Macrophages-derived exosomal lncRNA LIFR-AS1 promotes osteosarcoma cell progression via miR-29a/NFIA axis

Abstract

Background Osteosarcoma (OS) is the most common primary malignant bone tumor in young people. Tumor-associated macrophages (TAMs) have been reported to play an important role in the development of osteosarcoma. However, the detailed molecular mechanisms remain largely unknown and need to be elucidated. Recently, exosomes have been reported as the crucial mediator between tumor cells and the tumor microenvironment. And a lot of lncRNAs have been reported to act as either oncogenes or tumor suppressors in osteosarcoma. In this research, we aim to explore the role of macrophages-derived exosomal lncRNA in osteosarcoma development and further elucidated the potential molecular mechanisms involved. Methods TAMs were differentiated from human mononuclear cells THP-1, and a high-throughput microarray assay was used to analyze the dysregulated lncRNAs and miRNAs in osteosarcoma cells co-cultured with macrophages-derived exosomes. Western blot, qRT-PCR assays, and Dual-luciferase reporter assay were used to verify the interaction among LIFR-AS1, miR-29a, and NFIA. Cck-8, EdU, colony formation assay, wound-healing, and transwell assay were performed to explore the characterize the proliferation and metastasis ability of OS cells. And qPCR, Western blots, immunohistochemistry, and cell immunofluorescence were used to detect the expression of relative genes or proteins. Results In this study, we found that THP-1-induced macrophage-derived exosomes could facilitate osteosarcoma cell progression both in vitro and in vivo. Then, the results of the high-throughput microarray assay showed that LIFR-AS1 was highly expressed and miR-29a was lowly expressed. Furthermore, LIFR-AS1 was identified as a miR-29a sponge, and NFIA was validated as a direct target of miR-29a. Functional assays demonstrated that knockdown of exosomal LIFR-AS1 could attenuate the promotion effects of macrophages-derived exosomes on osteosarcoma cell progression and miR-29a inhibition could reserve the effect of LIFR-AS1-knockdown exosomes. Correspondingly, NFIA-knockdown could partially reverse the tumor inhibition effect of miR-29a on osteosarcoma cells. Conclusions Taken together, macrophages-derived exosomal lncRNA LIFR-AS1 can promote osteosarcoma cell proliferation, invasion, and restrain cell apoptosis via miR-29a/NFIA axis, which can act as a potential novel therapeutic target for osteosarcoma therapy.

Long Non-Coding RNAs in the Tumor Immune Microenvironment: Biological Properties and Therapeutic Potential

“…In pancreatic cancer, studies have shown that the blocking Sbf2-AS1 in M2 macrophage-derived exosomes inhibited XIAP expression through the negative regulation of miR-122-5p, and played a role in reducing the oncogenic ability of tumor cells ( 81 ). In the report by Zhang et al., RNA sequencing and other methods were used to identify differentially expressed miRNAs and lncRNAs in MΦ-CM co-cultured osteosarcoma cells and the corresponding control group, which confirmed that lncRNA LIFR-AS1 was upregulated in MΦ-CM co-cultured osteosarcoma cells ( 97 ). In addition, LIFR-AS1 can be transmitted from macrophages to osteosarcoma cells via exosomes, and promote tumor progression via spongy transfection of miR-29a ( 97 ).…”

“…In the report by Zhang et al., RNA sequencing and other methods were used to identify differentially expressed miRNAs and lncRNAs in MΦ-CM co-cultured osteosarcoma cells and the corresponding control group, which confirmed that lncRNA LIFR-AS1 was upregulated in MΦ-CM co-cultured osteosarcoma cells ( 97 ). In addition, LIFR-AS1 can be transmitted from macrophages to osteosarcoma cells via exosomes, and promote tumor progression via spongy transfection of miR-29a ( 97 ). These findings show that abnormally expressed lncRNAs can be used as potential biological targets for cancer therapy.…”

“…However, some lncRNAs can negatively regulate TAM M2 polarization. In endometrial cancer, NIFK-AS1 inhibited the M2-like polarization of macrophages by targeting miR-146a, thereby reducing the proliferation, migration, and invasion of estrogen-induced endometrial (97). In addition, LIFR-AS1 can be transmitted from macrophages to osteosarcoma cells via exosomes, and promote tumor progression via spongy transfection of miR-29a (97).…”

Exosomes as Efficient Nanocarriers in Osteosarcoma: Biological Functions and Potential Clinical Applications

“…As a result, the growth, invasion and metastasis of osteosarcoma cells with low AXL expression were able to be promoted by osteosarcoma cells with high AXL expression ( Figure 2 ; Li Q. et al, 2020 ). Zhang et al reported that macrophages derived exosomal lncRNA LIFR-AS1 via the miR-29a/NFIA axis promoted osteosarcoma cell proliferation and invasion ( Zhang H. et al, 2021 ). Pan et al demonstrated that CDDP drug-resistant osteosarcoma cell derived exosomes could transfer hsa_circ_103801 to chemotherapy-sensitive osteosarcoma cells to enhance the resistance of osteosarcoma cells to CDDP ( Pan et al, 2021 ).…”

“…Han et al demonstrated that overexpression of AGAP1 could inhibit the function of exosomal miR-1307 in osteosarcoma ( Han et al, 2021 ). Zhang et al reported that exosomal lncRNA LIFR-AS1 promote osteosarcoma progression via the miR-29a/NFIA axis ( Zhang H. et al, 2021 ). The above studies highlight novel therapeutic targets for osteosarcoma.…”