title: Integrated Analysis of Dysregulated miRNA-gene Expression in HMGA2-silenced Retinoblastoma Cells.
abstract: Retinoblastoma (RB) is a primary childhood eye cancer. HMGA2 shows promise as a molecule for targeted therapy. The involvement of miRNAs in genome-level molecular dys-regulation in HMGA2-silenced RB cells is poorly understood. Through miRNA expression microarray profiling, and an integrated array analysis of the HMGA2-silenced RB cells, the dysregulated miRNAs and the miRNA-target relationships were modelled. Loop network analysis revealed a regulatory association between the transcription factor (SOX5) and the deregulated miRNAs (miR-29a, miR-9*, miR-9-3). Silencing of HMGA2 deregulated the vital oncomirs (miR-7, miR-331, miR-26a, miR-221, miR-17~92 and miR-106b∼25) in RB cells. From this list, the role of the miR-106b∼25 cluster was examined further for its expression in primary RB tumor tissues (n = 20). The regulatory targets of miR-106b∼25 cluster namely p21 (cyclin-dependent kinase inhibitor) and BIM (pro-apoptotic gene) were elevated, and apoptotic cell death was observed, in RB tumor cells treated with the specific antagomirs of the miR-106b∼25 cluster. Thus, suppression of miR-106b∼25 cluster controls RB tumor growth. Taken together, HMGA2 mediated anti-tumor effect present in RB is, in part, mediated through the miR-106b∼25 cluster.
authors.affiliation: Larsen and Toubro Department of Ocular Pathology, Vision Research Foundation, Sankara Nethralaya, Chennai, India. ; Birla Institute of Technology and Science (BITS), Pilani, Rajasthan, India.
authors.forename: Nalini
authors.initials: N
authors.lastname: Venkatesan
authors.affiliation: Department of Biological Sciences, Birla Institute of Technology and Science (BITS) - Pilani, Rajasthan, India.
authors.forename: Pr
authors.initials: P
authors.lastname: Deepa
authors.affiliation: Bionivid Technology [P] Ltd, Kasturi Nagar, Bangalore, India.
authors.forename: Madavan
authors.initials: M
authors.lastname: Vasudevan
authors.affiliation: Sri Bhagawan Mahavir Department of Vitreoretinal and Ocular Oncology, Medical Research Foundation, Sankara Nethralaya, Chennai, India.
authors.forename: Vikas
authors.initials: V
authors.lastname: Khetan
authors.affiliation: Department of Ophthalmology, Barts Health NHS Trust, London, UK.
authors.forename: Ashwin M
authors.initials: AM
authors.lastname: Reddy
authors.affiliation: Larsen and Toubro Department of Ocular Pathology, Vision Research Foundation, Sankara Nethralaya, Chennai, India.
authors.forename: Subramanian
authors.initials: S
authors.lastname: Krishnakumar
keywords: Antagomirs; High mobility group proteins (HMG)A2; Integrated mRNA-miRNA analysis; Retinoblastoma; miR-106b-25 cluster