多学科交叉探究UBE2S对人结直肠癌发生发展的促进及其调控机制

Colorectal cancer seriously threats human health. Development of new drugs with high efficiency and low toxicity is very important to improve the curative effect of colorectal cancer. Abnormal accumulation of β-Catenin in Wnt/β-Catenin signaling pathway leads to continuous activation of the pathway, which is the most extensive and early event resulting in colorectal cancer. Inhibiting this abnormality could effectively curb the malignant development of colorectal cancer. However, to obtain drugs specifically targeting this abnormality in colorectal cancer is restricted by limited understanding of specific factors regulating β-Catenin and the mechanism underlying this regulation. Most recently, our group identified Ubiquitin conjugating enzyme E2 S (UBE2S) as a novel regulator of β-Catenin. We demonstrated that it inhibits β-Catenin degradation and promotes the proliferation and metastasis of colorectal cancer cells, suggesting that UBE2S is a potential therapeutic target for malignant colorectal cancer treatment. This project focuses on examining this hypothesis using interdisciplinary methods combining cell biology, molecular biology, medicine and biostatistics. We aim to reveal the molecular mechanism underlying UBE2S-mediated regulation of β-Catenin stability and confirm whether UBE2S can serve as a novel cure target for a better treatment of colorectal cancer in future.

结直肠癌严重威胁人类生命健康，研发高效、低毒的新药物对提高结直肠癌的疗效至关重要。研究发现，Wnt/β-Catenin信号通路中β-Catenin降解异常，导致通路持续激活，是导致结直肠癌发病的最广泛的早期事件。抑制该异常是有效遏制结直肠癌恶性发展的突破口，然而获取结直肠癌细胞Wnt/β-Catenin信号通路特异性靶向药物，受限于β-Catenin特异调控因子的发现及其调控机制的研究。我们的前期研究发现了β-Catenin新的调控因子——泛素化缀合酶UBE2S，并进一步证明UBE2S通过抑制β-Catenin降解，进而促进结直肠癌细胞的增殖和转移，暗示着UBE2S是潜在的遏制结直肠癌恶性发展的治疗靶点。项目将采用细胞生物学、分子生物学、医学和生物统计学多学科交叉的研究方法，进一步揭示UBE2S对人结直肠癌发生发展的促进及调控机制，为UBE2S作为结直肠癌治疗新靶点提供重要依据。

结直肠癌严重威胁人类生命健康，研发高效、低毒的新药物对提高结直肠癌的疗效至关重要。研究发现，Wnt/β-Catenin信号通路中β-Catenin降解异常，导致通路持续激活，是结直肠癌发病的最广泛、最早期事件。抑制该异常是有效遏制结直肠癌恶性发展的突破口，然而获取结直肠癌细胞Wnt/β-Catenin信号通路特异性靶向药物，受限于β-Catenin特异调控因子的发现及其调控机制的研究。本课题通过系统深入研究结直肠癌病人UBE2S和β-Catenin的表达调控机制，首次明确了UBE2S在结直肠癌病人发病及恶性度决定过程中的关键作用，并将其界定成为潜在的结直肠癌治疗新靶点。同时，通过系统细致的生化研究，我们将UBE2S和β-Catenin相互作用的具体氨基酸区段缩短至47个氨基酸片段，为将来抑制性药物分子的合成、选择和优化决策提供必要的数据。截至目前，在本项目资助下，我们已经发表高水平SCI论文4篇，专利申请递交受理2份，培养博士、硕士研究生7名，圆满完成所有申请预定目标。