ERK/PKM2信号轴介导的上皮细胞糖酵解在牙源性角化囊肿发展中的作用及机制研究

Odontogenic keratocyst (OKC) is the one of highly aggressive lesions in jaws. Recent documents have confirmed that the PKM2-mediated glycolysis contributes to the progression of various diseases. Our preliminary investigation has showed the significantly increased expression of PKM2 in the OKC. Moreover, we have found that the direct interaction between ERK and PKM2, which might be the important mechanism for the expression and activation of PKM2, and the development of OKC. Thus, the present project is designed to further investigate: (1) the expression and distribution of PKM2 and other glycolysis-related proteins in the epithelial cells of OKC; (2) the underlying mechanism by which ERK regulates the expression and activation of PKM2 in epithelial cells of OKC, and the influence on the glycolysis; (3) the potential feasibility and validity of PKM2-targeting in treating OKC. Our research will further uncover the cell energy metabolism features during the development of OKC, and would be beneficial for developing novel therapeutic strategies against cystic lesions in jaws.

牙源性角化囊肿是一种侵袭性较强的颌骨囊性病变。近来文献认为PKM2介导的细胞糖酵解水平异常升高是导致疾病发展的重要因素。本项目预实验结果已证实，牙源性角化囊肿上皮细胞中PKM2表达显著上调。此外，我们还发现ERK可与PKM2直接结合，并调控上皮细胞中PKM2的表达水平和酶活性。ERK/PKM2信号轴的激活可能是调控牙源性角化囊肿上皮细胞能量代谢的重要机制，并参与疾病的发展。本项目旨在进一步研究：(1)PKM2等糖酵解相关分子在牙源性角化囊肿组织中的表达及分布；(2)牙源性角化囊肿上皮细胞中ERK调控PKM2的具体分子机制，及其对细胞糖酵解水平的影响；(3)探讨靶向PKM2抑制糖酵解治疗牙源性角化囊肿的可行性及有效性。本项目的成功实施将有助于揭示牙源性角化囊肿发病过程中的能量代谢变化，并为开发治疗颌骨囊性病变的新疗法提供理论依据。

2019年，本人获得国家自然科学基金青年基金，该基金题目是：ERK/PKM2信号轴介导的上皮细胞糖酵解在牙源性角化囊肿发展中的作用及机制研究。牙源性角化囊肿（dontogenic keratocyst, OKC），以往称为牙源性角化囊性瘤，是一种常见的颌骨囊性病变，其生长缺乏自限性，局部浸润性较强，术后复发率较高。目前，临床上针对牙源性角化囊肿的治疗方式仍存在争议，且停滞不前，根本原因在于有关该囊肿的致病因素仍不清楚。在该项基金的支持下，针对牙源性角化囊肿的特点，本课题组进行了与基金密切相关的研究。目前取得的进展是：(1)牙源性角化囊肿上皮细胞中的PKM2的表达水平显著升高；体外培养的人牙源性角化囊肿上皮细胞以及成纤维细胞中PKM2 的表达也较人口腔黏膜细胞明显上调。(2) 展示了PKM2等糖酵解相关分子在牙源性角化囊肿组织中的表达及分布。(3)探讨PKM2调控的牙源性角化囊肿骨吸收的可能机制。(4)探讨糖酵解关键酶PKM2作为牙源性角化囊肿治疗靶点的可能性。总之，我们的研究表明，糖酵解在OKC中被激活，而PKM2介导的糖酵解调节OKC的生长和局部侵略性。目前该文章已发表在The American Journal of Pathology （二区Top）上。题目为：Increased M2 Isoform of Pyruvate Kinase in Fibroblasts Contributes to the Growth, Aggressiveness, and Osteoclastogenesis of Odontogenic Keratocysts。在这篇文章中，本项目为第一标注，本人为通讯作者。这篇SCI论文与该项目密切相关。另外，2020-2021年，在本项目的实践中，还有两篇标注该项目基金号的SCI论文获得接收（一篇二区Top，一篇三区）。分别发表于The American Journal of Pathology（二区Top）和 Journal of Histochemistry & Cytochemistry（三区）。这些研究也与糖代谢及PKM2密切相关。扩展了课题研究范畴。