長鏈非編碼RNA NORAD 藉由抑制S100P調節腫瘤細胞發生、遷移及入侵

Abstract

腫瘤細胞轉移到體內其他位置是多數癌症死亡的主要原因，其涉及一連串複雜的調控過程。近年，長鏈非編碼RNA被視為癌症研究中一個新興的研究領域，更有不少長鏈非編碼RNA被發現於癌症進展和轉移中扮演關鍵角色。因此，闡明長鏈非編碼RNA如何調控腫瘤細胞的生長與轉移，可能提供我們制定用於治療癌症患者的新策略。在本論文中，我們發現了長鏈非編碼RNA NORAD的新功能—抑制肺癌和乳腺惡性腫瘤。統計分析上，我們觀察到NORAD在肺癌和乳癌中表現量較低，且NORAD表現量較低與預後不良有關。功能上，NORAD能抑制癌細胞不依賴錨定生長、裸鼠體內的腫瘤發生、癌細胞遷移和侵襲。機制上，我們則進一步的發現NORAD與促腫瘤轉移蛋白S100P之間有相互作用，且此相互作用會干擾S100P與其下游調控蛋白Ezrin的結合。這說明了，NORAD可以藉由隔離S100P，達到抑制肺癌和乳癌發生、遷移和侵襲。此外，我們也探討了在肺癌和乳癌中，NORAD表現量下降的機制。研究結果顯示，NORAD在乳癌及肺癌中，經由YAP / TAZ-TEAD，這個已知會被異常激活並促進癌細胞發展的途徑，抑制其轉錄。綜合以上，本研究闡述了NORAD 抑制腫瘤的功能和機制，以及發現了NORAD可能參與在YAP / TAZ-TEAD介導的促腫瘤網絡中。

Metastasis is a complex process and responsible for the most cancer mortality. Recently, lncRNA is an emerging topic in cancer research and several lncRNAs play key roles in cancer progression and metastasis. In this thesis, we identify novel suppressive functions of lncRNA NORAD in the lung and breast malignancy. NORAD is downregulated in lung and breast cancers and this downregulation is associated with poor prognosis. Functionally, NORAD suppresses anchorage-independent growth in vitro and tumor growth in vivo. Additionally, NORAD inhibits migration and invasion of lung and breast cancer cells. Consistent with these tumor suppressive functions, NORAD interacts with a pro-tumor protein S100P and interferes with S100P binding to its effector Ezrin. Using rescue experiments, we show that S100P sequestration accounts for a major mechanism for the aforementioned tumor suppressive effects of NORAD. Finally, we explored the mechanism for NORAD downregulation in lung and breast cancers. Our data suggest that NORAD is repressed by YAP/TAZ-TEAD, a pathway known to be aberrantly activated in lung and breast cancers to promote cancer progression. Together, this study identifies tumor suppressive functions and mechanism of NORAD and suggest a participation of NORAD in YAP/TAZ-TEAD-mediated pro-tumor network.