting transfected cells. (n = 5, *P < 0.05).
Mentions: On the basis of the clinical findings described above, we evaluated the effect of PA28γ on OSCC cell lines and xenograft models. We hypothesized that PA28γ might act as a tumor promoter. If so, PA28γ silencing should reverse some of the early processes of tumorigenesis. PA28γ silencing in both OSCC cell lines caused decreased cell viability and colony growth (Fig. S6, Fig. 4a). However, this silencing had no such effect on HOK cells. A significant induction of apoptosis was observed after treatment of cells with PA28γ-specific siRNA (Fig. 4b). Similar results were also observed in the TUNEL assay (Fig. S7). These results suggest that PA28γ silencing can inhibit cell proliferation via induction of apoptosis in OSCC cells. Moreover, our data suggested that PA28γ silencing could inhibit the migration and invasion of OSCC cells in vitro (Fig. S8).

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