Department of Thoracic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan, 430022, Hubei, China.
Department of Traditional Chinese Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan, 430022, Hubei, China.
J Exp Clin Cancer Res. 2023 Nov 2;42(1):289. doi: 10.1186/s13046-023-02871-2.
TAMs (tumor-associated macrophages) infiltration promotes the progression of esophageal cancer (EC). However, the underlying mechanisms remain unclear.
Abnormal expression of LINC01592 from EC microarrays of the TCGA database was analyzed. LINC01592 expression level was validated in both EC cell lines and tissues. Stable LINC01592 knockdown and overexpression of EC cell lines were established. In vitro and in vivo trials were conducted to test the impact of LINC01592 knockdown and overexpression on EC cells. RNA binding protein immunoprecipitation (RIP), RNA pulldown assays, and Immunofluorescence (IF) were used to verify the combination of E2F6 and LINC01592. The combination of E2F6 and NBR1 was verified through the utilization of ChIP and dual luciferase reporter assays.
LINC01592 is carried and transferred by exosomes secreted by M2-TAMs to tumor cells. The molecular mechanism underlying the promotion of NBR1 transcription involves the direct binding of LINC01592 to E2F6, which facilitates the nuclear entry of E2F6. The collaborative action of LINC01592 and E2F6 results in improved NBR1 transcription. The elevation of NBR1 binding to the ubiquitinated protein MHC-I via the ubiquitin domain caused a higher degradation of MHC-I in autophagolysosomes and a reduction in MHC-I expression on the exterior of cancerous cell. Consequently, this caused cancerous cells to escape from CD8 CTL immune attack. The tumor-promoting impacts of LINC01592, as well as the growth of M2-type macrophage-driven tumors, were significantly suppressed by the interruption of E2F6/NBR1/MHC-I signaling through the effect of siRNA or the corresponding antibody blockade. Significantly, the suppression of LINC01592 resulted in an upregulation of MHC-I expression on the tumor cell membrane, thereby enhancing the efficacy of CD8+ T cell reinfusion therapy.
The investigation conducted has revealed a significant molecular interaction between TAMs and EC via the LINC01592/E2F6/NBR1/MHC-I axis, which facilitates the progression of malignant tumors. This suggests that a therapeutic intervention targeting this axis may hold promise for the treatment of the disease.
肿瘤相关巨噬细胞（TAMs）浸润促进食管癌（EC）的进展。然而，其潜在机制尚不清楚。
分析 TCGA 数据库 EC 微阵列中 LINC01592 的异常表达。验证 EC 细胞系和组织中 LINC01592 的表达水平。建立 EC 细胞系的稳定 LINC01592 敲低和过表达。进行体外和体内试验以测试 LINC01592 敲低和过表达对 EC 细胞的影响。使用 RNA 结合蛋白免疫沉淀（RIP）、RNA 下拉测定和免疫荧光（IF）来验证 E2F6 和 LINC01592 的结合。通过使用 ChIP 和双荧光素酶报告基因测定来验证 E2F6 和 NBR1 的结合。
LINC01592 是由 M2-TAMs 分泌的外泌体携带和传递的。促进 NBR1 转录的分子机制涉及 LINC01592 与 E2F6 的直接结合，这有助于 E2F6 进入核内。LINC01592 和 E2F6 的协同作用导致 NBR1 转录增强。NBR1 通过泛素结构域与泛素化的 MHC-I 结合，导致 MHC-I 在自噬溶酶体中的更高降解和癌细胞表面 MHC-I 的表达减少。因此，这导致癌细胞逃避 CD8 CTL 免疫攻击。通过 siRNA 或相应的抗体阻断作用阻断 E2F6/NBR1/MHC-I 信号，LINC01592 的促肿瘤作用以及 M2 型巨噬细胞驱动的肿瘤生长均显著受到抑制。值得注意的是，抑制 LINC01592 导致肿瘤细胞膜上 MHC-I 表达上调，从而增强了 CD8+T 细胞再输注治疗的疗效。
该研究揭示了 TAMs 和 EC 之间通过 LINC01592/E2F6/NBR1/MHC-I 轴的显著分子相互作用，促进了恶性肿瘤的进展。这表明靶向该轴的治疗干预可能为该疾病的治疗提供新的途径。
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