Abstract
The epithelial-mesenchymal transition (EMT) process is believed to play a crucial role in nasopharyngeal carcinoma (NPC) progression, a squamous cell carcinoma of the head and neck with the tendency to metastasize early. At present, much attention has been given to the inducer of EMT involved in NPC progression, while antagonists have been less intensively characterized. In this study, unbiased analysis of EMT-associated gene expression patterns was performed using data mining of global gene expression profiles derived from NPC samples, leading to the successful identification of NOR1, FOXA1, and Slug, all of which showed aberrant expression during NPC progression. The effect of tumor suppressor NOR1 on Slug-induced NPC cells during the EMT process was investigated by use of ectopic expression and RNA interference methods. The molecular mechanisms underlying the tumor-suppressing effect of NOR1 on Slug-induced EMT were thought to be dependent on the cooperation of NOR1 with the FOXA1-HDAC2 complex. We also showed that FOXA1 and HDAC2 bind the slug promoter and directly repress its transcription. Our data revealed a previously unrecognized role of the NOR1-FOXA1/HDAC2-Slug network in the regulation of the EMT process and aggressiveness of NPC.
Highlights
Nasopharyngeal carcinoma (NPC) is a nonlymphomatous, squamous-cell carcinoma derived from malignant transformation of mucosal epithelial cells in the nasopharyngeal cavities [1]
We analyzed the mRNA levels of other epithelial-mesenchymal transition (EMT)-regulating candidates during NPC progression and found that mRNA levels of nitro domain containing protein 1 gene (NOR1), FOXA1, keratin 4, and keratin 13 were significantly lower in NPC tissue samples than in their normal counterparts (Figure 1A)
We found the levels of NOR1 mRNA to be positively and readily correlated with FOXA1 (R = 0.516, P < 0.001) and keratin www.impactjournals.com/oncotarget
Summary
Nasopharyngeal carcinoma (NPC) is a nonlymphomatous, squamous-cell carcinoma derived from malignant transformation of mucosal epithelial cells in the nasopharyngeal cavities [1]. NPC is rare in most parts of the world but has especially high incidence in Southern China and Southeast Asia [2]. NPC characteristically exhibits an early tendency to locally spread to the parapharyngeal space at an early stage [3]. According to one prospective study, cervical lymphadenopathy occurred in 204 of 271 (75.3%) consecutive patients with newly diagnosed NPC [4]. About 18% of nonmetastatic NPC patients eventually develop isolated distant metastasis irrespective of a successful locoregional treatment [5]. Distant metastasis continues to be considered a major cause of treatment failure and death from NPC. Control of regional spread and distant metastasis of NPC remains a difficult and challenging problem
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