表观因子SMYD2所调控的异常在肝癌索拉非尼治疗耐药过程中的作用和分子机制的研究

The tyrosine kinase inhibitor sorafenib is a promising strategy for patients with advanced hepatocelluar carcinoma(HCC). However, in both preclinical and clinical settings, the benefits are at best transitory and are following by a restoration of tumour growth and progression. Multiple mechanisms can be invoked to manifest resistence, including epigenetic alterations, which play key roles in the initiation, development and recurrence of liver cancer. Thus, we aim to motivate assessment of the prevalence and importance of epigenetic alterations in sorafenib resistence and in turn to use adjuvant therapy along with sorafenb in order to obtain long-term clinical remissions. Our expression analysis of epigenetic modifiers by qPCR array showed that expression levels of SMYD2 are significantly elevated in human hepatoma cells after sorafenib treatment. More importantly, the combination of AZ505, a novel SMYD2 inhibitor, and sorafenib restord the sensitivity of resistant cells to sorafenib-induced cell growth arrest and apoptosis. This project will expand experimental samples range from cell lines to animal model to further explore the mechanism of SMYD2 expression regulated by sorafenib, and to examine the effect of dysregulated SMYD2 on acquired resisitence to sorafenib by promoting cell growth, survival, invasion, metastasis, and antiangiogenesis. By collecting relevant cases, this project also will valid relevance between sorafenib resistence and expression of SMYD2. Thus, this project will provide a novel mechanism of resistence to sorafenib and help to explore innovative combined therapies for overcoming this resistance in advanced-stage HCC.

随着索拉非尼等靶向药物在晚期肝癌治疗中的广泛应用，如何处理耐药引起的新一轮肿瘤生长和恶性进展成为新难题。而表观调控异常在肝癌的起始、进展和预后等方面发挥关键作用，成为治疗新靶点，因此我们期望通过研究索拉非尼治疗耐药中的表观调控异常来阐述耐药产生的分子基础。我们用索拉非尼处理肝癌细胞株，对肿瘤发展中起重要作用的多个表观调控因子进行表达图谱分析，发现组蛋白H3K4和H3K36的甲基化转移酶SMYD2的表达发生明显变化，且初步研究显示：小分子药物AZ505抑制SMYD2蛋白的活性可使耐药肝癌细胞对索拉非尼处理诱导的生长抑制和凋亡等作用更敏感。在该项目中我们将深入研究索拉非尼对SMYD2调控的分子机制，并从生长、凋亡、侵袭迁移和血管新生等方面研究异常表达的SMYD2对索拉非尼耐药的影响，最后将在裸鼠模型和肝癌病人标本中进一步验证，以期为合理化个性化用药、逆转耐药和开发耐药规避治疗策略奠定理论基础。