Abstract
Metastasis is the main cause of cancer-related deaths. Nasopharyngeal carcinoma (NPC) is characterized by severe local invasion and high incidence of regional lymph node metastasis, which represents poor prognosis. However, the underlying mechanism that induces lymph node metastasis of NPC remains largely unknown. Herein, we report that flotillin-1 (FLOT1), a component of lipid raft, which was reported to be involved in tumor progression, was robustly upregulated in the NPC samples with lymph node metastasis. High FLOT1 expression was significantly associated with N classification as well as poorer overall and disease-free survivals in 169 archived clinical NPC samples. Overexpression of FLOT1 enhanced the migratory and invasive abilities of NPC cells in vitro, and more importantly, promoted invasion into the surrounding tissues and metastasis to lymph nodes in vivo. Whereas silencing of endogenous FLOT1 in NPC cells decreased the local invasion and metastasis to lymph nodes. Furthermore, FLOT1 induced the expression and secretion of TGF-β1, facilitated the activation of TGF-β/Smad3 signaling to effectuate epithelial-mesenchymal transition. Our findings present new evidence that FLOT1 plays an important role in promoting aggressive behavior of NPC and provide new insights into the regulatory mechanism of TGF-β signaling.
Highlights
Nasopharyngeal carcinoma (NPC) is a highly invasive and metastatic tumor type with high incidence in southern China and Southeast Asia
Western blotting analysis revealed that FLOT1 was markedly overexpressed in 22 primary NPC tissues compared with non-cancerous nasopharyngeal tissues, and in 6 tested NPC cell lines as compared with normal nasopharyngeal epithelial cells (NPECs) (Figure 1A–1C)
We further assessed whether FLOT1 expression was clinically correlated with lymph node metastasis in 169 paraffin-embedded, archived NPC tissues, including 57 lymph node metastasis-negative (LN−) cases and 112 lymph node metastasis-positive cases (LN+; Supplementary Table 1)
Summary
Nasopharyngeal carcinoma (NPC) is a highly invasive and metastatic tumor type with high incidence in southern China and Southeast Asia. To better understand the molecular mechanisms which regulate the invasion and metastasis of NPC and to identify valuable molecular biomarkers are essential for prognosis prediction and development of novel therapeutic strategies for NPC metastasis. Mounting evidence demonstrates the TGF-β signaling pathway is constitutively activated in a wide range of tumor types and is involved in tumor progression by promoting local invasion and even distant metastasis [4,5,6,7,8]. TGF-β signaling-associated induction of the EMT is considered an important step in the progression of tumor metastasis. Blockade of TGF-β signaling has been shown to dramatically inhibit invasion and metastasis and has been considered as a therapeutic approach in multiple types of cancer [6, 13,14,15]. Further delineation of the mechanisms that regulate TGF-β signaling may provide new clues for the development of targeted cancer therapies
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