Abstract
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.
Highlights
Retinoblastoma (RB) is the most common intraocular malignancy in infants and childhood, with an incidence of 1/15,000–20,000 live births, and mortality from RB is about 70% in developing countries [1, 2]
Inhibition of miR-184 expression was rapid, starting at day 1 on exposure of Y79 (Figure 1D) and WERI cells (Figure 1E) in culture to vincristine (VCR), ETO, and carboplatin (CBP), which are agents commonly used systemically in RB treatment. These results indicate that miR184 may function as a tumor-suppressive miRNA and regulate chemosensitivity of RB cells
We measured the expression pattern of top 20 potential RB-suppressive miRNAs identified by microarray [5, 18] and confirmed that miR-184 is the most significantly decreased miRNA in human RB tissues, as well as chemoresistant cell line
Summary
Retinoblastoma (RB) is the most common intraocular malignancy in infants and childhood, with an incidence of 1/15,000–20,000 live births, and mortality from RB is about 70% in developing countries [1, 2]. This dismal outcome is mainly attributed to delayed diagnosis with the absence of perceptible pathological change and, more crucially, its inherent propensity of resistance to chemotherapy, which is currently one of the important treatment modalities for RB [3, 4]. MiRNAtargeted therapy provides an attractive antitumor approach for integrated cancer therapy
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