纖維母細胞生長因子受器第二型在頭頸部鱗狀上皮細胞癌中對細胞遷移的影響

Abstract

頭頸部鱗狀上皮細胞癌（Head and neck squamous cell carcinoma , HNSCC）在台灣有較高的發病率和致死率，但目前對於HNSCC的治療方法並沒有太大的突破。HNSCC屬於容易轉移及復發的癌症，病患預後亦和轉移的出現有高度的相關；因此對於HNSCC的治療來說，如何有效阻止腫瘤轉移或許可以成為治療的關鍵。 因此我們嘗試去找出會影響頭頸癌移動的目標。由於先前有研究顯示FGFR (Fibroblast growth factor receptor)的突變﹑表現量增加等異常與乳癌﹑肺癌﹑多發性黑色素瘤等癌症的形成相關；而FGFR本身的功能亦涉及Epithelial–mesenchymal transition﹑血管新生等細胞移動的調控。那麼FGFR會否也有作用在頭頸癌的轉移中，能否有潛力作為治療頭頸癌的目標？為了回答這個問題，我們參考實驗室先前所做的一個針對FGFR的Screening結果中發現，FGFR2似乎可以抑制HNSCC細胞的移動，於是我們挑選FGFR2作為研究的目標。 我們分析了53位頭頸癌病人的腫瘤和正常組織中的FGFR2表現量，結果發現隨着臨床分期增加，FGFR2的總量有着下降的趨勢。為了知道FGFR2對細胞遷移的影響，我們進一步透過knockdown、overexpression等方法，改變細胞中FGFR2的表現量來研究FGFR2的功能。我們發現在FGFR2 knockdown後，頭頸癌細胞的移動速度會有明顯下降，細胞運動的方向性以及細胞間的協調性亦會變差。表示FGFR2在頭頸癌的遷移中可能有着促進的的角色。而分別overexpression FGFR2IIIb和IIIc後，細胞的移動也有輕微的下降，這個結果暗示著FGFR2可能需要FGFR2IIIb和FGFR2IIIc同時存在才能增加細胞的遷移速度。根據我們目前的研究結果，顯示FGFR2有可能影響頭頸癌細胞轉移，然而FGFR2調控頭頸癌細胞遷移的機轉仍需要更進一步的研究與探討才能釐清。

Head and neck squamous cell carcinoma (HNSCC) has high metastasis and recurrent rates and causes high cancer-related mortality in Taiwan. However, there is still no effective treatment for HNSCC. We therefore aimed to identify novel therapeutic targets to prevent HNSCC metastasis. Mutations and amplification of FGFR (Fibroblast growth factor receptor) genes were reported to be important in cell proliferation, differentiation and migration of many cancers, including breast cancer, lung cancer and melanoma. FGFRs were also reported to be associated with epithelial–mesenchymal transition, angiogenesis and regulation of cell migration. Therefore, our question is: Does FGFR participate in HNSCC metastasis? Could it be a potential targret in curing HNSCC? To answer this question, we used shRNAs targeting FGFRs to systemically examine the effect of FGFR on HNSCC cell migration. The screen result revealed that FGFR2 knockdown significantly reduced HNSCC motility. Therefore, we proposed that FGFR2 may promote HNSCC cell migration. To validate our hypothesis, we examined the expression level of FGFR2 in 53 tumor samples from HNSCC patients of various stages. We found that FGFR2 expression was decreased in late-stage HNSCC. To further understand the role of FGFR2 in cancer cell migration, we knocked-down, overexpressed and rescued FGFR2 levels in SAS cells, and measured how such treatments affected HNSCC cell migration. We found that FGFR2 knockdown significant decreased cell migration, probably through impairing directionality and cell-cell coordination. These results implied that FGFR2 might promote HNSCC cell migration. Interesingly, FGFR2IIIb or IIIc overexpression slightly decreased cell migration. These results suggested that there might be some interaction between FGFR2IIIb and FGFR2IIIc. Based on our findings, FGFR2 may play an important role in HNSCC metastasis. Further investigations are currently under the way to clarify the mechanism how FGFR2 changes HNSCC migration.