Exosomal Transfer of LCP1 Promotes Osteosarcoma Cell Tumorigenesis and Metastasis by Activating the JAK2/STAT3 Signaling Pathway

Xuhui Ge; Wei Liu; Wene Zhao; Shuang Feng; Ao Duan; Chengyue Ji; Kai Shen; Wanshun Liu; Jiawen Zhou; Dongdong Jiang; Yuluo Rong; Fangyi Gong; Jiaxing Wang; Zhiyang Xu; Xiaoyan Li; Jin Fan; Yongzhong Wei; Jianling Bai; Weihua Cai

doi:10.1016/j.omtn.2020.07.025

Exosomal Transfer of LCP1 Promotes Osteosarcoma Cell Tumorigenesis and Metastasis by Activating the JAK2/STAT3 Signaling Pathway

Mol Ther Nucleic Acids. 2020 Sep 4:21:900-915. doi: 10.1016/j.omtn.2020.07.025. Epub 2020 Jul 23.

Authors

Xuhui Ge¹, Wei Liu¹, Wene Zhao², Shuang Feng³, Ao Duan¹, Chengyue Ji¹, Kai Shen¹, Wanshun Liu¹, Jiawen Zhou⁴, Dongdong Jiang¹, Yuluo Rong¹, Fangyi Gong¹, Jiaxing Wang¹, Zhiyang Xu², Xiaoyan Li², Jin Fan¹, Yongzhong Wei⁵, Jianling Bai⁶, Weihua Cai⁷

Affiliations

¹ Department of Orthopedics, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, China.
² Department of Analytical & Testing Center, Nanjing Medical University, Nanjing, Jiangsu 211166, China.
³ Department of Encephalopathy, The Third Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210001, China.
⁴ Research Center for Bone and Stem Cells, Department of Human Anatomy, Key Laboratory for Aging & Disease, The State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, Jiangsu 211166, China.
⁵ Department of Orthopedics, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, China. Electronic address: weiyongzhong@jsph.org.cn.
⁶ Department of Biostatistics, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu 211166, China. Electronic address: baijianling@njmu.edu.cn.
⁷ Department of Orthopedics, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, China. Electronic address: caiwhspine@sina.com.

Abstract

Increasing evidence indicates that lymphocyte cytosolic protein 1 (LCP1) overexpression contributes to tumor progression; however, its role in osteosarcoma (OS) remains unclear. We aimed to investigate the potential effect of LCP1 in OS and the underlying mechanisms. We first demonstrated that LCP1 is upregulated in OS cell lines and tissues. Then, we found that aberrant expression of LCP1 could induce the proliferation and metastasis of OS cells in vitro and in vivo by destabilizing neuregulin receptor degradation protein-1 (Nrdp1) and subsequently activating the JAK2/STAT3 signaling pathway. When coculturing OS cells with bone marrow-derived mesenchymal stem cells (BMSCs) in vitro, we validated that oncogenic LCP1 in OS was transferred from BMSCs via exosomes. Moreover, microRNA (miR)-135a-5p, a tumor suppressor, was found to interact upstream of LCP1 to counteract the pro-tumorigenesis effects of LCP1 in OS. In conclusion, BMSC-derived exosomal LCP1 promotes OS proliferation and metastasis via the JAK2/STAT3 pathway. Targeting the miR-135a-5p/LCP1 axis may have potential in treating OS.

Keywords: BMSCs; JAK2/STAT3 pathway; exosomal LCP1; miR-135a-5p; osteosarcoma.