Focal adhesion kinase表現於口腔鱗狀細胞癌之預後價值

Abstract

Focal adhesion kinase (FAK)在細胞黏著的訊息傳遞中，佔有重要角色。過去研究顯示，在腫瘤細胞的運動和增生過程中，FAK之mRNA及蛋白質表現都會顯著增加，然而FAK表現與口腔鱗狀細胞癌各臨床變數間之關係至今未明，而且過往大多數的實驗都是探測全體FAK (total FAK)，但FAK其實是在tyrosine 397位置被磷酸化之後，才開始活化。本研究利用total FAK及FAK pY397抗體，以免疫組織化學染色法，探討FAK於76例口腔鱗狀細胞癌中的表現及其預後價值，並以21例正常口腔黏膜為對照組，利用Fisher’s exact test分析FAK表現與各臨床變數之相關性，再以Kaplan-Meier Method顯現FAK表現與存活率之關係。結果發現total FAK與FAK pY397之染色在正常口腔黏膜均為陰性。口腔鱗狀細胞癌中，total FAK呈陰性、弱陽性與強陽性之比例分別為48.7%、23.7%與27.6% ; FAK pY397之陰性、弱陽性與強陽性之比例則是34.3%、28.9%與36.8%。total FAK的表現與腫瘤大小(p =0.002)與有無局部淋巴轉移(0.003)及臨床分期(p = 0.001)有顯著的相關性，腫瘤較小時，total FAK過度表現的比例較高，較大的腫瘤與局部淋巴轉移的病例，total FAK的表現反而較不明顯，在臨床分期上，分期低者較分期高者有較強烈的total FAK表現。因此total FAK表現較低之病例，整體存活率也明顯較差(p =0.007)。飲酒歷史較長久之患者，其total FAK的表現較不明顯(0.013)。至於FAK pY397之表現，研究發現除了細胞質外，在部分腫瘤中FAK pY397還會表現在細胞核，有部分在細胞核與細胞質均有表現。但是其表現與各項臨床變數間並無顯著相關性，在統計學上並無顯著差異。 本研究顯示total FAK之過度表現出現在腫瘤成長的初期，伴隨著較佳的預後。至於 FAK pY397在腫瘤成長中所扮演的角色，則尚待釐清。

Focal adhesion kinase (FAK) has been considered as a key player of the signal transduction in cell adhesion. Studies have demonstrated that motility and proliferation of tumor cells are associated with increased expression of FAK, both at mRNA and protein levels. However, the relationship between FAK expression and various clinical parameters of oral squamous cell carcinoma (OSCC) remains controversial. Furthermore, most of the previous studies examined only total FAK, but FAK becomes activated only after phosphorylation at the position of tyrosine 397. In this study, the expressions of total FAK and FAK pY397 and their prognostic values were examined in 76 OSCC specimens. Twenty-one cases of normal oral mucosa were used as control. The relation between FAK expression and clinical parameters was analyzed by Fisher’s exact test and Kaplan-Meier method was employed to examine the influence of FAK expression on survival. Results showed that normal mucosa was negative for immunostaining of total FAK and FAK pY397. In OSCC specimens, the rates of negative, weakly positive and strongly positive staining for total FAK were respectively 48.7%, 23.7% and 27.6%, and for FAK pY397 were respectively 34.3%, 28.9% and 36.8%. Expression of total FAK was significantly related to the size of primary tumor (0.002), nodal metastasis status (0.003) and clinical stage (0.001). A higher rate of total FAK expression was found in tumors of smaller size and those without lymph node metastasis. Larger tumors and cases with metastasis node had lower expression of total FAK. Early stage diseases had stronger expression of total FAK than cases of late stage. Therefore, expression of total FAK was negatively related to survival (0.007). Lower expression of total FAK was also found in patients with longer history of alcohol drinking (0.013). As for FAK pY397, both cytoplasmic and nuclear stains were found but no significant relationship between immunostaining and various clinical parameters was noted. In conclusion, the study demonstrated that overexpression of total FAK tended to occur in early stage OSCC and denoted a better prognosis. The role of FAK pY397 expression in tumor growth was unclear and need further investigation.