黄连素基于脂肪微环境介导PLOD2/PGK1调控糖代谢重编程抗三阴乳腺癌转移作用机制研究

代谢重编程与肿瘤恶性进展密切相关。肿瘤微环境对代谢的影响日益受到重视，乳腺最重要的微环境成分—脂肪细胞对恶性程度最高的三阴乳腺癌（TNBC）的代谢调控作用尚未阐明。已报道中药黄连的活性成分—黄连素具有调节糖脂代谢及抗肿瘤功效。申请者前期发现：脂肪微环境通过上调PLOD2/PGK1促进TNBC糖酵解代谢，黄连素在微环境中逆转PLOD2介导的TNBC糖酵解和转移。申请者推测：黄连素在脂肪微环境中抑制PLOD2/PGK1介导的TNBC糖酵解代谢，从而发挥抗TNBC转移作用。为了验证该假说，本项目拟从肿瘤代谢异常入手，在分子、细胞、整体动物及临床样本水平等多层次研究PLOD2调控TNBC代谢重塑的机制；基于该理论，阐明黄连素基于脂肪微环境中PLOD2/PGK1逆转TNBC转移的作用机制。本研究将揭示PLOD2在TNBC代谢重编程和转移中的作用机制，并为黄连素治疗TNBC提供理论依据。

Metabolic reprogramming is associated with cancer progression. Nowadays, tumor microenvironment has been paid more and more attention as its effect on cancer metabolism. Although adipocytes are the main stromal cells in mammary gland, the effect of adipocytes on TNBC metabolism is unknown. Berberine is the main active ingredients of Coptis chinensis, which has been found to regulate glucose and lipid metabolism and exert antitumor effects. Recently, we found adipocytes promoted glycolytic metabolism via activating PLOD2 in TNBC cells. Meanwhile, Berberine reversed PLOD2 expression and glycolytic metabolism in adipocyte-breast cancer microenvironment. Thus, we speculate PLOD2 may regulate PGK1 in glycolytic metabolism to promote TNBC metastasis, while Berberine may inhibit the role of microenvironment on PLOD2 to inhibit TNBC glycolytic metabolism and metastasis. In this project, we are going to investigate the effect of PLOD2 on TNBC metastasis at molecular, cellular, animals and clinical levels, which begins with tumor metabolic abnormality. Meanwhile, we intended to comprehensively evaluate anti-metastasis effect of Berberine on the theoretical basis of adipocyte-breast cancer microenvironment. The study will provide a theoretical basis for the role of PLOD2 in TNBC metabolic reprogramming and metastasis, and will provide a new idea for the treatment of TNBC, and providing a framework for developing of Berberine.