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Title: The prognostic potential of the long non-coding RNA MALAT1 and LDH related metabolism in prostate cancer
Author: Hiew, Kenneth
Awarding Body: University of Manchester
Current Institution: University of Manchester
Date of Award: 2018
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Purpose: To identify the role of MALAT1 expression during prostate cancer progression (Chapter 2). To examine the association of MALAT1 expression and clinico-pathological demographics of the Salford and Christie cohort (Chapter 3). To explore the relationship between MALAT1 and EMT and PI3K/Akt pathway (Chapter 4). The Christie cohort comprised a classic group with mature clinical data linked to docetaxel treatment response at castrate level. As such, this biomarker project diverged to explore the genomic landscape of primary prostate cancer between responders and nonresponders to docetaxel chemotherapy for the treatment of mCRPC (Chapter 5). Methods: I have performed a meta-analysis of MALAT1 expression in a pan-cancer cohort (the Bittner Multi-cancer dataset) and several independent PCA patient cohorts. I have examined MALAT1 expression in a panel of prostate cancer cell lines using RT-PCR (Chapter 2). Tumour specific RNA was extracted from diagnostic prostate biopsies with matured clinical data and analysed using 405-gene NanoStringÒ gene expression platform (Chapter 3). Volcano plot analysis in NanoStringÒ gene expression platform and Immunoflurorescence stain in diagnostic prostate biopsies was performed (Chapter 4). Validation studies using multitranscript FluidigmÒ RT-PCR platform in PC3 cell lines (Chapter 4). In vitro knockdown of MALAT1 with siRNA was conducted in association with assays for invasion (Chapter 4). Meta-analysis of the MSKCC cohort was performed to study the correlation between MALAT1 and genes related to EMT and PI3K/Akt pathway (Chapter 4). Targeted next-generation sequencing from the training and test set (a subset of the Christie cohort) were performed (Chapter 5). Results: MALAT1 was consistently altered between normal tissue and metastatic prostate tumours. MALAT1 was associated with higher Gleason score (Chapter 2 &3). The addition of MALAT1 to D'Amico classification improved the performance of the prognostic tool and MALAT1 expression is a predictor in survival outcome (Chapter 3). There was consistent link between MALAT1 and ZEB1 expression in our NanoStringÒ gene expression platform analysis and meta-analysis of MSKCC cohort (Chapter 4). Knockdown of MALAT1 suppressed PIK3CB but increased expression of TP53. Finally, the knockdown of MALAT1 suppressed PC3 cellular invasion (Chapter 4). Genomic analysis showed that patients with LDH =450U/L (9/14,64.3%) were more likely to have had DNA repair gene mutation(s) (BRCA1/2, ATM, CHEK2 and Fanconi's anemia gene) in their primary biopsy (Chapter 5). Meta-analysis of MSKCC database revealed a positive correlation between LDHA and PARP1 gene (r=0.667, p < 0.01) and other DNA repair genes (Chapter 5). This correlation was also observed in the SU2CF-PCF cohorts (Chapter 5). Conclusions: MALAT1 displayed significantly altered expression throughout prostate cancer progression (Chapter 2). MALAT1 expression in diagnostic biopsies had prognostic potential in prostate cancer (Chapter 3). MALAT1 expression mediated the EMT processes via PI3K/Akt pathway (Chapter 4). High pre-treatment serum LDH is coupled with mutations in the DNA repair pathway in primary biopsy and this correlates with poor docetaxel response and overall survival in men with mCRPC (Chapter 5).
Supervisor: Brown, Michael Sponsor: Not available
Qualification Name: Thesis (M.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: prostate cancer ; LncRNA ; MALAT1 ; cancer metabolism ; prognostic biomarker