IL-20RB mediates tumoral response to osteoclastic niches and promotes bone metastasis of lung cancer
Yunfei He, Wenqian Luo, Yingjie Liu, Yuan Wang, Chengxin Ma, Qiuyao Wu, Pu Tian, Dasa He, Zhenchang Jia, Xianzhe Lv, Yu-Shui Ma, Haitang Yang, Ke Xu, Xue Zhang, Yansen Xiao, Peiyuan Zhang, Yajun Liang, Da Fu, Feng Yao, Guohong Hu
Yunfei He, Wenqian Luo, Yingjie Liu, Yuan Wang, Chengxin Ma, Qiuyao Wu, Pu Tian, Dasa He, Zhenchang Jia, Xianzhe Lv, Yu-Shui Ma, Haitang Yang, Ke Xu, Xue Zhang, Yansen Xiao, Peiyuan Zhang, Yajun Liang, Da Fu, Feng Yao, Guohong Hu
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Research Article Cell biology

IL-20RB mediates tumoral response to osteoclastic niches and promotes bone metastasis of lung cancer

Abstract

Bone is a common site of metastasis in lung cancer, but the regulatory mechanism remains incompletely understood. Osteoclasts are known to play crucial roles in osteolytic bone metastasis by digesting bone matrix and indirectly enhancing tumor colonization. In this study, we found that IL receptor 20 subunit β (IL-20RB) mediated a direct tumoral response to osteoclasts. Tumoral expression of IL-20RB was associated with bone metastasis of lung cancer, and functionally, IL-20RB promoted metastatic growth of lung cancer cells in bone. Mechanistically, tumor cells induced osteoclasts to secrete the IL-20RB ligand IL-19, and IL-19 stimulated IL-20RB–expressing tumor cells to activate downstream JAK1/STAT3 signaling, leading to enhanced proliferation of tumor cells in bone. Importantly, blocking IL-20RB with a neutralizing antibody significantly suppressed bone metastasis of lung cancer. Overall, our data revealed a direct protumor role of osteoclastic niche in bone metastasis and supported IL-20RB–targeting approaches for metastasis treatment.

Authors

Yunfei He, Wenqian Luo, Yingjie Liu, Yuan Wang, Chengxin Ma, Qiuyao Wu, Pu Tian, Dasa He, Zhenchang Jia, Xianzhe Lv, Yu-Shui Ma, Haitang Yang, Ke Xu, Xue Zhang, Yansen Xiao, Peiyuan Zhang, Yajun Liang, Da Fu, Feng Yao, Guohong Hu

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Figure 6

STAT3 inhibition suppresses IL-20RB–induced tumor proliferation and bone metastasis.

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STAT3 inhibition suppresses IL-20RB–induced tumor proliferation and bon...
(A) Organoid formation of A549 with IL20RB overexpression and/or STAT3 knockdown after treatment of OC CM. (B–G) Intracardiac injection of A549 with IL20RB overexpression and/or STAT3 knockdown into nude mice for bone metastasis analysis (n ≥ 7 mice per group). Whole-body BLI quantification at week 4 after tumor inoculation (B), ex vivo hind limb BLI quantification (C), micro-CT quantification of relative bone volumes of hind limbs (D), representative BLI images of whole bodies and hind limbs, and micro-CT analyses of hind limbs (E, arrows point to osteolytic areas), representative H&E images of bone sections (F), and immunofluorescent analysis of EdU+ tumor cells in bone (G). (H–K) Napabucasin treatment of mice with intracardiac injection of control and IL20RB-overexpressing A549 cells for bone metastasis (n = 5 mice per group). Whole-body BLI quantification at week 4 after tumor inoculation (H), micro-CT quantification of relative bone volumes of hind limbs (I), representative BLI images of whole bodies and hind limbs and micro-CT analyses of hind limbs (J, arrows point to osteolytic areas), and immunofluorescent analysis of EdU+ tumor cells in bone (K). Scale bars: 100 μm. P values were obtained by Mann-Whitney U test (B, C, and H) and 2-tailed unpaired t test (A, D, G, I, and K). Box plots display values of minimum, first quartile, median, third quartile, and maximum. Data are represented as mean ± SD.