Department of Laboratory Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University, 200030, Shanghai, China.
Department of Laboratory Medicine, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, 200080, Shanghai, China.
Cell Death Dis. 2023 May 1;14(5):298. doi: 10.1038/s41419-023-05819-8.
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.
骨转移是肺癌的主要并发症之一，也是导致肺癌患者生活质量下降和生存率降低的重要因素。然而，肺癌骨转移的调控机制仍不清楚。在这里，我们报告 microRNA-182（miR-182）在调节肺癌细胞成骨转移中起着关键作用。我们发现 miR-182 在骨转移的人非小细胞肺癌（NSCLC）细胞系和肿瘤标本中均显著上调。我们进一步证明，miR-182 显著增强了 NSCLC 细胞在裸鼠中的溶骨性骨转移能力。在机制上，miR-182 通过激活破骨细胞祖细胞中的 STAT3 信号通路促进 NSCLC 细胞分泌白细胞介素 8（IL-8），进而促进破骨细胞形成。重要的是，系统给予 IL-8 中和抗体可抑制裸鼠 NSCLC 骨转移。总之，我们的研究结果确定了 miR-182/IL-8/STAT3 轴作为控制肺癌细胞诱导的溶骨性骨转移的关键调控途径，并提出了一种有前途的治疗策略，即靶向该调控轴以阻断肺癌骨转移。
