Purpose: Metastasis is one of the most important causes of treatment failure in nasopharyngeal carcinoma (NPC). In T4 or N2-3 patients at high-risk of metastasis, concurrent chemoradiotherapy (CCRT) is inadequate and additional induction chemotherapy (IC) is controversial. There is a critical need to develop a better patient stratification to efficiently identify patients at high-risk of metastasis for additional IC. Recently, Sequestosome 1 (SQSTM1)/p62, an autophagy adaptor protein, was identified as one of the metastasis-related proteins in NPC. However, the mechanism by which SQSTM1 is involved in NPC metastasis was not investigated.
Experimental Design: The effect of SQSTM1 on cell migration and invasion was examined in vitro and in vivo. SQSTM1 expression was analyzed in clinical NPC samples using IHC. Luciferase reporter analyses were conducted to identify the effects of SQSTM1 on NF-B transcriptional activity. A prediction bio-model was constructed by Cox analysis. Retrospective and prospective randomized clinical data were adopted to build and test the model, respectively.
Results: SQSTM1 mediated epithelial to mesenchymal transition (EMT) through the NF-B pathway to promote NPC metastasis. Inhibiting SQSTM1 enhanced sensitivity to cisplatin in NPC cells. In NPC patients, high SQSTM1 expression was associated with increased risk of distant metastasis. Furthermore, we propose a prognostic bio-model based on SQSTM1 and N-stage to predict NPC metastasis. Most importantly, our prospective randomized study suggested that IC is beneficial for NPC patients with high metastasis risk.
Conclusions: The prognostic bio-model identifies NPC patients at high-risk of metastasis for additional IC. Clin Cancer Res; 24(3); 648–58. ©2017 AACR.
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