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Deregulation of manganese superoxide dismutase (SOD2) expression and lymph node metastasis in tongue squamous cell carcinoma
- Xiqiang Liu†1, 2,
- Anxun Wang†3,
- Lorenzo Lo Muzio4,
- Antonia Kolokythas5,
- Shihu Sheng3,
- Corrado Rubini6,
- Hui Ye1,
- Fei Shi1, 7,
- Tianwei Yu8,
- David L Crowe1, 9 and
- Xiaofeng Zhou1, 2, 9Email author
© Liu et al; licensee BioMed Central Ltd. 2010
Received: 16 July 2009
Accepted: 9 July 2010
Published: 9 July 2010
Lymph node metastasis is a critical event in the progression of tongue squamous cell carcinoma (TSCC). The identification of biomarkers associated with the metastatic process would provide critical prognostic information to facilitate clinical decision making. Previous studies showed that deregulation of manganese superoxide dismutase (SOD2) expression is a frequent event in TSCC and may be associated with enhanced cell invasion. The purpose of this study is to further evaluate whether the expression level of SOD2 is correlated with the metastatic status in TSCC patients.
We first examined the SOD2 expression at mRNA level on 53 TSCC and 22 normal control samples based on pooled-analysis of existing microarray datasets. To confirm our observations, we examined the expression of SOD2 at protein level on an additional TSCC patient cohort (n = 100), as well as 31 premalignant dysplasias, 15 normal tongue mucosa, and 32 lymph node metastatic diseases by immunohistochemistry (IHC).
The SOD2 mRNA level in primary TSCC tissue is reversely correlated with lymph node metastasis in the first TSCC patient cohort. The SOD2 protein level in primary TSCC tissue is also reversely correlated with lymph node metastasis in the second TSCC patient cohort. Deregulation of SOD2 expression is a common event in TSCC and appears to be associated with disease progression. Statistical analysis revealed that the reduced SOD2 expression in primary tumor tissue is associated with lymph node metastasis in both TSCC patient cohorts examined.
Our study suggested that the deregulation of SOD2 in TSCC has potential predictive values for lymph node metastasis, and may serve as a therapeutic target for patients at risk of metastasis.
Oral squamous cell carcinoma (OSCC) is a complex disease arising in various sites. Tumors from these different sites have distinct clinical presentations and outcomes, and are associated with different genetic characteristics . In this study, we focused on tongue SCC (TSCC), one of the most common sites for OSCCs. The TSCC is significantly more aggressive than other forms of OSCCs, with a propensity for rapid local invasion and spread .
Lymph node metastasis is identified as the single most adverse independent prognostic factor in patients with OSCC . Currently, the detection of nodal metastasis is based on clinical and radiographic examination as well as histopathologic examination of the surgical specimen if a neck dissection is performed. However, regional lymph node metastasis cannot always be reliably detected by these routine examinations. This points to the immediate need for new diagnostic strategies to better identify those tumors with potentially higher metastatic abilities. Since several genes have been reported in retrospective trials to yield prognostic information independently of the TNM classification, it is reasonable to hypothesize that molecular "fingerprints" could exist that might define sub-groups of patients with significantly more aggressive disease.
The effects of redox state play important roles in malignancies. Superoxide dismutase 2 (SOD2) has been considered as one of the most important antioxidant enzymes that regulate the cellular redox state in normal and tumorigenic conditions. Studies suggested that alteration in SOD2 level may influence the metastatic potential of tumor cells via activating mitogen-activated protein kinases (MAPK), and regulating the expression of matrix metalloproteinase (MMP) gene family members (including MMP-1 and MMP-9) [4–7]. The object of this study is to evaluate whether the expression level of SOD2 is correlated with metastatic status in TSCC patients. We first performed pooled-analysis on existing TSCC microarray datasets to explore the potential associations between of SOD2 mRNA levels and clinicopathological characteristics. We then tested an additional independent TSCC patient group to confirm and further elucidate the role of SOD2 in TSCC.
