| Summary: | 碩士 === 國立臺灣大學 === 醫學檢驗暨生物技術學研究所 === 102 === Sorafenib is a drug for standard systemic therapy in patients with advanced hepatocellular carcinoma (HCC), and it is also the first drug with survival benefits. Although Sorafenib was originally designed as a specific Raf kinase inhibitor, we and other investigators have found many off-target effects of Sorafenib that may have significant implications regarding its anti-tumor activity and the resistance mechanism of Sorafenib in HCC cells. In the past, our laboratory had tried to treat some effective targeted drugs combination solving Sorafenib resistance problems in HCC cells. In Addition, we found that Wnt pathway and DKK1 are effectively marked the most significant inhibiting in drug combinations treatment. This suggests that DKK1 may play certain roles in HCC, and may thus be a good therapeutic target for treating liver cancer. Past studies have also found that in a certain proportion of patients with liver cancer, the Wnt/beta-catenin signaling pathway and DKK1 exhibit abnormal activation. Therefore, the present study had 3 primary specific aims: (1) to clarify whether DKK1 is a Sorafenib therapeutic biomarker; (2) to clarify whether DKK1 is a good therapeutic target and to clarify the regulatory mechanisms in HCC cells treated with Sorafenib and DKK1 inhibitor; and (3) to clarify whether the combination of Sorafenib and DKK1 inhibitor could overcome Sorafenib resistance in HCC cells. To these ends, we used DKK1 inhibitor (WAY-262611) and Sorafenib in in vitro and in vivo tests. In the mice tests and cell line results, we found that the proliferation inhibition of HCC cells and DKK1 expression were decreased after Sorafenib treatment. The results further showed that the expression of DKK1 were inversely correlated with the effect of Sorafenib, but correlated with tumor volume. Furthermore, WAY-262611 and siDKK1 did not exhibit only more activity in apoptosis induction in a Sorafenib-resistant HCC cell line, Huh-7R, than in a Sorafenib-sensitive cell line, Huh-7, but also enhance effectiveness of Sorafenib in inducing all HCC cell lines into apoptosis. Moreover, we investigated the mechanism of Sorafenib inhibition of DKK1 via WAY-26261, siDKK1, and overexpression of DKK1. The results showed that Sorafenib inhibits DKK1 by up-regulating c-Jun levels, as c-Jun, in turn, competes with the regulation of beta-catenin activating DKK1. These results so far indicated that DKK1 might be a good therapeutic target for providing a solution to Sorafenib resistance problems.
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