Department of General Surgery, Pancreatic Disease Center, Research Institute of Pancreatic Diseases, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200025, China.
Research Institute of Pancreatic Diseases, Shanghai Jiaotong University School of Medicine, Shanghai, 200025, China.
J Hematol Oncol. 2022 May 7;15(1):52. doi: 10.1186/s13045-022-01272-w.
LncRNA-PACERR plays critical role in the polarization of tissue-associated macrophages (TAMs). In this study, we found the function and molecular mechanism of PACERR in TAMs to regulate pancreatic ductal adenocarcinoma (PDAC) progression.
We used qPCR to analyse the expression of PACERR in TAMs and M1-tissue-resident macrophages (M1-NTRMs) which were isolated from 46 PDAC tissues. The function of PACERR on macrophages polarization and PDAC proliferation, migration and invasion were confirmed through in vivo and in vitro assays. The molecular mechanism of PACERR was discussed via fluorescence in situ hybridization (FISH), RNA pull-down, ChIP-qPCR, RIP-qPCR and luciferase assays.
LncRNA-PACERR was high expression in TAMs and associated with poor prognosis in PDAC patients. Our finding validated that LncRNA-PACERR increased the number of M2-polarized cells and facilized cell proliferation, invasion and migration in vitro and in vivo. Mechanistically, LncRNA-PACERR activate KLF12/p-AKT/c-myc pathway by binding to miR-671-3p. And LncRNA-PACERR which bound to IGF2BP2 acts as an m6A-dependent manner to enhance the stability of KLF12 and c-myc in cytoplasm. In addition, the promoter of LncRNA-PACERR was a target of KLF12 and LncRNA-PACERR recruited EP300 to increase the acetylation of histone by interacting with KLF12 in nucleus.
This study found that LncRNA-PACERR functions as key regulator of TAMs in PDAC microenvironment and revealed the novel mechanisms in cytoplasm and in nucleus.
长链非编码 RNA-PACERR 在组织相关巨噬细胞（TAMs）的极化中发挥关键作用。在这项研究中，我们发现了 PACERR 在 TAMs 中调节胰腺导管腺癌（PDAC）进展中的功能和分子机制。
我们使用 qPCR 分析了从 46 个 PDAC 组织中分离的 TAMs 和 M1 组织驻留巨噬细胞（M1-NTRMs）中 PACERR 的表达。通过体内和体外实验证实了 PACERR 对巨噬细胞极化和 PDAC 增殖、迁移和侵袭的功能。通过荧光原位杂交（FISH）、RNA 下拉、ChIP-qPCR、RIP-qPCR 和荧光素酶测定等方法探讨了 PACERR 的分子机制。
LncRNA-PACERR 在 TAMs 中高表达，并与 PDAC 患者的预后不良相关。我们的研究结果验证了 LncRNA-PACERR 增加了 M2 极化细胞的数量，并促进了细胞在体外和体内的增殖、侵袭和迁移。在机制上，LncRNA-PACERR 通过结合 miR-671-3p 激活 KLF12/p-AKT/c-myc 通路。并且与 IGF2BP2 结合的 LncRNA-PACERR 以 m6A 依赖的方式增强细胞质中 KLF12 和 c-myc 的稳定性。此外，LncRNA-PACERR 的启动子是 KLF12 的靶标，LncRNA-PACERR 通过与 KLF12 相互作用招募 EP300 在核内增加组蛋白的乙酰化。
这项研究发现 LncRNA-PACERR 作为 PDAC 微环境中 TAMs 的关键调节因子发挥作用，并揭示了细胞质和核内的新机制。
