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. 2013 Dec 27;8(12):e83479.
doi: 10.1371/journal.pone.0083479. eCollection 2013.

Clinical significance of Keap1 and Nrf2 in oral squamous cell carcinoma

Cong-Fa Huang  1 , Lu Zhang  1 , Si-Rui Ma  1 , Zhi-Li Zhao  1 , Wei-Ming Wang  1 , Ke-Fei He  1 , Yi-Fang Zhao  2 , Wen-Feng Zhang  2 , Bing Liu  2 , Zhi-Jun Sun  2
Affiliations

Clinical significance of Keap1 and Nrf2 in oral squamous cell carcinoma

Cong-Fa Huang et al. PLoS One. .

Abstract

Oxidative stress has been reported to play an important role in progression and prognostication in various kinds of cancers. However, the role and clinical significance of oxidative stress markers Keap1 and Nrf2 in oral squamous cell carcinoma (OSCC) has not been elucidated. This study aimed to investigate the correlation of oxidative stress markers Keap1 and Nrf2 expression and pathological features in OSCC by using tissue microarray. Tissue microarrays containing 17 normal oral mucosa, 7 oral epithelial dysplasia and 43 OSCC specimens were studied by immunohistochemistry. The association among these proteins and pathological features were analyzed. Expression of oxidative stress markers Keap1, Nrf2, and antioxidants PPIA, Prdx6, as well as CD147 was found to increase consecutively from normal oral mucosa to OSCC, and the Keap1, Nrf2, PPIA, Prdx6, CD147 expression in OSCC were significantly higher when compared to normal oral mucosa. Expression of Keap1, Nrf2 in tumors was not found to be significantly associated with T category, lymph node metastases, and pathological grade. Furthermore, we checked the relationship among these oxidative stress markers and found that Keap1 was significantly correlated with Nrf2, Prdx6 and CD147. Significant relationship between Nrf2 and Prdx6 was also detected. Finally, we found patients with overexpression of Keap1 and Nrf2 had not significantly worse overall survival by Kaplan-Meier analysis. These findings suggest that ROS markers are associated with carcinogenesis and progression of OSCC, which may have prognostic value and could be regarded as potential therapeutic targets in OSCC.

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Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1
Figure 1. Keap1 and Nrf2 were overexpressed in human OSCCs.
A, Representative immunohistochemical staining of Keap1 and Nrf2 in human oral cancer tissue (right) compared with normal oral mucosa (left) (Scale bars = 100 umol). B, Quantatitive of histoscore of Keap1 and Nrf2 expression in normal oral mucosa, oral epithelial dysplasia and human oral cancer, Keap1 levels in OSCC was significant higher when compared with oral epithelial dysplasia or normal oral mucosa, and Nrf2 levels in OSCC was significant higher when compared with normal oral mucosa (Mean ± SEM; *, P<0.05; **, P<0.01; ***, P<0.001; One-way ANOVA). C, The expression of Keap1 and Nrf2 were not correlated with lymph node status of human oral cancer (Quantification using Aperio nuclear quantification software, and statistics using Graph Pad Prism 5. Mean ± SEM; *, P<0.05; Mann–Whitney U test). D, Overall survival of the OSCC patients with Keap1 and Nrf2 expression calculated and presented by Kaplan–Meier analysis, and both of Keap1 and Nrf2 expression were not significantly correlated with overall survival (P>0.05).
Figure 2
Figure 2. Prdx6, PPIA and CD147 were overexpressed in human OSCCs.
A, Representative immunohistochemical staining of Prdx6, PPIA and CD147 in human oral cancer tissue (right) compared with normal oral mucosa (left) (Scale bars = 100 umol). B, Quantatitive of histoscore of Prdx6, PPIA and CD147 expression in normal oral mucosa, oral epithelial dysplasia and human oral cancer, Prdx6, PPIA and CD147 levels in OSCC was significant higher when compared with oral epithelial dysplasia and/or normal oral mucosa (Mean ± SEM; *, P<0.05; **, P<0.01; ***, P<0.001; One-way ANOVA). C, Prdx6, PPIA and CD147 were not significantly associated with lymph node status (Quantification using Aperio nuclear quantification software, and statistics using Graph Pad Prism 5. Mean ± SEM; *, P<0.05; Mann–Whitney U test and One-way ANOVA).
Figure 3
Figure 3. Correlation of Keap1, Nrf2 with PPIA, Prdx6 and CD147 in human OSCC tissue array.
A, The expression of Keap1 had significant correlations with Nrf2 (P = 0.000, R = 0.549), and Prdx6 (P = 0.000, R = 0.735), and CD147 (P = 0.040, R = 0.268) by using the Pearson correlation coefficient test in human OSCC tissue array. B, The expression of Nrf2 was closely correlated with Keap1 (P = 0.000, R = 0.549) and Prdx6 (P = 0.000, R = 0.551) in human OSCC tissue array. C, Hierarchical Clustering of Keap1, Nrf2 with PPIA, Prdx6 and CD147 in human OSCC tissue array. Histoscore based on quantification using Aperio quantification software and statistics with Graph Pad Prism5. Mean ± SEM; 2-tailed Pearson correlation statistics.
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This work was supported by National Natural Science Foundation of China 81072203, 81272963 (ZJS). 81272964 (WFZ), 81371106 (LZ), 81371159 (YFZ). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.