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.