LRRPM 通过表观遗传调控 LINC00240 和 CSF1 限制肺腺癌进展和 M2 巨噬细胞极化。
LARRPM restricts lung adenocarcinoma progression and M2 macrophage polarization through epigenetically regulating LINC00240 and CSF1.
机构信息
Department of Lung Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin Lung Cancer Center, Tianjin, 300060, China.
出版信息
Cell Mol Biol Lett. 2022 Oct 11;27(1):91. doi: 10.1186/s11658-022-00376-y.
BACKGROUND
Long non-coding RNAs (lncRNAs) are critical regulators in lung adenocarcinoma (LUAD). M2-type tumor-associated macrophages (TAMs) also play oncogenic roles in LUAD. However, the involvement of lncRNAs in TAM activation is still largely unknown.
METHODS
The expressions of LARRPM, LINC00240 and CSF1 were determined by RT-qPCR. The regulation of LINC00240 and CSF1 by LARRPM was investigated by RNA-protein pull-down, RNA immunoprecipitation, chromatin immunoprecipitation and bisulfite DNA sequencing. In vitro and in vivo gain- and loss-of-function assays were performed to investigate the roles of LARRPM.
RESULTS
The lncRNA LARRPM was expressed at low levels in LUAD tissues and cells. The low expression of LARRPM was correlated with advanced stage and poor survival of patients with LUAD. Functional experiments revealed that LARRPM suppressed LUAD cell proliferation, migration and invasion, and promoted apoptosis. LARRPM also repressed macrophage M2 polarization and infiltration. Taken together, LARRPM significantly restricted LUAD progression in vivo. Mechanistically, LARRPM bound and recruited DNA demethylase TET1 to the promoter of its anti-sense strand gene LINC00240, leading to a decrease in DNA methylation level of the LINC00240 promoter and transcriptional activation of LINC00240. Functional rescue assays suggested that the lncRNA LINC00240 was responsible for the roles of LARRPM in the malignant behavior of LUAD cells. LARRPM decreased the binding of TET1 to the CSF1 promoter, resulting in increased DNA methylation of the CSF1 promoter and transcriptional repression of CSF1, which is responsible for the roles of LARRPM in macrophage M2 polarization and infiltration. The TAMs educated by LUAD cells exerted oncogenic roles, which was negatively regulated by LARRPM expressed in LUAD cells.
CONCLUSIONS
LARRPM restricts LUAD progression through repressing both LUAD cell and macrophages. These data shed new insights into the regulation of LUAD progression by lncRNAs and provide data on the potential utility of LARRPM as a target for LUAD treatment.
背景
长非编码 RNA（lncRNA）是肺腺癌（LUAD）的关键调控因子。M2 型肿瘤相关巨噬细胞（TAMs）在 LUAD 中也发挥致癌作用。然而，lncRNA 在 TAM 激活中的作用在很大程度上仍然未知。
方法
通过 RT-qPCR 测定 LARRPM、LINC00240 和 CSF1 的表达。通过 RNA-蛋白下拉、RNA 免疫沉淀、染色质免疫沉淀和亚硫酸氢盐 DNA 测序研究 LARRPM 对 LINC00240 和 CSF1 的调控。进行体外和体内增益和缺失功能测定以研究 LARRPM 的作用。
结果
在 LUAD 组织和细胞中，lncRNA LARRPM 表达水平较低。LARRPM 的低表达与 LUAD 患者的晚期阶段和不良预后相关。功能实验表明，LARRPM 抑制 LUAD 细胞的增殖、迁移和侵袭，并促进凋亡。LARRPM 还抑制巨噬细胞 M2 极化和浸润。总之，LARRPM 显著抑制体内 LUAD 进展。机制上，LARRPM 结合并募集 DNA 去甲基化酶 TET1 到其反义链基因 LINC00240 的启动子，导致 LINC00240 启动子的 DNA 甲基化水平降低和 LINC00240 的转录激活。功能挽救实验表明，lncRNA LINC00240 负责 LARRPM 在 LUAD 细胞恶性行为中的作用。LARRPM 减少 TET1 与 CSF1 启动子的结合，导致 CSF1 启动子的 DNA 甲基化增加和 CSF1 的转录抑制，这是 LARRPM 在巨噬细胞 M2 极化和浸润中的作用的原因。由 LUAD 细胞教育的 TAMs 发挥致癌作用，这受到 LUAD 细胞中表达的 LARRPM 的负调控。
结论
LARRPM 通过抑制 LUAD 细胞和巨噬细胞来限制 LUAD 的进展。这些数据为 lncRNA 调节 LUAD 进展提供了新的见解，并为 LARRPM 作为 LUAD 治疗靶点的潜在应用提供了数据。
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