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Title: Long and short noncoding RNAs in the control of cancer stem cell traits
Author: de Giorgio, Alexander James Robert
ISNI:       0000 0004 9356 6360
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2017
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Noncoding RNAs (ncRNAs) are now viewed as integral components of gene expression networks in human cells, including cancerous ones. Investigating the precise roles they play in varied cellular contexts has become a separate field within cancer research. In pancreatic adenocarcinoma (PDAC), TGFβ signalling induces EMT and stemness, yet the involvement of specific ncRNAs remains unknown. We identified two miRNAs, miR-100 and -125b, to be substantially elevated following TGFβ stimulation, noting that they derive from the same primary transcript. Modulating levels of miR-100 and -125b decreases migration and pancsphere formation. Unexpectedly, miR-100 and -125b appear to use different rules of miRNA-target base pairing, with an enrichment of non-canonical miR-100 seed matches occurring in the CDS. Clinically, both miR-100 and -125b were elevated in a large PDAC dataset compared to normal tissue, with high expression associated with lower patient survival. In stark contrast to the persistently poor prognosis for PDAC patients, breast cancer survival has improved markedly. Lethal properties of this disease, such as chemoresistance and metastasis, have been linked to insufficiently characterised minority breast cancer stem cell (BCSC) populations that may survive available treatments to regenerate tumours, and can be migratory and invasive. Whether ncRNAs play prominent roles in BCSC generation and behaviour is also largely unresolved. Generating mammospheres to enrich for BCSCs, we found several long noncoding RNAs (lncRNAs) to be differentially expressed compared to adherent cells. Silencing three of these lncRNAs produced significant impacts on mammsphere formation efficiency. We focused on Candidate 1, strongly upregulated in mammospheres, yet unexpectedly increasing mammsphere formation when silenced. Candidate 1 was chromatin-associated, correlated with chromatin-regulators in TCGA data, and positively associated with survival. Candidate 1 silencing produced marked transcriptomic changes when silenced, and bound strongly to the polyfunctional protein HNRNP L, enabling us to speculate as to its potential mechanism of action.
Supervisor: Stebbing, Justin ; Castellano, Leandro Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral