Cancer cell-derived exosomal LINC00313 induces M2 macrophage differentiation in non-small cell lung cancer

• Wencui Kong ^[1] ; Lei Zhang ^[1] ; Ying Chen ^[1] ; Zongyang Yu ^[1] ; Zhongquan Zhao ^[1]
  1. [1] Department of Pulmonary and Critical Care Medicine, 900TH Hospital of Joint Logistics Support Force, Fuzhou, 350025, Fujian, China
• Localización: Clinical & translational oncology, ISSN 1699-048X, Vol. 24, Nº. 12 (December), 2022, págs. 2395-2408
• Idioma: inglés
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• Resumen

  • Purpose Non-small cell lung cancer (NSCLC) is the major subtype of lung cancer, which is the leading cause of cancer death worldwide. Tumor-associated macrophages (TAMs) are one of the main non-tumor cells in the tumor microenvironment. Here, we investigated the effect of cancer cell-derived exosomal LINC00313 on the M2 macrophage differentiation in NSCLC and clarified its underlying mechanism.

    Methods Flow cytometry, Western blotting, ELISA and immunohistochemical staining were performed to identify the macrophage phenotype by detecting the expression of M2 markers. The expression levels of LINC00313 and miR-135a-3p were measured by qRT-PCR, and luciferase reporter assay was used to validate the binding of lncRNA to miRNA, and miRNA to the target gene STAT6. The mouse-xenograft models were established by subcutaneous injection of the NCl-H1299 cells with stable overexpression or knockdown of LINC00313. GW4869 was injected intra-tumorally after tumor implantation.

    Results It was found that the cancer cells promoted M2 macrophage differentiation by secreting exosomes. LINC00313 was overexpressed in H1299-derived exosomes, and its knockdown abolished the effect of H1299-induced M2 macrophage differentiation. LINC00313 sponged miR-135a-3p to increase the STAT6 expression, resulting in the M2 macrophage differentiation. LINC00313 promoted tumor progression and promoted the expression of M2 markers in isolated tumor macrophages. A novel regulatory mechanism of M2 macrophage differentiation in NSCLC was revealed. It was found that cancer cell-derived exosomal LINC00313 promoted M2 macrophage differentiation in NSCLC by up-regulating STAT6 as miR-135a-3p sponge.

    Conclusions This study provides a new mechanism and direction to prevent the M2 macrophage differentiation in NSCLC.