脂肪酸代谢相关信号通路PRRX1/PPARG2动态调控口腔鳞癌EMT和侵袭转移的分子机制

Fatty acid metabolism reprogramming plays an important role in the invasion and metastasis of malignant tumors. Recently, PRRX1, one of homeobox genes, has been regarded to be an important transcription factor of EMT,but also it has been shown to mediate fat synthesis and fatty acid metabolism of adipocytes. Thus, based on our previous data of the relationship between EMT and the invasion and metastasis of oral squamous cell carcinoma (OSCC), we hypothesise that PRRX1/PPARG2 signaling pathway engages in EMT plasticity to contribute to the invasion and metastasis of OSCC through fatty acid metabolism reprogramming. From the new perspective of fatty acid metabolism reprogramming association with tumor EMT plasticity, this project will investigate the following questions: Whether can the balance between PRRX1 two isoforms (PRRX1a and PRRX1b) switch, and can the PRRX1 isoform switching play different roles during the PRRX1 regulating fatty acid metabolism reprogramming and EMT plasticity of OSCC? Which are the key genes,enzymes,proteins and signaling pathways during PRRX1/PPARG2 signaling pathway controlling fatty acid metabolism reprogramming in OSCC metastasis? How does fatty acid metabolism reprogramming dynamically engage in EMT plasticity to contribute to the invasion and metastasis of OSCC? The data of this project will have promising to yield a novel therapeutic strategy to the precision medicine for OSCC invasion and metastasis in the future.

脂肪酸代谢在肿瘤侵袭转移中发挥重要作用。最新发现，同源盒基因PRRX1不仅是一种新的EMT转录因子，而且其负性调控PPARG2的信号通路在脂肪细胞脂肪酸代谢中发挥关键作用。基于此，课题组在前期研究基础上提出假设：PRRX1/PPARG2通过驱动口腔鳞癌脂肪酸代谢重编程，调控EMT和MET动态转换，促进不同阶段侵袭转移。拟从肿瘤脂肪酸代谢重编程与EMT可塑性关系新维度，以PRRX1/PPARG2信号通路为把手，研究和明确在PRRX1调控口腔鳞癌脂肪酸代谢重编程从而影响EMT可塑性中，两个亚型PRRX1a和PRRX1b是否发挥不同作用？是否可相互转换？PRRX1/PPARG2通路通过下游哪些脂肪酸代谢关键分子、酶和信号通路影响肿瘤脂肪酸代谢，影响哪些EMT通路，进而动态调控侵袭转移不同阶段EMT和MET转换，协调与整合口腔鳞癌侵袭转移全过程？结果将为靶向口腔鳞癌侵袭转移的精准治疗提供新思路。

脂肪酸代谢在肿瘤侵袭转移中发挥重要作用。最新发现，同源盒基因PRRX1不仅是一种新的EMT转录因子，而且其负性调控PPARG2的信号通路在脂肪细胞脂肪酸代谢中发挥关键作用。基于此，课题组在前期研究基础上提出假设：PRRX1/PPARG2通过驱动口腔鳞癌脂肪酸代谢重编程，调控EMT和MET动态转换，促进不同阶段侵袭转移。结果显示：1)PRRX1与HNSCC侵袭前沿的细胞表型可塑性和肿瘤休眠密切相关；PRRX1高表达诱导HNSCC细胞的EMT和细胞休眠；PRRX1的缺失使EMT转化为MET，并激活休眠细胞；PRRX1与激活的TGF-β1协同促进EMT；HNSCC细胞中PRRX1靶向调控miR-642b-3p；miR-642b-3p介导PRRX1诱导的HNSCC细胞休眠和EMT；miR-642b-3p通过TGF-β2和p38抑制HNSCC细胞休眠；PRRX1过表达诱导裸鼠移植瘤肿瘤休眠和EMT。2)PRRX1与唾液腺腺样囊性癌患者游离脂肪酸积聚呈正相关；PRRX1诱导EMT促进唾液腺腺样囊性癌细胞迁移和侵袭；PRRX1诱导SACC细胞游离脂肪酸的积聚；FFAs处理后PPARG2下调导致PRRX1上调；游离脂肪酸通过Src和MMP-9依赖途径诱导Stat5-DNA结合活性增加；PRRX1和PPARG2促进裸鼠移植瘤SACC肺转移。3)在hADSCs成软骨分化的研究表明，PRRX1促进细胞基质糖胺聚糖以及ADSCs细胞基质聚集蛋白多糖的合成，促进ADSCs细胞基质II型胶原的合成。结果将为靶向口腔鳞癌侵袭转移的精准治疗提供新思路。