索拉非尼是目前被批准用于晚期肝细胞癌的唯一靶向治疗药物，耐药的出现严重影响了索拉非尼的疗效。上皮细胞间充质转化(EMT) 是肝癌转移的基础，也是肝癌耐药的关键过程。蛋白激酶D2(PKD2) 参与调控多种肿瘤的增殖、侵袭和耐药，但其是否与肝癌的索拉非尼耐药相关目前未见报道。我们以往的研究发现，PKD2参与调控肝癌的EMT；索拉非尼耐药肝癌细胞中，PKD2表达上调，且耐药细胞呈现EMT特征；下调耐药细胞PKD2的表达可以增加细胞对索拉非尼的敏感性。这些结果提示PKD2可能通过调节EMT，诱导肝癌细胞对索拉非尼耐药。本项目拟在前期基础上，探究PKD2调控的EMT对肝癌索拉非尼耐药的影响及其调节机制；探讨PKD2与临床索拉非尼耐药的相关性；并通过抑制PKD2活性探索耐索拉非尼肝癌的治疗。本研究将进一步阐明肝癌索拉非尼耐药的机制，为索拉非尼耐药的晚期肝癌治疗寻找新的靶点。

Sorafenib is the only targeted drug approved by US Food and Drug Administration for advanced hepatocellular carcinoma(HCC) . Sorafenib resistance significantly restricts the treatment effect of sorafenib on HCC. Epithelial mesenchymal transition (EMT)is a crucial process in tumor progression. EMT of tumor cells not only causes increased metastasis, but also contributes to drug resistance. Protein kinase D2(PKD2) plays an important and complicated role in cell proliferation,invasiveness as well as drug reisistance in many malignancies. However, little is known about the effect of PKD2 on drug resistance in HCC. We previously found that PKD2 regulated EMT of HCC both in vitro and in vivo. HCC cell lines with sorafenib resistance had upregulated expression of PKD2 and typical feature of EMT. We suppose that PKD2 could regulate sorafenib resistance of HCC through promoting EMT. We design to explore the role and mechanism of PKD2 in EMT and sorafenib resistance in HCC both in vitro and in vivo by artificial regulation of PKD2 expression using siRNA or plasmids. The relationship between PKD2 expression in clinical HCC tissue samples and sorafenib resistance as well as the prognosis of HCC patients will also be determined. Moreover, we will also investigate the effect of combination treatment of inhibitor of PKD2 and sorafenib in HCC both in vitro and in vivo. Our study would reveal a new regulatory mechanism in sorafenib resistance of HCC and may reveal new therapeutic targets for advanced HCC patients with sorafenib resistance.