| 摘要: | 酪蛋白激酶 1ε (CK1ε) 於正常生理情況下參與了 DNA 修復、細胞分裂、分化和細胞凋亡、Wnt 訊息傳遞，目前已證實和人類癌症有關，如大腸癌、乳癌，其中在胰腺導管腺癌中更是發現 CK1ε 都會出現過度表現，我們先前的研究發現，在口腔鱗狀上皮細胞癌病人CK1ε 沒有表現與病人預後較差有關，CK1ε 可能是一個存活預測因子，同時也扮演著抑癌基因的角色，然而，CK1ε 在肝細胞癌 (HCC) 中的作用仍不清楚，所以我們進一步探討 CK1ε 在肝癌的表現情形與其臨床意義。本研究從彰化基督教醫院病理部收集了 230 個肝細胞癌組織蠟塊，製作成組織晶片 (tissue microarray)，進行免疫組織化學染色，並透過統計分析探討 CK1ε 的表現與肝細胞癌病人臨床參數之間的相關性，並以 CK1ε 的 RNA 干擾技術來探討其對肝癌細胞侵襲以及移動能力的影響，透過不同肝癌細胞株與 siRNA 細胞實驗來驗證臨床實驗的結果。免疫組織化學染色結果顯示，低度 CK1ε 表現與腫瘤分化 (P=0.008)、腫瘤大小 (P=0.016)、腫瘤血管浸潤 (P=0.002)，和癌症分期 (P=0.010) 有顯著關係。單變項與多變相回歸分析發現在肝細胞癌患者中，CK1ε 低度表現的患者其存活率比 CK1ε 高度表達的患者低 (P=0.041，危險比=1.4; P=0.039，危險比=1.4)。此外，我們也利用細胞實驗 siRNA 方式來抑制 CK1ε 的表現，結果發現抑制 CK1ε 的表現會促進肝細胞癌細胞的遷移能力與轉移能力。我們的結果顯示 CK1ε 低度表達與肝細胞癌患者低生存率相關， CK1ε 是一個存活預測因子，在肝細胞癌中亦扮演著抑癌基因的角色。
CK1ε phosphorylates various substrates playing key roles in diverse physiological processes, such as DNA repair, cell cycle progression, cytokinesis, differentiation, apoptosis and Wnt signaling pathways. Recent research has been proposed over-expression of CK1ε is associated with human malignant cancers, colon cancer, breast cancer and ductal adenocarcinoma of the pancreas. In our previous study, we investigated the associations between CK1ε expression and the clinical parameters of oral cancer using immunohistochemical study methods on oral squamous cell carcinoma specimens. Our data indicated that loss of cytoplasmic CK1ε expression is greatly associated with poor survival and might be an adverse survival factor. However, the role of CK1ε in hepatocellular carcinoma (HCC) remains unclear. Therefore, we further investigate CK1ε expression in hepatocellular carcinoma and it’s related to patients’ clinicopathologic parameters and survival. We collected 230 HCC specimens from the Department of Pathology at Changhua Christian Hospital, Taiwan. These samples were used to construct a tissue microarray. We perform immunohistochemical study and statistical analysis to clarify the correlation with CK1ε expression and hepatocellular carcinoma clinical pathological parameters. For verifying the results of clinical data, we performed RNA interference technology to evaluate cancer cell capability of invasion and migration. The results of our immunohistochemical analysis showed that low CK1ε expression was greatly associated with tumor differentiation (P=0.008), T classification (P=0.016), tumor vascular invasion (P=0.002), and cancer stage (P=0.010). The univariate and multivariate analyses showed that patients with low CK1ε expression had a considerably lower OS rate than that of the patients with high CK1ε expression (P=0.041, hazard ratio=1.4; P =0.039, hazard ratio=1.4). Cell proliferation, migration, and invasion assays were performed and the HCC cell migration and invasion abilities significantly increased after CK1ε siRNA treatment. Our data indicated that low CK1ε expression is correlated with a low survival rate and CK1ε may play a role as a tumor suppressor in hepatocarcinogenesis. |
