Tumor Suppressor miR-184 Enhances Chemosensitivity by Directly Inhibiting SLC7A5 in Retinoblastoma

• Main Authors: Tian-Geng He, Zi-Yun Xiao, Yi-Qiao Xing, Hua-Jing Yang, Hong Qiu, Jian-Bin Chen
• Format: Article
• Language: English
• Published: Frontiers Media S.A. 2019-11-01
• Series: Frontiers in Oncology
• Subjects: miR-184; SLC7A5; apoptosis; cell cycle; chemosensitivity; retinoblastoma
• Online Access: https://www.frontiersin.org/article/10.3389/fonc.2019.01163/full

The expression patterns and functional roles of miRNAs in retinoblastoma (RB) are poorly understood, especially those involved in chemoresistance. Here, we validated the expression pattern of 20 potential RB-suppressive miRNAs and confirmed that miR-184 is the most significantly decreased miRNA in human RB tissues, as well as chemoresistant cell line. Bioinformatic and molecular analyses revealed that SLC7A5 has three binding sites of miR-184 and significantly increased in RB tissues. miR-184 negatively correlated with SLC7A5 expression in RB tissues and mainly target position 2494-2513 of the SLC7A5 3′UTR to inhibit its expression. Furthermore, enforced expression of miR-184 reversed the oncogenic roles of SLC7A5 on proliferation, migration, and invasion of RB cells. In addition, miR-184 also enhances chemosensitivity of RB cells via inducing apoptosis and G2/M cell cycle arrest. Molecular studies revealed that miR-184-decreased phosphorylation status of known DNA damage repair sensors of the ATR/ATM pathways and induced persistent formation of γH2AX foci depend on targeting SLC7A5, leading to persistent DNA damage. Thus, targeting the miR-184/SLC7A5 pathway will provide new opportunities for drug development to reverse chemotherapeutic resistance in RB.