Please use this identifier to cite or link to this item: https://scholarbank.nus.edu.sg/handle/10635/143083
Title: ANTISENSE OLIGONUCLEOTIDES: FROM MECHANISTIC STUDIES TO CANCER THERAPY
Authors: TABAGLIO TOMMASO
Keywords: antisense oligonucleotide, MDM4, MBNL1, splicing, AON, ASO
Issue Date: 24-Jan-2018
Citation: TABAGLIO TOMMASO (2018-01-24). ANTISENSE OLIGONUCLEOTIDES: FROM MECHANISTIC STUDIES TO CANCER THERAPY. ScholarBank@NUS Repository.
Abstract: Alternative splicing (AS) plays a pivotal role in the insurgency and/or progression of a vast number of diseases, including cancer. Different isoforms can critically influence the biological function of SFs, with reported cases of a single gene behaving as oncogene or oncosuppressor, depending on its AS. In the first section of this thesis, we exploited a naturally occurring splicing event in order to downregulate the expression of the MDM4 in melanoma. Specifically, we used an Antisense OligoNucleotide (AON) that induces the skipping of MDM4 exon 6 with a subsequent nonsense-mediated decay of the transcript, triggering apoptosis in multiple cancer cells. In the second part, we looked for differential AS events involving splicing factors in prostate cancer datasets. We identified the MBNL1 transcript being differently spliced between normal prostate and prostate cancer tissues. In fact, exon7 of MBNL1 is more included in the mRNA of tumor samples compared to normal tissues. Through RNAi screens we discovered that three of the main components of the U2 splicing complex are required for efficient exon7 inclusion. We next demonstrated that ex7 is indispensable for cell survival in vitro, showing that MBNL1 isoforms lacking this exon act as dominant negative factors.
URI: http://scholarbank.nus.edu.sg/handle/10635/143083
Appears in Collections:Ph.D Theses (Open)

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