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Abstract 529: PTEN status regulates let-7a-3p mediated therapeutic response in glioma stem cells

Cancers of the brain and central nervous system are among the leading cause of deaths in patients less than 40 years of age and second most common cancer types in children and adolescents. Glioblastoma (GBM) is the most common primary tumor of the central nervous system, and is highly invasive, proliferative and vascularized. A key player in the GBM pathogenesis is a distinct subpopulation of tumor cells which are capable of self-renewal, highly angiogenic and possess the potential for extensive proliferation and multi-lineage differentiation. This cell population termed Glioma Stem Cells (GSCs) is highly resistant to the chemo- and radiotherapies and plays an important role in tumor initiation, progression, and recurrence. In response to radiation therapy, GSCs can trigger the activation of multiple signaling pathways including Wnt, Notch, and Hedgehog, and their DNA damage repair system is proactive. The miRNA network adds a dimension of regulatory control, which serves to maintain pluripotency and reprograms multiple stemness and radioresistance promoting pathways. However, not much information is available that could provide mechanistic insights regarding how specific miRNAs modulate radioresistance pathways. Our initial efforts involving a global screening of microRNA profiles in different GSCs after radiation treatment resulted in identification of multiple microRNAs that were significantly altered in response to radiation. Based on our preliminary data, we selected let-7a-3p as one of the potential candidates. We used specific lentiviral constructs to manipulate let-7a-3p in GSCs, and carried out multiple in vitro studies to analyze the effects of the respective alteration in relation to radioresistance and proliferation. We also carried out an extensive in silico analysis to identify the potential targets of these microRNAs, followed by analyzing various downstream components of the target genes. Additionally, we carried out an assessment of the overall effects to probe if there is an integration of one or more pathways that could lead to radiation sensitivity. Our in vitro findings revealed a specific roles of let-7a-3p in regulating the radioresistance and proliferation of glioma cells, which was contingent upon the PTEN status of the cell type. Furthermore, we analyzed miR-seq data from TCGA for functional validation of our study and discovered a defined correlation of let-7a-3p and its downstream effectors. In conclusion, our study provides a basis for understanding the role of miRNAs in radioresistance phenotype and furthermore, it may lead towards another tool to inhibit GSC proliferation. Citation Format: Rajbir Singh, Kamalakannan Palanichamy, Saikh Jaharul Haque, Arnab Chakravarti. PTEN status regulates let-7a-3p mediated therapeutic response in glioma stem cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 529.