滑膜肉瘤乏氧微环境介导HIF-1α/miR-130a/FRZB-ASPN/CCL2通路招募巨噬细胞的机理研究

Synovial sarcoma tissue has a hypoxic microenvironment and recruits a large number of tumor-associated macrophages (TAMs). However, the specific mechanism has not been well clarified. Previous studies in our research group found that hypoxia or introduction of HIF-1α plasmid could up-regulate miR-130a and recruited macrophages; inhibition of miR-130a up-regulated FRZB expression; FRZB may interact with ASPN; inhibition of miR-130a under hypoxic conditions decreased CCL2 and reduced the recruitment of macrophage. This study will further explore the mechanism of that HIF-1α regulates miR-130a transcriptionally by targeting its promoter region; that miR-130a directly targets FRZB to reduce its expression, reduces interaction with ASPN protein and therefore increases the level of ASPN, further activates AKT signaling pathway to promote CCL2 secretion and at last recruits TAMs. Our work should reveal the recruitment and regulation of TAMs by HIF-1α/miR-130a/FRZB-ASPN/CCL2 pathway in hypoxic microenvironment of synovial sarcoma, and the significance of those key factors in the diagnosis and prognostic judgment of synovial sarcoma. It will provide theoretical and experimental basis for targeted therapy of synovial sarcoma.

滑膜肉瘤存在乏氧微环境并招募大量肿瘤相关巨噬细胞，而具体机制尚未明确。课题组前期研究发现乏氧条件或导入HIF-1α质粒可上调滑膜肉瘤miR-130a表达并招募巨噬细胞；抑制miR-130a可上调FRZB表达；FRZB可能与ASPN存在互作关系；乏氧条件下抑制miR-130a可逆转下调趋化因子CCL2并减少巨噬细胞招募。本研究将通过转录调控、转录后抑制、蛋白互作等层面进一步全面探索HIF-1α靶向启动子区上调miR-130a表达；miR-130a直接靶击FRZB减少其表达、降低与ASPN蛋白互作而增加ASPN水平，进一步激活AKT信号通路促进CCL2分泌招募巨噬细胞导致滑膜肉瘤恶化的机制。揭示滑膜肉瘤乏氧微环境中HIF-1α/miR-130a/FRZB-ASPN/CCL2通路对肿瘤相关巨噬细胞的招募调控，以及关键节点对滑膜肉瘤的诊断及预后判断意义，为滑膜肉瘤微环境靶向治疗提供新的实验依据。

肿瘤是一种系统性疾病，可导致体内多器官功能异常，特别肝脏。肝外转移倾向的肿瘤（如骨与软组织肿瘤：骨肉瘤、黑色素瘤等）无需转移至肝脏即可通过分泌细胞外囊泡和颗粒（EVP），包括各类亚型Exo-S、Exo-L和Exomere影响肝脏功能。通过抑制控制EVP分泌的关键因子Rab27a可减少脂肪肝形成。EVP在肝内主要由库普细胞（KC）摄取，其内包裹着活性物质棕榈酸（PA）可激活KC表面Tlr4并诱导KC分泌肿瘤坏死因子alpha（TNF-a），形成促炎微环境；TNF-a可抑制肝细胞（HC）脂肪酸代谢和氧化磷酸化、促进脂肪肝形成，同时抑制肝细胞内参与药物代谢的关键酶细胞色素P450（Cyp450），进而增强肿瘤化疗副作用之骨髓抑制和心脏毒性作用，引起化疗耐药。该研究揭示肿瘤通过Tb-EVP(PA)-KC-TNFa-HC-Cyp450/NAFLD引起化疗耐药的新机制，为抑制脂肪肝形成、增强化疗效果提供理论基础。