探討轉移相關蛋白-2調控蛋白酪氨酸激酶-7在人類肝細胞癌之功能性角色及分子機轉

衛福部的資料統計中，肝癌一直位居十大癌症死因的前三名，每年因肝癌而死亡的人數在5000至7000之間。因早期沒有明顯症狀不易發現，加上轉移造成的高死亡率，其分子機制的探究已成為一項棘手的問題。轉移相關蛋白2（Metastasis Associated Protein 2）與酪氨酸蛋白激酶7（Protein Tyrosine Kinase 7）兩者與癌症密切相關，在許多文獻中皆顯示其表現量對腫瘤細胞轉移及侵襲的發生具有影響力，但相關機制仍在各環境下略有不同。藉由UALCAN資料庫分析臨床的癌組織樣本發現發生轉移的樣本中MTA2、PTK7確實都有高表達現象，並且與癌症生存率、惡性腫瘤期程（Stage）及分化程度（Grade）具相關性。透過資料散佈圖的分析結果我們發現MTA2與PTK7的表達量呈一致性，推測MTA2藉由調控PTK7蛋白表現影響腫瘤發展。本研究主要探討MTA2、PTK7與肝細胞癌是否相關，並釐清兩者究竟透過何種途徑影響肝細胞癌轉移。我們運用shRNA方式將MTA2基因抑制，證實SK-Hep-1、PLC/PRF/5細胞的轉移與侵襲能力變差，並透過西方墨點法觀察到MTA2與PTK7蛋白表現量同步降低，p-ERK蛋白表現量增加，推測MTA2應是藉由調控PTK7影響下游ERK路徑造成肝細胞癌轉移與侵襲。後續我們利用shMTA2的肝癌細胞株SK-Hep-1添加ERK抑制劑U0126處理，實驗結果發現其抑制轉移及侵襲能力的效果高於原先未添加U0126處理的細胞，且PTK7的蛋白表現量也隨之降低。本次研究說明MTA2藉由調控PTK7影響下游的ERK訊號傳遞路徑，期許在不久後的將來能利用這些基因及其所調控的靶點有效抑制肝細胞癌發生轉移，並提高存活率達到更棒的預後。

關鍵字

轉移相關蛋白2 ；酪氨酸蛋白激酶7 ；肝細胞癌； p-ERK

並列摘要

Indicated from the statistics by the Ministry of Health and Welfare, liver cancer has been in top three causes of cancer deaths, and the number of deaths due to liver cancer is from 5,000 to 7,000 every year. As a result that symptoms were not discovered easily in early stage, plus high mortality rate caused by metastasis, exploring its molecular mechanism becomes a tough issue. A large number of research have suggested high expression of Metastasis Associated Protein 2 (MTA2) and protein tyrosine kinase 7 (PTK7) are closely related with tumor progression and metastasis. However, the molecular mechanisms remain unknown. Using the clinical cancer tissue samples via UALCAN Database to suggest that are HCC patients with high MTA2 and PTK7 expression, compared with normal tissues. Besides, increased MTA2 and PTK7 expression were significantly associated with overall survival rate (OS), tumor stage and grade. MTA2 expression was also positively correlated with PTK7 expression in patients with HCC. To understanding the molecular mechanism of MTA2 regulate PTK7 expression in HCC, we found that knockdown of MTA2 inhibit the PTK7 expression and metastasis in SK-Hep-1 and PLC/PRF/5 cells, independent on cell proliferation. In addition, we also demonstrated that the p-ERK expression is upregulation in knockdown MTA2-treated SK-Hep-1 and PLC/PRF/5 cells. Therefore, the reason for increased p-ERK protein should be MTA2 affecting the downstream ERK pathway causing hepatocellular carcinoma metastasis and invasion by regulating PTK7. Thereafter we added ERK inhibitor U0126 to SK-Hep-1 shMTA2 cell. The effect of inhibiting metastasis and invasion is better than cells without U0126. This study suggests that MTA2 affects ERK pathway by regulating PTK7. Expecting these genes and their regulated targets can be used to effectively inhibit the metastasis of hepatocellular carcinoma, and improve the survival rate to achieve a better prognosis in the near future.

並列關鍵字

MTA2 ； PTK7 ； hepatocellular carcinoma ； p-ERK

參考文獻

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探討轉移相關蛋白-2調控蛋白酪氨酸激酶-7在人類肝細胞癌之功能性角色及分子機轉

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