长链非编码RNA FILNC1介导的有氧糖酵解和M1型肿瘤相关巨噬细胞组蛋白乳酸化修饰在食管鳞癌进展中的作用及其分子机制

LncRNA FILNC1在调节肿瘤糖代谢中发挥重要作用，但其在食管鳞癌中的作用尚不明确。预实验结果表明，食管鳞癌中低FILNC1组患者预后较差；食管癌细胞下调FILNC1可升高LDHA表达水平及乳酸生成量，并可促进其增殖、迁移和浸润，其上清可促使M1型巨噬细胞向M2型转化，同时增加M1细胞组蛋白乳酸化水平；且食管癌样本中低FILNC1肿瘤微环境中M2巨噬细胞数目显著增多。由此，申请者推测FILNC1可能通过能量代谢重编程调控食管鳞癌细胞肿瘤生物学行为；增加肿瘤细胞分泌乳酸促进肿瘤微环境中M1巨噬细胞组蛋白乳酸化修饰，使其从M1向M2型极化，加速食管鳞癌进展。为证实该假说，本项目拟通过组织标本、细胞实验及动物模型探讨FILNC1调控食管鳞癌细胞生物学的机制，揭示其在介导M1型巨噬细胞向M2型巨噬细胞转化过程中的分子机制。该研究有望揭示食管鳞癌进展新的调控机制，为食管鳞癌靶向治疗提供新策略。

LncRNA FILNC1 plays an important role in regulating glucose metabolism in tumors, but its definite function in Esophageal Squamous Cell Carcinoma(ESCC) is still unclear. Preliminary experimental results showed that the low FILNC1 group of patients with ESCC carcinoma had poorer prognosis. Down-regulation of FILNC1 in esophageal cancer cell lines can increase its LDHA expression level and lactic acid production level, and promote its proliferation, migration and infiltration. Its supernatant can promote the transformation of M1-type macrophages into M2-type macrophages, and increase the histone lactating level in M1 cells. Moreover, the number of peri-tumoral M2 macrophages significantly increased in the low FILNC1 ESCC samples. Thus, we Speculate that FILNC1 might influence the biological behavior of esophageal squamous cell carcinoma cells through reprogramming the energy metabolism; lactic acid is secreted to promote the lactating modification of histone in M1 macrophage, which further induce the polarization from M1 type to M2 type, and accelerate the progress of ESCC. To confirm this hypothesis, this project intends to explore the regulatory mechanism of FILNC1 on the biological behavior of ESCC through clinical specimens, cell experiments and animal models, and to analyze the molecular mechanism of FILNC1 in mediating the transformation of m1-type macrophages into m2-type macrophages. This study is expected to reveal a new regulatory mechanism for the development of ESCC and lay a foundation for molecular targeted therapy of ESCC.