Abstract
Cancer-induced bone pain (CIBP) is the pain caused by metastasis of malignant tumors to the bone, accounting for more than half of all chronic cancer pain, which seriously affects the quality of life among tumor patients. Up to 40% of patients with advanced lung cancer suffer from CIBP. MicroRNA (miRNA) transfers between cells through exosomes, mediates cell-to-cell communication, and performs various biological functions. Studies have shown that miRNAs secreted by cancer can modify the tumor microenvironment, but whether exosome-mediated miRNA transfer plays a role in CIBP is still unknown. In this study, the expression levels of 15 miRNAs in exosomes derived A549 cells and 18 miRNAs in exosomes derived NCI-H1299 cells were significantly up-regulated, and qRT-PCR further confirmed that the level of let-7d-5p was increased most considerably. In vitro, exosomal let-7d-5p (EXO let-7d-5p) can be taken up by dorsal root ganglion (DRG) neurons and inhibit the protein level of the target gene opioid receptor mu 1 (OPRM1). EXO let-7d-5p was further confirmed to be involved in the generation and maintenance of CIBP in vivo. Our findings clarify the molecular mechanism of CIBP caused by the inhibition of OPRM1 by EXO let-7d-5p, providing new clues and intervention targets for the prevention and treatment of CIBP.
Highlights
Lung cancer is one of the most aggressive tumors, and bone is the most common metastatic site of lung cancer (Lee et al, 2008; Wang et al, 2010; Jemal et al, 2011)
In order to test the internalization of exosomes in dorsal root ganglion (DRG) neuron cells, exosomes isolated from A549 and NCI-H1299 cells were labeled with PKH67 dye, washed thoroughly, and added to DRG neuron cells
Almost all DRG neuron cells showed green signals (Figure1C). These results indicated that A549 and NCI-H1299 cell exosomes were internalized by DRG neuron cells
Summary
Lung cancer is one of the most aggressive tumors, and bone is the most common metastatic site of lung cancer (Lee et al, 2008; Wang et al, 2010; Jemal et al, 2011). Up to 40% of patients with advanced lung cancer have bone metastases, which are the primary source of pain and disability (Siegel et al, 2012). Patients with bone metastases have severe cancer-induced bone pain (CIBP), spinal cord compression, anemia, hypercalcemia or other nerve compression symptoms, which seriously affects the patients’ quality of life and reduces survival rate (Schneider et al, 2012; Ke et al, 2017). CIBP presents with persistent dull pain, but is often accompanied by unbearable breakthrough pain (Zhou et al, 2015). There is a lack of effective treatment for CIBP
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