PIM2介导PFKFB3磷酸化调控乳腺癌糖酵解及紫杉醇耐药性的分子机制研究

乳腺癌（BC）是全球女性最常见的恶性肿瘤，化疗药物抵抗是导致BC治疗失败继而引起肿瘤复发和转移的主要原因。有研究表明糖酵解与BC进展及其耐药密切相关，PFKFB3作为糖酵解关键调节因子在此过程中发挥重要调控作用，但具体机制尚不明确。项目组前期研究证实BC紫杉醇耐药株中PFKFB3异常高表达，且PIM2能够与其相互结合并改变其特定位点磷酸化，促进其蛋白稳定性表达，并进一步促进BC增殖。其它研究证实PIM2与BC药物抵抗密切相关。据此，我们提出科学假说“BC中PIM2介导PFKFB3磷酸化调控糖酵解和紫杉醇耐药性，促进肿瘤进展”。通过深入了解PIM2与PFKFB3的相互作用、PIM2对PFKFB3的磷酸化及蛋白稳定性调控、PFKFB3修饰后对乳腺癌的生物学功能糖酵解及耐药性影响，阐明PFKFB3通过糖酵解调控BC进展及其耐药的潜在分子机制，为临床BC的靶向治疗提供新的研究思路。

Breast cancer (BC) is the most common malignancy in women worldwide. Chemotherapeutic resistance is the major cause of BC therapy failure, leading to tumor recurrence and metastasis. Studies have shown that glycolysis was closely related to BC progression and drug resistance. The key glycolysis regulator, PFKFB3 plays an important role during BC progression and drug resistance. However, the mechanism remains to be unknown. Our team have confirmed that PFKFB3 were highly expressed in the paclitaxel BC resistant strains.We pre-experiments have also confirmed that PIM2 was a new binding protein of PFKFB3, which could mediate PFKFB3 specific site phosphorylation to promote its stable expression, and which further to promote BC proliferation. Other studies have reported that PIM2 was closely related to BC drug resistance. According to the evidences we could infer that PIM2 mediates PFKFB3 phosphorylation thus regulates glycolysis and paclitaxel resistance to promote tumor progression in BC. We will focus on the specific mechanism of interaction between PIM2 and PFKFB3 in BC, the molecular mechanism by which PIM2 phosphorylates PFKFB3 in regulating the protein function, and the effects of PFKFB3 modification on biological function, glycolysis and drug resistance in BC. This work will unravel the mechanism responsible by which PFKFB3 regulates tumor progress through glycolysis in BC and provide a new strategy for targeted therapy on BC.