肝細胞癌的致死率是全球排名第二，且在台灣的五年存活率大約只有20 %。蕾莎瓦是一種口服的多激酶抑制劑，是用來治療晚期肝細胞癌病人的第一線標靶治療藥物，但是蕾莎瓦的治療效果很短暫，易有抗藥性發生且緩解率很低，所以找出蕾莎瓦抗藥性的機制是很重要的。TARBP2是一個多功能的核糖核酸結合蛋白，例如在Ewing肉瘤中，TARBP2會影響癌症幹細胞的特性表現，但是在肝細胞癌中TARBP2的角色還是未確定的。我們的結果顯示在蕾莎瓦抗藥性的肝癌細胞中，TARBP2會顯著的減少。TARBP2的增加會使肝癌細胞降低對蕾莎瓦的抗藥性，並且當TARBP2下降後，肝癌細胞又會再對蕾莎瓦產生抗藥性。在Huh7 / SR和PLC5 / SR細胞中TARBP2的蛋白穩定性會下降。此外，在蕾莎瓦抗藥性細胞中，TARBP2會透過增加Nanog的降解速度來抑制Nanog的表現，而TARBP2的減少會使Nanog的蛋白穩定性上升，進而使Nanog表現量增加。結果顯示TARBP2的下降導致蕾莎瓦抗藥性的發生是透過Nanog增加所造成。這項研究說明了TARBP2在蕾莎瓦抗藥性肝細胞癌的作用。

Hepatocellular carcinoma (HCC) is the second leading cause of cancer deaths in the world. The five-year survival rate is about twenty percent in Taiwan. Sorafenib is a multikinase inhibitor used in first-line treatment for patients with advanced HCC. However, the therapeutic effects of sorafenib are temporary and the response rate is low. Thus, it is important to investigate the molecular mechanism leading to sorafenib resistance. TARBP2 is a multifaceted RNA-binding protein regulating cancer stem cell (CSC) properties in Ewing sarcoma. However, the role of TARBP2 in HCC remains unknown. Our results showed that TARBP2 is significantly downregulated in sorafenib-resistant (SR) HCC cells. Overexpression of TARBP2 re-sensitized SR cells to sorafenib treatment. Consistently, knockdown of TARBP2 enhanced sorafenib resistance in parental Huh7 and PLC5 cells. The protein stability of TARBP2 was decreased in Huh7/SR and PLC5/SR cells. TARBP2 suppresses Nanog protein expression in Huh7/SR cells through accelerating Nanog protein degradation, whereas knockdown of TARBP2 promotes Nanog protein expression in Huh7 cells through stabilization of Nanog protein. These data suggest that TARBP2 protein destabilization induces sorafenib resistance possibly through upregulation of Nanog in SR cells. This study demonstrates a functional role of TARBP2 in regulating sorafenib resistance in HCC cells.

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