Defining microRNA mediated regulation of CD157 involved in colon cancer progression
Session type: Poster / e-Poster / Silent Theatre session
Progressive accumulation of mutations in oncogenic and tumour suppressor pathways (e.g., KRAS and p53) and also microRNA (miR) deregulation are associated with colorectal cancer (CRC) development. Very little has been done to dissect specific CRC pathways involved in miR regulation in response to stress and metabolic changes. Therefore, we investigated the interaction between miR-mediated regulation of bone marrow stromal cell antigen 1 (BST1) or CD157, a metabolic enzyme involved in the conversion of nicotinamide adenine dinuclease (NAD) to paracrine factor cyclic ADP ribose (cADPR), following the acquisition of KRAS mutation in metastatic CRC.
A combination of array analysis data, in-silico prediction tools and nuclear magnetic resonance (NMR) system were used to analyse gene (mRNA) and miR expression, as well as metabolic changes associated with different rounds of knock in/out mutations in Apc, Kras, and p53 CRC mouse models and their tumour-derived organoids (TDOs). Subsequently, we genetically modified human CRC cell lines and patients KRAS mutant (mut) TDOs from CRC metastases to modulate the candidate gene and miR. Organoids formation, growth rate and viability were measured with Live-Cell imaging systems.
We identified mRNA/miR networks involved in cancer metabolic pathways and assessed the most significant candidates. Further target validation and analysis of human tissues microarrays showed an association between KRAS mutations, miR-203 down-regulation and over-expression of BST1, which was identified as a direct target of miR-203 regulation in our studies. Repressing BST1 and over-expressing miR-203 had a significant effect on the proliferation and migration abilities of organoids in 3D culture in normal and calorie-deprived conditions.
This project aimed to find a promising candidate as a therapeutic target in KRAS mut CRC. Although we showed KRAS mut CRC cells lost a growth advantage with miR-203 and BST1 deregulation ex vivo, work is on going to confirm the consequence of their interaction in vivo.