lncRNA-LNMICC介导的肿瘤相关巨噬细胞代谢应激促进宫颈癌淋巴结转移

Lymph node metastasis is the primary cause of cervical cancer death. Numerous studies have shown that the reprogramming of macrophage phenotype can promote tumor metastasis.Its underlying molecular mechanisms, however, remain poorly understood. In our preliminary experiments, we observed that lncRNA-LNMICC was highly expressed in M2 TAM. And knockdown of LNMICC clearly triggered macrophage reprogramming from M2 phenotype towards an M1 phenotype and thus, significantly reduced metastatic ability of cervical cancer cells and lymphangiogenesis. Our previous studies also confirmed that lncRNA-LNMICC promoted lymph node metastasis of cervical cancer through taking part in cancer metabolism reprogramming. Therefore, our present project determines to further clarify the mechanisms of LNMICC in activating the EMT of cervical cancer cells and inducing lymphangiogenesis by regulating the metabolic of arginine and fatty acids in arousing M2 TAM. This project might reveal certain new mechanisms of lymph node metastasis from the perspective of cellular metabolic stress mediated by lncRNA in TAM, and provide novel biomarkers and strategies for achieving individualized precision treatment of cervical cancer, thus improving the overall prognosis of the disease.

淋巴结转移是导致宫颈癌患者死亡的主要原因。研究发现肿瘤相关巨噬细胞（TAM）表型重编程可促进肿瘤转移的发生。然而，TAM调控宫颈癌淋巴结转移的具体机制尚未阐明。我们预实验发现lncRNA-LNMICC在M2型TAM中显著高表达，抑制其表达可将M2型TAM逆转回M1型，进而抑制宫颈癌细胞转移及新生淋巴管生成。前期研究也证实LNMICC参与代谢重塑促进宫颈癌转移。由此我们推测：LNMICC可能通过介导TAM代谢应激变化使其表型重编程，进而促进宫颈癌发生淋巴结转移。因此，本项目拟进一步阐明LNMICC通过调控TAM精氨酸酶代谢及脂肪酸氧化应激变化，唤醒M2型TAM，从而激活宫颈癌细胞EMT及诱导淋巴管生成，促进宫颈癌淋巴结转移的机制。本研究将从lncRNA调控肿瘤相关巨噬细胞代谢应激的角度，揭示宫颈癌发生淋巴结转移的新机制，为宫颈癌患者的个体化精准治疗和预后改善提供潜在新靶标和新视角。

淋巴结转移是导致宫颈癌患者死亡的主要原因；鉴定关键调控性非编码RNA及其作用机制，阐明肿瘤代谢及免疫逃逸机制，将为宫颈癌淋巴结转移提供新的新靶标和新视角。围绕该主线，本项目取得的主要成果包括：1.lncRNA-LNMICC在M2型TAM中显著高表达，抑制其表达可将M2型TAM逆转回M1型，进而抑制宫颈癌细胞转移及淋巴管生成；环状RNA hsa_circ_0043280在宫颈癌中低表达，并可作为分子海绵吸附miR-203a-3p，阻止miR-203a-3p介导的PAQR3的下调，抑制宫颈癌细胞的侵袭能力，进而抑制宫颈癌的淋巴结转移（Cell Death Dis，2021）；通过对正常组织以及宫颈癌组织进行circRNA芯片检测，构建参与宫颈癌进展的重要circRNA分子网络，并证实hsa_circ_0002157在肿瘤迁移、侵袭中的重要作用（Genomics，2022）。2.巨噬细胞介导的免疫逃逸是驱动宫颈癌淋巴结转移的重要因素。LNMAS通过竞争性结合HMGB1阻止TWIST1和STC1基因的染色质可及性，抑制TWIST1介导的部分上皮间质转化并促进STC1依赖性的巨噬细胞吞噬作用，进而抑制宫颈癌的淋巴结转移（Oncogene，2022）。3.肿瘤代谢研究方面，我们研究发现，FABP5在淋巴结转移的宫颈癌组织中高表达，并与患者的生存预后相关。FABP5通过促进脂质分解和脂肪酸合成，增加细胞内游离脂肪酸含量，从而激活NF-κB信号通路介导的淋巴血管生成，促进宫颈癌的淋巴结转移（Theranostics，2020）。4.肿瘤干细胞特性维持是肿瘤转移的重要原因。宫颈癌细胞中TAB2的表达上调引起干性基因SOX2的高表达，促进肿瘤细胞增殖和细胞干性，导致肿瘤的进展（Stem Cells Int，2021）。这些研究成果揭示了宫颈癌淋巴结转移的新机制，为临床宫颈癌患者的精准治疗提供了潜在的新靶点。项目资助发表通讯作者论文6篇，发明专利2项。