LINC01094/SPI1/CCL7 Axis Promotes Macrophage Accumulation in Lung Adenocarcinoma and Tumor Cell Dissemination

Abstract

Objective. Infiltration of tumor-associated macrophages is closely linked to the malignant development of human cancers. This research studies the function of C-C motif chemokine ligand 7 (CCL7) in the macrophage accumulation in lung adenocarcinoma (LUAD) and the underpinning mechanism. Methods. The expression profile of CCL7 in LUAD and its correlations with patient’s prognosis and macrophage infiltration were predicted via bioinformatics systems. Artificial up- or downregulation of CCL7 was induced in LUAD cells to explore its function in the mobility, EMT of cancer cells, and migration of M2 macrophages. Cancer cells were implanted in NOD/SCID mice to induce xenograft tumors. The CCL7-related transcription factors or factors were predicted by bioinformatic tools, and the molecular interactions were confirmed by immunoprecipitation or luciferase assays. Results. CCL7 was highly expressed in LUAD and linked to increased TAM infiltration. Knockdown of CCL7 suppressed the chemotaxis and M2 skewing of macrophages, and it blocked the EMT and mobility of LUAD cells. CCL7 downregulation also suppressed macrophage infiltration in xenograft tumors in mice. Spi-1 proto-oncogene (SPI1) was confirmed as an upstream factor activating CCL7 transcription, and LINC01094 was found to bind to SPI1 to promote its nuclear translocation. Upregulation of SPI1 restored the chemotactic migration and M2 polarization of macrophages in LUAD cells. Conclusion. This paper reveals that LINC01094 binds to SPI1 to promote its nuclear translocation, which further activates CCL7 transcription by binding to its promoter, leading to M2 macrophage accumulation and dissemination of tumor cells.