Clinical Characterization of the cohorts†
Male: n (%)
Female: n (%)
Stage 4: n (%)
Stage 3: n (%)
Stage 2: n (%)
Stage 1: n (%)
N stage (Pathological)
Stage 2: n (%)
Stage 1: n (%)
Stage 0: n (%)
Stage 4: n (%)
Stage 3: n (%)
Stage 2: n (%)
Stage 1: n (%)
Well: n (%)
Mod: n (%)
Poor: n (%)
Pooled-analysis to extract SOD2 expression values from existing microarray datasets
The CEL files from all datasets (53 TSCCs and 22 normal tongue samples) were imported into the statistical software R 2.4.1  using Bioconductor . The pooled-analysis was performed as described , and the genome-wide expression pattern has been presented in our previous study . In brief, the Robust Multi-Array Average (RMA) expression measures  were computed after background correction and quantile normalization for each microarray dataset. Then, expression values of the overlapping probesets between U133A and U133 Plus 2.0 arrays were extracted. Probeset-level quantile normalization was performed across all samples to make the effect sizes similar among the four datasets . The expression values for probesets corresponding to SOD2 gene (215223_s_at and 216841_s_at) and for Ki67 gene (212020_s_at, 212021_s_at, 212022_s_at, and 212023_s_at) were then extracted from each datasets. Relative expression level for SOD2 and Ki67 genes for each TSCC samples were computed as follows:
First, for every probeset, we found the mean expression level in normal samples, , where j denotes the probeset. Second, the expression values derived from the probeset were normalized by the mean normal expression level, , where i denotes the TSCC sample and j denotes the probeset. Third, for every TSCC sample, the expression value of the gene was assigned by taking the average over the normalized expression levels of the probesets representing the same gene, , where n is the number of probesets for each gene (n = 2 for SOD2 and n = 4 for Ki67).
Tissue samples were dehydrated in an ethanol series, cleared in xylene, and embedded in paraffin. Five-micrometer sections were prepared and mounted on poly-L-lysine-coated slides. Representative sections were stained with H&E and histologically evaluated by a pathologist. Immunohistochemical analysis was done using a commercially available kit (Invitrogen, Carlsbad, CA). Sections were incubated at 60°C for 30 min and deparaffinized in xylene. Endogenous peroxidase activity was quenched by incubation in a 9:1 methanol/30% hydrogen peroxide solution for 10 min at room temperature. Sections were rehydrated in PBS (pH 7.4) for 10 min at room temperature. Sections were blocked with 10% normal serum for 10 min at room temperature followed by incubation with anti-SOD2 and anti-Ki67 antibodies (ABCam) at a dilution of 1:200 for 16 h at room temperature. After washing thrice in PBS, the sections were incubated with secondary antibody conjugated to biotin for 10 min at room temperature. After additional washing in PBS, the sections were incubated with streptavidin-conjugated horseradish peroxidase enzyme for 10 min at room temperature. Following final washes in PBS, antigen-antibody complexes were detected by incubation with a horseradish peroxidase substrate solution containing 3,3'-diaminobenzidine tetrahydrochloride chromogen reagent. Slides were rinsed in distilled water, coverslipped using aqueous mounting medium, and allowed to dry at room temperature. The relative intensities of the completed immunohistochemical reactions were evaluated using light microscopy by 3 independent trained observers who were unaware of the clinical data. All areas of tumor cells within each section were analyzed. All tumor cells in ten random high power fields were counted. A scale of 0 to 3 was used to score relative intensity, with 0 corresponding to no detectable immunoreactivity and 1, 2, and 3 equivalent to low, moderate, and high staining, respectively. As for Ki67, nuclear staining was evaluated by calculating the percentage of positive nuclei (Ki67 index).
Spearman Correlation Coefficient was used to assess correlations among the gene expression and clinical and histopathological parameters. One-way ANOVA was used to assess the association of SOD2 expression with clinical and histopathological parameters (e.g., TNM and grade). The normality of the observed SOD2 expression data were tested by quantile-quantile plot (QQ plot) (Additional File 1).
The SOD2 mRNA level in TSCC
The SOD2 protein level in TSCC
The protein expression of SOD2 in TSCC†
Normal: n (%)
Premalignant: n (%)
TSCC: n (%)
LN metastasis: n (%)
Correlation between SOD2 expression and clinicopathological characteristics in TSCC
Correlations among clinical features and SOD2 gene expression of primary TSCC†
Patient cohort # 1 (n = 53)
Patient cohort #2 (n = 100)
Association of reduced SOD2 expression in primary TSCC and lymph node metastasis (pN)†
Patient Cohort #1
(p = 0.043)
Patient Cohort #2
(p = 0.0004)
Discussion and Conclusions
An essential characteristic of cancer is the ability to invade surrounding tissues and metastasize to regional lymph nodes and distant sites . Detection of local lymph node metastasis is pivotal for choosing appropriate treatment, including individuals diagnosed with OSCC. It is believed that the underlying molecular features of the tumors play an essential role in determining the aggressiveness of the tumors. Previous studies suggested that the deregulation of SOD2 gene expression is a common event in OSCC and appears to be associated with invasion [8, 17, 18].
