IL-20RB mediates tumoral response to osteoclastic niches and promotes bone metastasis of lung cancer
Yunfei He, … , Feng Yao, Guohong Hu
Yunfei He, … , Feng Yao, Guohong Hu
Published August 25, 2022
Citation Information: J Clin Invest. 2022;132(20):e157917. https://doi.org/10.1172/JCI157917.
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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 2

IL-20RB promotes bone metastasis of lung cancer.

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IL-20RB promotes bone metastasis of lung cancer. (A) IL20RB overexpressi...
(A) IL20RB overexpression in A549 and knockdown in HBM1. (B–F) Intracardiac injection of A549 with or without IL20RB overexpression into nude mice for bone metastasis analysis. Weekly BLI quantitation of tumor burden of the mice (B, n = 7 mice per group), representative images of BLI analyses of whole bodies and hind limbs and micro-CT analyses for bone destruction of hind limbs (C, arrows point to osteolytic areas), ex vivo BLI analysis of hind limbs (D), micro-CT quantification of relative bone volumes of hind limbs (E), and H&E and EdU labeling analysis of bone metastases (F). (G and H) Intracardiac injection of HBM1 cells with IL20RB knockdown for bone metastasis analysis (n = 6, pLKO.1; n = 7, shIL20RB#2; n = 7, shIL20RB#4). Ex vivo hind limb BLI analysis (G) and H&E- and EdU-labeling analysis of bone metastases (H). (I) Il20rb overexpression in LLC. (J–M) Intracardiac injection of LLC with or without Il20rb overexpression for bone metastasis analysis (n = 6 mice per group). Ex vivo BLI quantification of hind limbs (J), micro-CT quantification of relative bone volumes of hind limbs (K), representative BLI and micro-CT images of hind limbs (L, arrows point to osteolytic areas), and H&E- and EdU–labeling analysis of bone metastases (M). BV/TV, bone volume/total volume; T, tumor; B, bone. Scale bars: 100 μm. P values were obtained by Mann-Whitney U test (B, D, G, and J) and 2-tailed unpaired t test (E, F, H, K, and M). Box plots display values of minimum, first quartile, median, third quartile, and maximum. Data are represented as mean ± SD.