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.
Highlights
Head and neck squamous cell carcinoma (HNSCC) ranks sixth among the most common cancers in the world, it has a high propensity to metastasize to locoregional lymph nodes due to the presence of a rich lymphatic network and the overall high number of lymph nodes in the neck region [1]
To assess the expression of the oxidative stress markers Kelch-like ECH-associated protein-1 (Keap1), Nrf2, and antioxidants PPIA, Prdx6, as well as CD147 in human Oral squamous cell carcinoma (OSCC), we stained the tumor sections from human tissue arrays for OSCC (n = 43) with antibodies for Keap1, Nrf2, PPIA, Prdx6 and CD147 compared them with oral epithelial dysplasia (n = 67) and normal oral mucosa samples (n = 17)
The data showed us that the level of PPIA, Prdx6, and CD147 in OSCC was significant higher when compared with oral epithelial dysplasia and/or normal oral mucosa (P,0.05) (Fig. 2)
Summary
Head and neck squamous cell carcinoma (HNSCC) ranks sixth among the most common cancers in the world, it has a high propensity to metastasize to locoregional lymph nodes due to the presence of a rich lymphatic network and the overall high number of lymph nodes in the neck region [1]. It is widely recognized that increased ROS lead to signaling pathways activation that benefit cancer cells for initiation, survival and progression [4]. Overexpressed Nrf activates the antioxidant response and induce transcription of a wide array of genes, which are able to combat the harmful effects of oxidative stress. Keap1/Nrf signaling pathway of have been identified to have important roles in the cellular response to oxidative stress, electrophiles and xenobiotics [6,7]. KEAP1 mutations lead to constitutively active Nrf and subsequent protection of cancer cells from chemotherapeutic drugs, constitutive activation of Nrf is prominently expressed in various kinds of cancers, which has been shown to protect against cancer and leads to progression and poor survival [6,7]
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