Dottoressa di ricerca

ciclo: XXXV

supervisore: Rosa Sorrentino
relatore: Lucia Ricci Vitiani
co-supervisore: Lucia Ricci Vitiani

Titolo della tesi: Molecular expression and characterisation of non-coding RNA in tumor growth and invasiveness of glioblastoma stem-like cells

Glioblastoma (GBM) is an aggressive form of glioma in adults that owes its worse characteristics, like recurrence and resistance to therapy, mainly to GBM stem-like cells (GSCs). In vitro studies employ GSCs to generate self-renewing cell lines that can mimic the original tumor. We performed analyses on our collection of patient-derived GSC lines to study long non-coding RNAs (lncRNAs) and micro RNAs (miRNAs), important oncogenic drivers and tumor suppressors in many tumors. Our work revealed that the microRNA miR-370-3p is significantly down-regulated in GSCs compared to a normal control and, when restored, the proliferation, migration and clonogenic abilities of GSCs are impaired. Another effect of miR-370-3p restoration became clear after gene expression analyses, which identified several transcripts involved in Epithelial to Mesenchymal Transition (EMT), and Hypoxia signalling pathways. Surprisingly, among the genes down-regulated as a result of miR-370-3p restored expression, we found more genes correlated to GBM, like the EMT-inducer high-mobility group AT-hook 2 (HMGA2), the master transcriptional regulator of the adaptive response to hypoxia, Hypoxia-inducible factor (HIF)1A, and the long non-coding RNA (lncRNA) Nuclear Enriched Abundant Transcript (NEAT1). In particular, NEAT1 is an oncogenic lncRNA, associated to worse prognosis for several cancers: we found by luciferase assay that miR-370-3p directly binds NEAT1, so that the expression levels of these ncRNAs are inversely correlated in GSCs. Our results suggest that a complex “cascade” interplaying among different ncRNAs is partially responsible for GBM’s most malignant features. Indeed, miR-370-3p shows a prominent tumor-suppressor function by targeting mRNAs involved in EMT, in hypoxia pathways, and cell growth and the invasiveness enhancer NEAT1, making this microRNA another promising candidate for novel GBM treatments.

Produzione scientifica

  • 11573/1486457 - 2020 - Mir-370-3p impairs glioblastoma stem-like cell malignancy regulating a complex interplay between HMGA2/HIF1A and the oncogenic long non-coding RNA (LncRNA) NEAT1 (01a Articolo in rivista)
  • 11573/1665700 - 2023 - Molecular expression and characterisation of non-coding RNA in tumor growth and invasiveness of glioblastoma stem-like cells (07a Tesi di Dottorato)

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