A novel microRNA-182/Interleukin-8 regulatory axis controls osteolytic bone metastasis of lung cancer.

Bone metastasis is one of the main complications of lung cancer and most important factors that lead to poor life quality and low survival rate in lung cancer patients. However, the regulatory mechanisms underlying lung cancer bone metastasis are still poor understood. Here, we report that microRNA-182 (miR-182) plays a critical role in regulating osteoclastic metastasis of lung cancer cells. We found that miR-182 was significantly upregulated in both bone-metastatic human non-small cell lung cancer (NSCLC) cell line and tumor specimens. We further demonstrated that miR-182 markedly enhanced the ability of NSCLC cells for osteolytic bone metastasis in nude mice. Mechanistically, miR-182 promotes NSCLC cells to secrete Interleukin-8 (IL-8) and in turn facilitates osteoclastogenesis via activating STAT3 signaling in osteoclast progenitor cells. Importantly, systemically delivered IL-8 neutralizing antibody inhibits NSCLC bone metastasis in nude mice. Collectively, our findings identify the miR-182/IL-8/STAT3 axis as a key regulatory pathway in controlling lung cancer cell-induced osteolytic bone metastasis and suggest a promising therapeutic strategy that targets this regulatory axis to interrupt lung cancer bone metastasis.

Detection of Plasma EGFR Mutations in NSCLC Patients with a Validated ddPCR Lung cfDNA Assay.

Purpose: The clinical utility of cell-free DNA (cfDNA) to assess EGFR mutations is increasing. However, there are limited studies determining their clinical validity and utility. The value of cfDNA assays in cancer management remains controversial. Methods: In this study, we first evaluated the analytical performance of the ddPCR Lung cfDNA Assay. We next analyzed the concordance of the results with tissue amplification refractory mutation system PCR (ARMS-PCR) and plasma next-generation sequencing (NGS) genotyping. Finally, we assessed its clinical utility by exploring the association of cfDNA EGFR mutations with metastatic sites and the efficacy of EGFR-TKIs treatment. Results: The ddPCR Lung cfDNA Assay demonstrated a limit of blank of 1 droplet per reaction, an analytical specificity of 100%, and detection limit of 0.05%, 0.05%, and 0.1% for E746_A750del, L858R, and T790M, respectively. With tissue ARMS-PCR as a standard for comparison, the clinical sensitivity and specificity of ddPCR were 62.5% (15/24) and 100% (82/82) for E746_A750del, and 75.0% (15/20) and 94.2% (81/86) for L858R, respectively. The ddPCR showed high concordance with NGS in determining cfDNA EGFR mutations. Patients with bone and/or brain metastasis showed a higher detection rate and mutant abundance of cfDNA EGFR mutations compared to those with other sites of metastasis. Moreover, EGFR-TKIs treatment was effective in patients with sensitive EGFR mutations in either plasma cfDNA or tumor tissue-derived DNA. Conclusions: We validated in this study that the ddPCR Lung cfDNA Assay is reliable for detection of EGFR mutations in lung cancers, in terms of analytical performance, clinical validity and utility.