let-7调控DNA损伤修复因子SMARCAD1影响肾癌化疗敏感性的机制研究

Renal cell carcinoma (RCC) is a common form of urologic tumor, with a high metastatic index at the diagnosis and a high rate of relapse because of the resistance to chemotherapies. However, the molecular mechanism of chemoresistence of renal cell carcinoma was still largely unknown, and is the research focus of this project. In our preliminary results, we found several stem cell factors (c-Myc and Lin28) and the let-7 family of microRNAs were dysregulated in RCCs. A regulatory network including c-Myc, Lin28 and let-7 plays a critical role in regulating several target genes. In this project, we identified SMARCAD1 as a novel let-7 microRNA target. This gene encodes a member of the SWI/SNF subfamily of helicase proteins, and plays an important role in chemotherapy drug-induced DNA damage response. We will explore the potential role of c-Myc/Lin28/let-7/SMARCAD1 regulatory loop and chemotherapy drug-induced DNA damage response or apoptosis at the molecular, cellular and pathological levels. Targeting this novel pathway may be helpful for effective therapeutic strategies in RCC therapy.

肾癌属于对化疗非常不敏感的肿瘤。探索肾癌化疗不敏感性的分子机制，将为肾癌临床治疗新策略提供理论依据。我们在本项研究的前期工作中发现干细胞相关因子c-Myc、Lin28 和microRNA分子 let-7 家族在肾癌组织中异常表达。而在细胞内c-Myc、Lin28 和let-7 三者形成一个相互调控环路，调控许多重要靶基因的表达。我们已发现let-7可增强化疗药物诱导的肾癌细胞凋亡，通过生物信息学预测并验证了一个let-7的新靶基因SMARCAD1。SMARCAD1在化疗药物诱导的DNA 损伤修复过程起重要作用。我们将在分子、细胞和肿瘤病理等多个层次，利用荧光素酶报告、DNA损伤修复检测等技术，探讨肾癌中由c-Myc/Lin28/let-7/SMARCAD1 所组成的调控通路，与化疗药物诱导细胞DNA损伤修复或凋亡的内在关系，为揭示肾癌化疗不敏感性的机制提供有益的线索。

肾癌对化疗药物的“先天”不敏感性，导致复发转移的患者得不到有效的化疗， 因此探索其不敏感性的分子机制，将为优化肾癌临床治疗策略提供理论依据。我们前期工作 发现几个干细胞相关因子 Lin28、c-Myc、microRNA 分子 let-7 家族在肾癌中异常表达。而它们在细胞内相互间存在负反馈调控环路，调控许多重要靶基因。这引导我们发现 let-7 可增强化疗药物诱导的肾癌细胞凋亡，通过生物信息学预测并验证了一个 let-7 的新靶基因 SMARCAD1，它在化疗药物诱导的 DNA 损伤修复过程起重要作用。据此我们发现肾癌 Lin28/c-Myc/let-7 调控环路异常，致下游与 DNA 损伤修复相关的蛋白 SMARCAD1 表达上升， 增强了肾癌细胞对化疗药物诱导的 DNA 损伤修复能力，从而参与了肾癌化疗不敏感性机制的形成。我们利用荧光素酶报告、DNA 损伤修复检测等技术验证上述假设，为治疗肾癌提供化疗药物新靶点。