In our present study, by focusing on cancer from just one anatomic site (tongue), we were able to partially minimize the genetic variation and microenvironment effects among intraoral sites. We made two important observations. First, deregulation of SOD2 gene expression is a progressive event in the tumorigenesis of TSCC. Our study confirmed that the SOD2 level is increased in TSCC when compared to normal tissue. The SOD2 level is further enhanced in metastatic diseases when compared with primary tumors. Second, the association of reduced SOD2 expression in primary TSCC and the presence of lymph node metastasis was consistently observed in both patient groups. Similar observations have been made in esophageal cancer and melanoma, where inverse correlations were observed between SOD2 expression and metastatic potential of the cancer cells [19, 20]. Nevertheless, our sample size (total n = 153) is relatively small. Further validation studies with larger sample size and additional stratification to control potential confounding factors (e.g., age, gender, ethnicity, smoking histories) are needed to validate our findings.
Accumulating evidence indicates that the deregulations of the SOD2 expression and the intracellular redox state play important roles in the progression of TSCC. Our previous Gene Ontology-based analysis suggested that redox related biological activities, such as superoxide release (GO:0042554), hydrogen peroxide metabolism (GO:0042743), and response to hydrogen peroxide (GO:0042542), are significantly altered in TSCC . However, the precise roles of SOD2 and redox state in malignancies are not fully explored. In theory, reducing the oxidative stress may prevent DNA degeneration and therefore prevent the development of cancer. However, doing so may also offer increased growth potential to tumor cells and protect them from an excess of reactive oxygen species (ROS), which would otherwise lead to apoptosis or necrosis. SOD2 is mainly present in the mitochondrial matrix, where most oxygen is consumed and oxidative stress is most evident. The role of SOD2 in carcinogenesis has been widely studied but remains ambiguous. While some in vitro studies have reported a protective role of SOD2 against tumor progression in several type of cancer cell lines [21–26], in vivo studies suggest more complicated roles of SOD2 in tumorigenesis. Increased SOD2 levels have been observed in gastric, brain astrocytic, and colorectal carcinomas, and is often associated with metastasis and poor prognosis [27–35]. The status of SOD2 levels in breast cancer is not clear, with some studies showing increased SOD2 , while others showing a decrease in SOD2 . There seems to be a reduction in SOD2 levels also in prostatic carcinomas when compared to healthy tissue [38, 39]. It has been suggested that SOD2 may influence the metastatic potential of tumor cells via regulating the expression of MMP gene family members (including MMP-1 and MMP-9) [5–7]. Interestingly, a single nucleotide polymorphism (SNP) that creates an Ets site at the promoter region of the MMP-1 gene has been shown to be responsible for the SOD2 dependent MMP-1 expression . This SNP has been extensively investigated and has been shown in several populations to be associated with OSCC susceptibility and aggressiveness [40–43]. Studies also showed that hydrogen peroxide generated by SOD2 can activate MAPK and transcriptional factors such as c-fos, c-jun and NFκB [4, 44, 45]. Further studies are needed to fully explore the functional roles of these molecular regulators in the metastasis of TSCC.
In summary, our study confirmed that the SOD2 level is increased in TSCC when compared to normal tissue. The SOD2 level is further enhanced in metastatic disease when compared with primary tumors. In primary TSCC, reduced SOD2 expression is associated with presence of lymph node metastasis. Taken together, our findings suggested that SOD2 may be useful as a biomarker for the molecular classification of TSCC. Nevertheless, further validation studies with larger, independent sample sets and additional stratification to control potential confounding factors are needed to validate our findings.
This work was supported in part by NIH PHS grants CA135992, CA139596, DE014847, a grant from Prevent Cancer Foundation (to X.Z.), and a Science and Technique grant (2004B30901002) from Guangdong, China (to A.W.). X.L. is supported in part by grants from the National Natural Science Foundation (30700952), and the Natural Science Foundation of Guangdong (06300660), China. We thank Ms. Katherine Long for her editorial assistance.
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