肝癌為全球好發的癌症類型之一，並且具有高致死率。肝癌病患中有八成以上皆屬於肝細胞瘤(Hepatocellular carcinoma, HCC)。Sorafenib (Nexavar, 蕾莎瓦)是一種小分子的酪胺酸激?抑制劑可以抑制多種酪胺酸激?而影響腫瘤血管新生、細胞增生以及癌細胞轉移。即使Sorafenib已是現今肝癌治療的基本療法，但是部分病人對於Sorafenib的治療效果不佳，更有病人隨著用藥時間增加，而產生抗藥性。因此，研究病人對sorefenib產生抗藥性的分子機制是相當迫切的。 Dicer在MicroRNA生合成的過程中扮演著重要的角色，而許多癌症中Dicer也會調控腫瘤的發展。在我們的研究中，我們發現Sorafenib-Resistance的肝癌細胞Huh7/R其Dicer表現量較低。我們更發現在肝癌細胞株中，其對Sorafenib的IC50與Dicer的表現量有負相關的趨勢。進一步抑制肝癌細胞株的Dicer表現後細胞也會對Sorafenib產生抗藥性。我們的實驗結果指出Dicer會調控Sorafenib對肝癌細胞的作用。
Liver cancer is one of the most common cancers, and has high mortality worldwide. About 85% of liver cancer is hepatocellular carcinoma (HCC). Sorafenib is a small molecular inhibitor that targets to several tyrosine kinases and affects multiple cellular functions, including angiogenesis, proliferation, survival and metastasis. Although sorafenib is the standard treatment of advanced hepatocellular carcinoma, but not all of the HCC patients respond to sorafenib treatment and some patients can develop resistance after treatment of sorafenib for a few months. Therefore, it is needed to study the molecular mechanisms of sorafenib resistance in HCC. Dicer is an important enzyme in microRNA processing and is involved in regulation of tumor progression of different types of cancer. In this study, we found that dicer is downregulated in sorafenib-resistant Huh7 (Huh7/R) hepatoma cells. We also found the IC50 of sorafenib is reversely correlated with dicer expression in hepatoma cell lines. Furthermore, knockdown of dicer decreases the anti-tumor activity of sorafenib in HCCs. Our data indicate that dicer may play a critical role in the treatment of sorafenib of HCCs.
