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

Functional role of PA28γ on tumor growth. PA28γ-si could inhibit PA28γ expression in an OSCC xenografts model; angiogenesis in tumors was detected by CD34 staining. The average number of microvessels per vascular hot spot (mean ± SD) was significantly lower in PA28γ-si group tissues compared with those in the two control groups; Percentages of PCNA-positive nuclei (mean ± SD) in PA28γ-si group were significantly lower than those in the two control groups; Apoptosis was assessed by TUNEL assay. The scale bar represents 100 μm. (*P < 0.05).
© Copyright Policy - CC BY-NC-ND
Related In: Results  -  Collection

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

f0065: Functional role of PA28γ on tumor growth. PA28γ-si could inhibit PA28γ expression in an OSCC xenografts model; angiogenesis in tumors was detected by CD34 staining. The average number of microvessels per vascular hot spot (mean ± SD) was significantly lower in PA28γ-si group tissues compared with those in the two control groups; Percentages of PCNA-positive nuclei (mean ± SD) in PA28γ-si group were significantly lower than those in the two control groups; Apoptosis was assessed by TUNEL assay. The scale bar represents 100 μm. (*P < 0.05).

Mentions: We further investigated whether PA28γ silence could inhibit tumor growth in vivo. OSCC cells treated with PA28γ siRNA modified with 2ʹ OMe and 3ʹ Chol (PA28γ-si group) which have a high effective interference (Fig. 4c), scramble siRNA (NS-si group) or PBS (CTRL group) were transplanted subcutaneously on the right back of BALB/c nude mice. Tumor growth in the PA28γ-si group was much slower than the other two groups. There was a 40–50% reduction in the average tumor volume in the PA28γ-si group (Fig. 4d, e). To investigate the potential mechanisms underlying the effects of PA28γ silencing in vivo, we examined tumor cell proliferation, microvessel density (MVD) Rechsteiner and Hill, 2005, and tumor cell apoptosis. As shown in Fig. S9, dramatic reductions in PCNA expression and tumor angiogenesis and significant increases in TUNEL-positive nuclei were found in the tumors in the PA28γ-si group compared with those in the other two groups.


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 tumor growth. PA28γ-si could inhibit PA28γ expression in an OSCC xenografts model; angiogenesis in tumors was detected by CD34 staining. The average number of microvessels per vascular hot spot (mean ± SD) was significantly lower in PA28γ-si group tissues compared with those in the two control groups; Percentages of PCNA-positive nuclei (mean ± SD) in PA28γ-si group were significantly lower than those in the two control groups; Apoptosis was assessed by TUNEL assay. The scale bar represents 100 μm. (*P < 0.05).
© Copyright Policy - CC BY-NC-ND
Related In: Results  -  Collection

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

f0065: Functional role of PA28γ on tumor growth. PA28γ-si could inhibit PA28γ expression in an OSCC xenografts model; angiogenesis in tumors was detected by CD34 staining. The average number of microvessels per vascular hot spot (mean ± SD) was significantly lower in PA28γ-si group tissues compared with those in the two control groups; Percentages of PCNA-positive nuclei (mean ± SD) in PA28γ-si group were significantly lower than those in the two control groups; Apoptosis was assessed by TUNEL assay. The scale bar represents 100 μm. (*P < 0.05).
Mentions: We further investigated whether PA28γ silence could inhibit tumor growth in vivo. OSCC cells treated with PA28γ siRNA modified with 2ʹ OMe and 3ʹ Chol (PA28γ-si group) which have a high effective interference (Fig. 4c), scramble siRNA (NS-si group) or PBS (CTRL group) were transplanted subcutaneously on the right back of BALB/c nude mice. Tumor growth in the PA28γ-si group was much slower than the other two groups. There was a 40–50% reduction in the average tumor volume in the PA28γ-si group (Fig. 4d, e). To investigate the potential mechanisms underlying the effects of PA28γ silencing in vivo, we examined tumor cell proliferation, microvessel density (MVD) Rechsteiner and Hill, 2005, and tumor cell apoptosis. As shown in Fig. S9, dramatic reductions in PCNA expression and tumor angiogenesis and significant increases in TUNEL-positive nuclei were found in the tumors in the PA28γ-si group compared with those in the other two groups.

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