CD44对前列腺癌葡萄糖代谢的调控作用及其分子机制的研究

The incidence of prostate cancer increased markedly in recent years in China. There are no effective treatments for androgen resistant and metastatic prostate cancer. Malignant cells have unique features of glucose metabolism which is associated with their biological actions. CD44 has been proved to play an important role in the processes of tumorigenesis, invasion and metastasis. The results of our previous study indicated CD44 could regulate glucose consumption of prostate cancer cell lines. However, the regulatory functions and mechanisms of CD44 in glucose metabolic pathway remain unclear. This project tries to clarify the regulatory mechanism of CD44 in glucose metabolism of prostate cancer through the studies of molecular targeted therapy; in vivo and in vitro experiments. The metabolic genes regulated by CD44 will be identified, and the influence of glucose metabolism pathway on invasion, adhesion and migration of prostate cancer cells will be clarified via in vitro cell experiments. The studies of xenograft tumor model were performed to investigate the regulatory mechanism of CD44 in glucose metabolism and the change of oncologic features in vivo. The studies on targeted therapy will further confirm CD44 is a critical molecule involved in regulation of glucose metabolism. The antineoplastic effects of CD44 inhibitor/glucose intake inhibitor and the synergic effects combined with chemotherapy agents will be researched as well. The important significance of our project is to clarify the overall characters and difference of glucose metabolism in various type of prostate cancer, regulatory mechanism of CD44 and potential molecular targets for treatment of late stage prostate cancer.

近年来国内前列腺癌的发病率显著增高，晚期前列腺癌尚无满意的治疗方法。肿瘤细胞具有独特的葡萄糖代谢特点并与其生物学行为密切相关。CD44已被证实在肿瘤的发生，侵袭及转移过程中发挥了重要作用，我们前期研究显示CD44可调节前列腺癌细胞葡萄糖消耗量，但其对糖代谢的调节机制尚不清楚。本项目拟从体内，体外实验和靶向治疗三方面研究CD44对前列腺癌糖代谢活性的调控机制。细胞实验研究CD44对糖代谢相关基因的调控及糖代谢活性变化对细胞侵袭，粘附和转移的影响；裸鼠移植瘤模型研究阐明CD44在体内调控肿瘤糖代谢活性的分子机制及肿瘤生物学特性的变化；通过特异性抑制靶向分子进一步证实CD44是调节糖代谢关键分子之一，阐明CD44抑制剂/糖代谢抑制剂的抗肿瘤效应及其与化疗药物的协同作用的分子机制。本研究对全面阐明前列腺癌的糖代谢特点，揭示CD44对糖代谢活性的调控机制以及寻找潜在的分子治疗靶点具有十分重要的意义。

近年来国内前列腺癌的发病率显著增高，激素抵抗性和转移性前列腺癌尚无满意的治疗方法。肿瘤细胞具有独特的葡萄糖代谢特点并与其生物学行为密切相关。CD44已被证实在肿瘤的发生，侵袭及转移过程中发挥了重要作用，但其对整体糖代谢途径的调节作用和机制尚不清楚。本项目通过细胞学，动物学和药物协同及敏感性实验全面阐述了激素依赖性前列腺癌（LNCaP）和激素非依赖性前列腺癌（PC-3）具有不同的糖代谢特点和代谢途径，CD44介导的PDK1和PFKFB4表达水平对前列腺癌细胞和实体肿瘤的增殖，侵袭和迁移等生物学特性变化起到了关键作用，上述研究结论在LNCaP-AI细胞的建立和激素非依赖性转化过程中得到了进一步验证。研究筛选出来的CD44，PDK1和PFKFB4糖代谢相关基因可作为治疗去势抵抗性前列腺癌的潜在靶点，沉默CD44， PDK1和PFKFB4的表达可显著降低前列腺癌细胞和移植瘤的增殖，侵袭和迁移能力，并且沉默PFKFB4和CD44抑制剂还可提高前列腺癌细胞对传统化疗药物的敏感性。本项目在专业领域内较早关注葡萄糖代谢在去势抵抗性性前列腺癌发生发展过程中的作用和特点，研究成果在国内外期刊上发表多篇论文。项目成果丰富了去势抵抗性前列腺癌激素非依赖性转化的分子理论，证实了糖代谢相关基因作为治疗去势抵抗性前列腺癌潜在靶点的可行性和有效性，为下一步深入临床研究和应用提供了坚实的理论依据和实验基础。