Exosomal DLX6-AS1 from hepatocellular carcinoma cells induces M2 macrophage polarization to promote migration and invasion in hepatocellular carcinoma through microRNA-15a-5p/CXCL17 axis.

Abstract

BACKGROUND:

Hepatocellular carcinoma (HCC) cells-secreted exosomes (exo) could stimulate M2 macrophage polarization and promote HCC progression, but the related mechanism of long non-coding RNA distal-less homeobox 6 antisense 1 (DLX6-AS1) with HCC-exo-mediated M2 macrophage polarization is largely ambiguous. Thereafter, this research was started to unearth the role of DLX6-AS1 in HCC-exo in HCC through M2 macrophage polarization and microRNA (miR)-15a-5p/C-X-C motif chemokine ligand 17 (CXCL17) axis.

METHODS:

DLX6-AS1, miR-15a-5p and CXCL17 expression in HCC tissues and cells were tested. Exosomes were isolated from HCC cells with overexpressed DLX6-AS1 and co-cultured with M2 macrophages. MiR-15a-5p/CXCL17 down-regulation assays were performed in macrophages. The treated M2 macrophages were co-cultured with HCC cells, after which cell migration, invasion and epithelial mesenchymal transition were examined. The targeting relationships between DLX6-AS1 and miR-15a-5p, and between miR-15a-5p and CXCL17 were explored. In vivo experiment was conducted to detect the effect of exosomal DLX6-AS1-induced M2 macrophage polarization on HCC metastasis.

RESULTS:

Promoted DLX6-AS1 and CXCL17 and reduced miR-15a-5p exhibited in HCC. HCC-exo induced M2 macrophage polarization to accelerate migration, invasion and epithelial mesenchymal transition in HCC, which was further enhanced by up-regulated DLX6-AS1 but impaired by silenced DLX6-AS1. Inhibition of miR-15a-5p promoted M2 macrophage polarization to stimulate the invasion and metastasis of HCC while that of CXCL17 had the opposite effects. DLX6-AS1 mediated miR-15a-5p to target CXCL17. DLX6-AS1 from HCC-exo promoted metastasis in the lung by inducing M2 macrophage polarization in vivo.

CONCLUSION:

DLX6-AS1 from HCC-exo regulates CXCL17 by competitively binding to miR-15a-5p to induce M2 macrophage polarization, thus promoting HCC migration, invasion and EMT.

• Authors: Lin-Pei Wang, Jing Lin, Xiao-Qiu Ma, Dong-Yao Xu, Chun-Feng Shi, Wei Wang, Xiao-Jie Jiang
• Journal: Journal of experimental & clinical cancer research : CR (J Exp Clin Cancer Res) Vol. 40 Issue 1 Pg. 177 (05 26 2021) ISSN: 1756-9966 [Electronic] England
• PMID: 34039401 (Publication Type: Journal Article, Retracted Publication)

Chemical References

• CXCL17 protein, human
• Chemokines, CXC
• MIRN15 microRNA, human
• MicroRNAs
• RNA, Long Noncoding

Topics

• Animals
• Carcinoma, Hepatocellular (genetics, metabolism, pathology)
• Cell Movement (physiology)
• Cell Polarity (physiology)
• Chemokines, CXC (genetics, metabolism)
• Exosomes (metabolism)
• Humans
• Liver Neoplasms (genetics, metabolism, pathology)
• Macrophages (metabolism, pathology)
• Male
• Mice
• Mice, Nude
• MicroRNAs (genetics, metabolism)
• Neoplasm Invasiveness
• RNA, Long Noncoding (genetics, metabolism)
• Signal Transduction