A novel microRNA-182/Interleukin-8 regulatory axis controls osteolytic bone metastasis of lung cancer
Mingna Zhao, Ling-Fei Zhang, Zhen Sun, Li-Hua Qiao, Tao Yang, Yi-Zhe Ren, Xianzhou Zhang, Lei Wu, Wenli Qian, Qiaomei Guo, Wanxing Xu, Xueqing Wang, Fei Wu, Lin Wang, Yutong Gu, Mo‐Fang Liu, Jiatao Lou
Abstract
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.