Peroxiredoxin I expression in oral cancer: a potential new tumor marker
Introduction
The degree of cell proliferation in malignant tumors contributes to the understanding of predictive factors among patients with these neoplasms. There are many reports of markers for proliferation, argynophilic nucleolar organizer regions (AgNORs), Ki67 and proliferating cell nuclear antigen (PCNA) [1], [2], [3], [4], [5].
Recently, the proliferation associated gene (pag) was isolated from a ras-transformed human mammary epithelial cell line. This gene is constitutively expressed in human tissues and more highly expressed during proliferation [6]. The product of pag (Pag) is later classified into the peroxiredoxin (Prx) I family and is a physiological inhibitor of c-Abl tyrosine kinase activity [7]. Prx is an antioxidant protein family found in a wide variety of species [8], [9], [10], [11]. Yeast and mammalian Prx proteins have thioredoxin peroxidase (TPx) activity and reduce hydrogen peroxide [12]. The mammalian Prx group is divided into three subfamilies: Prx I, Prx II, and Prx III [13]. Prx I is well known as an oxidative stress-inducible protein. Proteins in this family include MSP23 in murine macrophages, natural killer enhancing factor (NKEF) in red blood cells (RBC) and Pag in human cells. MSP23 was cloned from murine peritoneal macrophages as an oxidative stress inducible protein, and its transcription level also increases in response to oxidative stress [9]. NKEF, which was identified in RBC cytosol and mediates an enhancement in natural killer activity, is induced by H2O2 [14]. Prx I participates in the signaling cascades of growth factors and tumor necrosis factor-alpha by regulating the intracellular concentration of H2O2 [12]. These facts suggest that Prx I activity may be associated with, not only proliferation, but also with formation of reactive oxygen species (ROS). ROS are produced by inflammatory cell infiltration and indicate that cellular response. Furthermore the relation between cancer and some ant-oxidatants, such as thiroedoxins and glutathion peroxidase, is presented [15], [16], [17], [18], [19].
Although the importance of Prx I in cancer is suggested by its association with proliferation, oncogene products and oxidative stress, there have been no studies investigating the possibility of using Prx I expression as a marker for clinical tumor status. Towards this goal, we have examined correlation between Prx I expression and the clinical status of squamous cell carcinoma in the oral cavity, using immunohistochemistry and histological classification.
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Patients
The specimens were obtained by surgical biopsy from the oral cavities from 53 Japanese patients with squamous cell carcinoma, who were referred to the Department of Oral and Maxillofacial Surgery at Tsukuba University Hospital from 1993 to 1997. The clinical features of these patients are summarized in Table 1. No patients received treatment for the malignant tumor prior to biopsy. The TNM categories were determined by clinical findings, radiographs, and CT scans. Staging of the tumors was
Immunohistological analysis of Prx I expression
Prx I expression was observed in 83% of the specimens examined, especially in the epithelium of the SCC (Fig. 2A). Prx I expression was also observed in the stratum basale of normal epidermis. Because both Prx I and PCNA immunostaining spots were assumed to correspond to proliferating cells, the locations of Prx I and PCNA were compared. Serial slices of one sample were stained by Prx I and PCNA antibodies individually, and the localization of the two different antigens were examined. We also
Discussion
The pag gene expression has been reported to increase in cells entering the S-phase [25]. Immunohistochemical localization revealed that PCNA increases in late G1, peaks in S, decreased through G2, and is undetectable in M-phase and quiescent cells [26]. Although the expression period in the cell cycle is considered to be same from these reports, the immunohistochemical distribution of each antigen is different. In this study, marked PCNA expression was observed in the nuclei of basal layer
Acknowledgements
This work is supported by Grants-in-Aid for Scientific Research from the Japanese Ministry of Education, Science, Sports, and Culture in Japan. We thank Dr Shimokama for pathological advice.
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