CCN2 promotes drug resistance in osteosarcoma by enhancing ABCG2 expression

• Published in: Journal of cellular physiology 2019-06, Vol.234 (6), p.9297-9307
• Main Authors: Tsai, Hsiao‐Chi, Chang, An‐Chen, Tsai, Chun‐Hao, Huang, Yuan‐Li, Gan, Lijun, Chen, Chi‐Kuan, Liu, Shih‐Chia, Huang, Te‐Yang, Fong, Yi‐Chin, Tang, Chih‐Hsin
• Format: Article
• Language: English
• Subjects: ABCG2; Animals; ATP; ATP Binding Cassette Transporter, Subfamily G, Member 2 - genetics; Base Sequence; Binding; Biocompatibility; Bone cancer; Breast cancer; Cancer; CCN2; Cell Line, Tumor; Cell Survival - genetics; Chemoresistance; chemotherapeutic resistance; Connective tissue growth factor; Connective Tissue Growth Factor - metabolism; Doxorubicin; Drug resistance; Drug Resistance, Neoplasm; Gene Expression Regulation, Neoplastic; Humans; Integrin alpha6beta1 - metabolism; Mice; MicroRNAs - genetics; MicroRNAs - metabolism; Models, Biological; Neoplasm Proteins - genetics; Osteosarcoma; Osteosarcoma - genetics; Proteins; Sarcoma; Signal Transduction; Survival; Xenobiotics; Xenografts; Xenotransplantation
• ISSN: 0021-9541; 1097-4652
• DOI: 10.1002/jcp.27611

In recent years, osteosarcoma survival rates have failed to improve significantly with conventional treatment modalities because of the development of chemotherapeutic resistance. The human breast cancer resistance protein/ATP binding cassette subfamily G member 2 (BCRP/ABCG2), a member of the ATP‐binding cassette family, uses ATP hydrolysis to expel xenobiotics and chemotherapeutics from cells. CCN family member 2 (CCN2) is a secreted protein that modulates the biological function of cancer cells, enhanced ABCG2 protein expression and activation in this study via the α6β1 integrin receptor and increased osteosarcoma cell viability. CCN2 treatment downregulated miR‐519d expression, which promoted ABCG2 expression. In a mouse xenograft model, knockdown of CCN2 expression increased the therapeutic effect of doxorubicin, which was reversed by ABCG2 overexpression. Our data show that CCN2 increases ABCG2 expression and promotes drug resistance through the α6β1 integrin receptor, whereas CCN2 downregulates miR‐519d. CCN2 inhibition may represent a new therapeutic concept in osteosarcoma. Chemoresistance is an important problem in osteosarcoma. CCN2 promotes drug resistance in osteosarcoma. CCN2 increases ABCG2 protein expression and activation in osteosarcoma