IL4/IL4R signaling promotes the osteolysis in metastatic bone of CRC through regulating the proliferation of osteoclast precursors
Abstract Background Bone metastasis of colorectal cancer (CRC) often indicates a poor prognosis. Osteolysis can be observed in metastatic sites, implying an aberrant activation of osteoclasts. However, how osteoclastogenesis is regulated in metastatic microenvironment caused by colorectal cancer is...
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2021
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oai:doaj.org-article:b5705a35020149179e6f97d2887d6a942021-12-05T12:08:04ZIL4/IL4R signaling promotes the osteolysis in metastatic bone of CRC through regulating the proliferation of osteoclast precursors10.1186/s10020-021-00411-21076-15511528-3658https://doaj.org/article/b5705a35020149179e6f97d2887d6a942021-12-01T00:00:00Zhttps://doi.org/10.1186/s10020-021-00411-2https://doaj.org/toc/1076-1551https://doaj.org/toc/1528-3658Abstract Background Bone metastasis of colorectal cancer (CRC) often indicates a poor prognosis. Osteolysis can be observed in metastatic sites, implying an aberrant activation of osteoclasts. However, how osteoclastogenesis is regulated in metastatic microenvironment caused by colorectal cancer is still unclear. Methods In this study, mice bone metastatic model of CRC was established through injection of MC-38 or CT-26 cells. BrdU assays showed primary CD115 ( +) osteoclast precursors (OCPs) proliferated at the first 2 weeks. Transcriptomic profiling was performed to identify differentially expressing genes and pathways in OCPs indirectly co-cultured with CRC cells Results The expression of IL4Rα was found to be significantly upregulated in OCPs stimulated by tumor conditioned medium (CM). Further investigation indicated that IL-4 signaling regulated proliferation of OPCs through interacting with type I IL4 receptor, and neutrophils were the main source of IL-4 in bone marrow. The proliferation of OCPs can be inhibited in IL4 deficiency mice. In addition, ERK pathway was activated by IL4/IL4R signaling. Ravoxertinib, an ERK antagonists, could significantly prevent bone destruction through inhibiting the proliferation of OCPs. Conclusion Our study indicates the essential role of IL4/IL4R signaling for the proliferation of OCPs in early metastasis of CRC predominantly through activating ERK pathway, which remarkedly impacts the number of osteoclasts in later stage and leads to osteolytic lesions. Moreover, Ravoxertinib could be a new therapeutical target for bone metastasis of CRC.Qian JinHe YangZhao JingWu Hong-huaSong Ben-jingWang Li-tingYe Li-juanXu WeiKang XiaWu JuanZheng WeiBMCarticleBone metastasisCRCOsteoclast precursorsIL-4/IL-4RTherapeutics. PharmacologyRM1-950BiochemistryQD415-436ENMolecular Medicine, Vol 27, Iss 1, Pp 1-13 (2021) |
| institution |
DOAJ |
| collection |
DOAJ |
| language |
EN |
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Bone metastasis CRC Osteoclast precursors IL-4/IL-4R Therapeutics. Pharmacology RM1-950 Biochemistry QD415-436 |
| spellingShingle |
Bone metastasis CRC Osteoclast precursors IL-4/IL-4R Therapeutics. Pharmacology RM1-950 Biochemistry QD415-436 Qian Jin He Yang Zhao Jing Wu Hong-hua Song Ben-jing Wang Li-ting Ye Li-juan Xu Wei Kang Xia Wu Juan Zheng Wei IL4/IL4R signaling promotes the osteolysis in metastatic bone of CRC through regulating the proliferation of osteoclast precursors |
| description |
Abstract Background Bone metastasis of colorectal cancer (CRC) often indicates a poor prognosis. Osteolysis can be observed in metastatic sites, implying an aberrant activation of osteoclasts. However, how osteoclastogenesis is regulated in metastatic microenvironment caused by colorectal cancer is still unclear. Methods In this study, mice bone metastatic model of CRC was established through injection of MC-38 or CT-26 cells. BrdU assays showed primary CD115 ( +) osteoclast precursors (OCPs) proliferated at the first 2 weeks. Transcriptomic profiling was performed to identify differentially expressing genes and pathways in OCPs indirectly co-cultured with CRC cells Results The expression of IL4Rα was found to be significantly upregulated in OCPs stimulated by tumor conditioned medium (CM). Further investigation indicated that IL-4 signaling regulated proliferation of OPCs through interacting with type I IL4 receptor, and neutrophils were the main source of IL-4 in bone marrow. The proliferation of OCPs can be inhibited in IL4 deficiency mice. In addition, ERK pathway was activated by IL4/IL4R signaling. Ravoxertinib, an ERK antagonists, could significantly prevent bone destruction through inhibiting the proliferation of OCPs. Conclusion Our study indicates the essential role of IL4/IL4R signaling for the proliferation of OCPs in early metastasis of CRC predominantly through activating ERK pathway, which remarkedly impacts the number of osteoclasts in later stage and leads to osteolytic lesions. Moreover, Ravoxertinib could be a new therapeutical target for bone metastasis of CRC. |
| format |
article |
| author |
Qian Jin He Yang Zhao Jing Wu Hong-hua Song Ben-jing Wang Li-ting Ye Li-juan Xu Wei Kang Xia Wu Juan Zheng Wei |
| author_facet |
Qian Jin He Yang Zhao Jing Wu Hong-hua Song Ben-jing Wang Li-ting Ye Li-juan Xu Wei Kang Xia Wu Juan Zheng Wei |
| author_sort |
Qian Jin |
| title |
IL4/IL4R signaling promotes the osteolysis in metastatic bone of CRC through regulating the proliferation of osteoclast precursors |
| title_short |
IL4/IL4R signaling promotes the osteolysis in metastatic bone of CRC through regulating the proliferation of osteoclast precursors |
| title_full |
IL4/IL4R signaling promotes the osteolysis in metastatic bone of CRC through regulating the proliferation of osteoclast precursors |
| title_fullStr |
IL4/IL4R signaling promotes the osteolysis in metastatic bone of CRC through regulating the proliferation of osteoclast precursors |
| title_full_unstemmed |
IL4/IL4R signaling promotes the osteolysis in metastatic bone of CRC through regulating the proliferation of osteoclast precursors |
| title_sort |
il4/il4r signaling promotes the osteolysis in metastatic bone of crc through regulating the proliferation of osteoclast precursors |
| publisher |
BMC |
| publishDate |
2021 |
| url |
https://doaj.org/article/b5705a35020149179e6f97d2887d6a94 |
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1718372215880155136 |