LASS2通过神经酰胺通路增加膀胱癌干细胞顺铂敏感性的研究

膀胱癌是泌尿系统最常见的恶性肿瘤之一，基于顺铂的化疗广泛用于根治性膀胱切除术后辅助治疗，但大部分患者最终会出现化疗抵抗。因此，进行膀胱癌化疗抵抗的机制研究，探索新的化疗增敏方案，是目前膀胱癌研究领域的重要方向。我们的前期工作和该领域的研究进展表明，LASS2表达水平与膀胱癌细胞对顺铂的敏感性密切相关，而LASS2参与神经酰胺合成并可能调节神经酰胺代谢相关酶，神经酰胺通路可能对维持肿瘤干细胞的干性和耐药性起重要作用。据此我们提出科学假设：LASS2通过抑制神经酰胺通路来增加膀胱癌干细胞对化疗药物的敏感性。本项目拟在研究LASS2和化疗抵抗相关性的基础上，阐明LASS2对膀胱癌干细胞自我更新能力、致瘤性和耐药性影响，并进一步探究LASS2对膀胱癌干细胞的影响是否依赖于神经酰胺通路。本项目的预期结果，有助于加深对膀胱癌化疗抵抗机制的理解，为膀胱癌化疗增敏提供新的依据和思路。

Bladder cancer is one of the most common urological malignancy. Cisplatin-based combination chemotherapy is widely used for the bladder cancer treatment after radical cystectomy, but most patients will suffer chemotherapy resistance. Thus, for a new method of chemotherapy-sensitization, it is of great importance to investigate the mechanism of chemotherapy resistance. Emerging data suggest that the expression of LASS2 is related to chemotherapy resistance of cisplatin, and LASS2 is required for the ceramide synthesis and regulates the enzyme involved in ceramide metabolic pathway. In addition, ceramide metabolic pathway may be closely associated with self-renewal and chemotherapy resistance of cancer stem cells. Thus, we hypothesize that LASS2 enhances the drug susceptibility of bladder cancer stem cells through inhibiting ceramide pathways. Then, we intend to investigate the effect of LASS2 on the self-renewal, tumorigenesis and drug-resistance of bladder cancer stem cells based on the correlations between cisplatin resistance and LASS2. Then we explore the molecular mechanism of ceramide metabolic pathway in the LASS2 effect and preliminarily evaluate the chemotherapy-sensitization function of overexpressing LASS2. This project will help to clarify the new mechanism of bladder cancer chemotherapy resistance and will provide new data and ideas for the sensitization of bladder cancer chemotherapy.