lncRNA RP11-363E6.3调控FABP5介导的脂肪酸代谢重塑促进宫颈癌淋巴结转移

Lymph node metastasis is the major cause of death in early-stage cervical cancer. Studies have shown that the reprogramming of fatty acid metabolism can promote metastasis of lymph node in a variety of malignant tumors. In our previous work, fatty acid binding protein 5 (FABP5) which a central regulatory molecule of fatty acid metabolism ,can promote lymph node metastasis of cervical cancer. Preliminary experiments found that knockdown of lncRNA RP11-363E6.3 suppressed FABP5, resulted in aberrant expression of key enzymes of fatty acid metabolism and significantly reduced metastatic ability of cervical cancer cells. Thus we assume that lncRNA RP11-363E6.3 regulates FABP5-mediated reprogramming of fatty acid metabolism to promote lymph node metastasis in cervical cancer. Therefor, this project intends to further clarify the role of FABP5-mediated reprogramming of fatty acid metabolism in lymph node metastasis promoted by lncRNA RP11-363E6.3; to establish the mechanism of lncRNA RP11-363E6.3 activating EMT and PPARδ/VEGF through reprogramming of fatty acid metabolism. This study reveal new mechanisms of lymph node metastasis from the perspective of fatty acid metabolism reprogromming mediated by lncRNA, and provide a new strategy for achieving individualized precision treatment of cervical cancer as well as improving its overall prognosis.

淋巴结转移是早期宫颈癌致死的主要原因。研究表明脂肪酸代谢重塑可促进多种恶性肿瘤发生淋巴结转移。我们前期工作证实脂肪酸代谢中枢调控分子脂肪酸结合蛋白5（FABP5）可促进宫颈癌淋巴结转移；预实验发现干扰lncRNA RP11-363E6.3可抑制FABP5，导致脂肪酸代谢关键酶表达失常，使得宫颈癌细胞侵袭迁移能力显著降低。由此我们假设：lncRNA RP11-363E6.3可调控FABP5介导的脂肪酸代谢重塑，从而促进宫颈癌淋巴结转移。为此，本项目拟进一步明确FABP5介导的脂肪酸代谢重塑在lncRNA RP11-363E6.3促进宫颈癌淋巴结转移中的作用；阐明lncRNA RP11-363E6.3通过脂肪酸代谢重塑激活EMT及PPARδ/VEGF通路的调控机制。本研究从lncRNA调控脂肪酸代谢重塑的角度揭示宫颈癌淋巴结转移的新机制，为实现宫颈癌个体化精准治疗，提高患者整体预后提供新策略。

淋巴结转移是宫颈癌患者死亡的主要原因。研究表明脂肪酸代谢重塑可促进多种恶性肿瘤发生淋巴结转移，但在宫颈癌中的机制尚不明确。我们的前期工作发现，脂肪酸代谢调控分子脂肪酸结合蛋白5（FABP5）可促进宫颈癌淋巴结转移，干扰lncRNA RP11-363E6.3可抑制FABP5，使得宫颈癌细胞侵袭迁移能力显著降低。本项目对lncRNA RP11-363E6.3（LNMICC）在宫颈癌转移过程中的作用和调控脂肪酸代谢重塑的机制进行了探究。研究结果显示：1、LNMIC在宫颈癌组织中高表达，与淋巴结转移相关，并且提示不良生存预后；2、LNMICC在细胞模型和动物模型中可以促进宫颈癌淋巴结转移；3、LNMICC通过调控FABP5介导的脂肪酸代谢重塑，促进宫颈癌细胞发生EMT和淋巴管新生；4、LNMICC通过募集NPM1到FAPB5启动子区域，促进FABP5的表达；5、MiR-190通过结合LNMICC，抑制LNMICC的表达。本项目有助于揭示宫颈癌淋巴结转移的新机制，为宫颈癌的临床治疗提供新的干预靶点