ISSN: 1837-9664Journal of Cancer
Global reach, higher impact
J Cancer 2021; 12(19):5903-5913. doi:10.7150/jca.60969 This issue Cite
Research Paper
The miR-193a-5p/NCX2/AKT axis promotes invasion and metastasis of osteosarcoma
1. Department of Orthopedics, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China.
2. Hunan Key Laboratory of Tumor Models and Individualized Medicine, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China.
3. Key Laboratory of Protein Chemistry and Developmental Biology of the Ministry of Education, College of Life Science, Hunan Normal University, Changsha 410081, Hunan, China.
4. Hunan Key Laboratory of Pharmacodynamics and Safety Evaluation of New Drugs & Hunan Provincial Research Center for Safety Evaluation of Drugs, Changsha 410331, Hunan, China.
# Present address: Department of Clinical Laboratory, Chongzuo People's Hospital, Chongzuo 532200, Guangxi, China.
Abstract
MiR-193a-5p has been observed to have oncogenic or tumor suppressive functions in different kinds of cancers, but its role and molecular mechanism in osteosarcoma are elusive. Na+/Ca2+ exchangers (NCX1, NCX2 and NCX3) normally extrude Ca2+ from the cell, and deregulation of the intracellular Ca2+ homeostasis is related to several kinds of diseases, including cancer. The present study demonstrated that miR-193a-5p was upregulated in osteosarcoma tissues compared with the corresponding adjacent noncancerous tissues, and promoted colony formation, migration, invasion and epithelial-mesenchymal transition (EMT) in osteosarcoma cells (SaOS-2 and U-2OS), as well as metastasis in a murine xenograft model. Tandem mass tag-based quantitative proteomics analysis identified NCX2 as a potential target of miR-193a-5p. Luciferase activity assays and Western blotting further confirmed that miR-193a-5p recognized the 3′-untranslated region of NCX2 mRNA, and negatively regulated NCX2 expression. NCX2 was downregulated in osteosarcoma tissues, and its expression was negatively correlated with miR-193a-5p levels. Ectopic expression of NCX2 in osteosarcoma cells could reverse the oncogenicity of miR-193a-5p, indicating that miR-193a-5p exerted its effects by targeting NCX2. Further study demonstrated that NCX2 suppresses Ca2+-dependent Akt phosphorylation by decreasing intracellular Ca2+ concentration, and then inhibited EMT process. Treatment with the antagomir against miR-193a-5p sensitized osteosarcoma to the Akt inhibitor afuresertib in a murine xenograft model. In conclusion, a miR-193a-5p/NCX2/AKT signaling axis contributes to the progression of osteosarcoma, which may provide a new therapeutic target for osteosarcoma treatment.
Keywords: miR-193a-5p, NCX2, AKT, osteosarcoma, metastasis
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