Abstract
Nasopharyngeal carcinoma (NPC) is etiologically associated with Epstein-Barr virus (EBV) infection. However, the exact role of EBV in NPC pathogenesis remains elusive. Activation of signal transducer and activator of transcription 3 (STAT3) is common in human cancers including NPC and plays an important role in the pathogenesis and progression of human cancers. Interleukin-6 (IL-6), a major inflammatory cytokine, is a potent activator of STAT3. In this study, we report that EBV-infected immortalized nasopharyngeal epithelial (NPE) cells often acquire an enhanced response to IL-6-induced STAT3 activation to promote their growth and invasive properties. Interestingly, this enhanced IL-6/STAT3 response was mediated by overexpression of IL-6 receptor (IL-6R). Furthermore, IL-6R overexpression enhanced IL-6-induced STAT3 activation in uninfected immortalized NPE cells in vitro, and promoted growth and tumorigenicity of EBV-positive NPC cell line (C666-1) in vivo. Moreover, it is shown for the first time that IL-6R was overexpressed in clinical specimens of NPC. IL-6 expression could also be strongly detected in the stromal cells of NPC and a higher circulating level of IL-6 was found in the sera of advance-staged NPC patients compared to the control subjects. Therefore, IL-6R overexpression, coupled with enhanced IL-6/STAT3 signaling may facilitate the malignant transformation of EBV-infected premalignant NPE cells into cancer cells, and enhance malignant properties of NPC cells.
Highlights
Nasopharyngeal carcinoma (NPC) is a distinct type of head of neck cancer with high prevalence in Southeast Asia [1]
This observation further supports that IL-6-induced signal transducer and activator of transcription 3 (STAT3) activation is much more potentiated in Epstein-Barr virus (EBV)-infected cells compared to uninfected ones
An enhanced STAT3 activation was observed in an EBV-infected NPC cell line, CNE2, despite to a lesser extent (Figure 1G) when compared to that of immortalized nasopharyngeal epithelial (NPE) cell lines
Summary
Nasopharyngeal carcinoma (NPC) is a distinct type of head of neck cancer with high prevalence in Southeast Asia [1]. This malignancy is characterized by Epstein-Barr virus (EBV) infection, as well as its highly inflammatory stroma and metastatic nature [2]. The role of inflammatory cytokines in cancer pathogenesis is well established, but their effects on EBV-infected premalignant and cancerous nasopharyngeal epithelia are poorly defined. STAT3 activation is common in human cancers including both hematological and solid tumors [7]. Constitutive activation of STAT3 can be caused by abnormal and sustained autocrine and/or paracrine signaling including interleukin-6 (IL-6) signaling [11,12,13]. A recent study proposed that IL-6mediated STAT3 activation may mediate iNOS induction in NPC, resulting in the formation of mutagenic DNA lesions which might contribute to its pathogenesis [19]
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