在頭頸癌中，表皮生長因子受器的過度表現和促發炎之細胞素的產生已充分釐清且與癌細胞侵入以及轉移有所關連。然而，表皮生長因子受器與細胞素調控頭頸癌細胞轉移之分子機制所知仍然相當缺乏。在本篇研究，我們確認PTX3是表皮生長因子調控頭頸癌轉移中的促進因子。藉由比較分析資料庫中正常與頭頸癌病人組織之間或病人原位癌組織與癌轉移組織之間PTX3表現，指出PTX3在惡性或癌轉移組織表現高於正常組織。我們發現表皮生長因子透過轉錄活化PTX3，藉由活化轉錄因子NF-κB和c-Jun結合啟動子AP-1/NF-κB結合位。探討表皮生長因子其下游訊息傳導路徑，發現PI3K/AKT與NF-κB訊息路徑對PTX3的活化是重要的。此外，分別抑制NF-κB和c-Jun狀態下，抑制表皮生長因子調控PTX3表現。表皮生長因子刺激PTX3分泌，促進頭頸癌細胞爬行、局部侵入、與內皮細胞的黏附和遠端傳播。表皮生長因子活化Fibronectin、MMP9與E-cadherin的抑制，在shPTX3細胞中被抑制。以上結果指出表皮生長因子調控PTX3促進頭頸癌細胞的轉移，可能透過PTX3自迴分泌調控促進轉移分子例如Fibronectin與MMP9。PTX3的活化也許反映表皮生長因子促進頭頸癌細胞的轉移與發炎反應有所關連。

SUMMARY

Overexpression of epidermal growth factor receptor (EGFR) and production of proinflammatroy cytokines are well clarified in head and neck squamous cell carcinoma (HNSCC) and correlates with invasion and metastasis. However, molecular mechanisms by which EGFR-mediated cytokines regulates metastasis of HNSCC remain unclear. Here, we identified that PTX3 is a metastasis-promoting factor that mediate EGF-induced HNSCC metastasis. Analysis of PTX3 expression between normal and malignant or metastatic tissues from HNSCC patients by using published datasets, our results indicated that expression level of PTX3 in malignant tissues was higher than in normal part in HNSCC patients. In addition, we found that EGF induced transcriptional activation of PTX3 by activating the binding of c-Jun and NF-κB factors to AP-1/NF-κB binding site of the PTX3 promoter. PI3K/AKT and NF-κB were essential for the induction of PTX3. EGF-induced PTX3 expression was significantly inhibited in c-Jun and NF-κB knockdown cells. Furthermore, we identify that NF-κB is upstream regulator to c-Jun in EGF signaling pathway. EGF stimulated the secretion of PTX3 from cancer cell, resulting in enhancing cell migration, local invasion, attachment with endothelium and distal dissemination. Effects of EGF on the induction of fibronectin and MMP9 expression, and inhibition of E-cadherin were abolished in PTX3 knockdown cells. These findings reveal the mechanism that autocrine production of EGF-induce PTX3-regulated HNSCC metastasis was through enhancing metastatic molecules, such as fibronectin and MMP9 expression. Induction of PTX3 possibly reflecting the EGFR-caused HNSCC metastasis associated with inflammation.

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