IGF2BP3-mediated regulation of the RNA isoform and modification landscape in pancreatic cancer
TL;DR
Data show that IGF2BP3 is expressed consistently in PDAC, plays a dominant role in regulation of RNA splicing and modification, and supports cancer stem cell proliferation and survival, and represents an important therapeutic target in this tumour of unmet need.
Abstract
The incidence of pancreatic ductal adenocarcinoma (PDAC) is increasing but clinical outcomes remain poor and new treatments are required. IGF2BP3 is an oncofetal m6A-reading RNA regulatory protein whose expression is commonly observed in PDAC and which may represent an important therapeutic target. IGF2BP3 protein is expressed in >95% of primary tumours whilst RNA expression ranges from 3 to 3000-fold above normal epithelium. siRNA knockdown reveals IGF2BP3 to strongly support expression of gene programs related to DNA replication, cell cycle and apoptosis, TNF signalling and epithelial-mesenchymal transition. Direct sequencing of native RNA further reveals IGF2BP3-mediated enhancement of 863 RNA isoforms with suppression of 389 isoforms. m6A, m5C and pseudouridine (ψ) RNA modifications were seen in 97% of transcripts within the PDAC transcriptome and enriched within MYC gene targets. IGF2BP3 regulated the pattern of RNA modification with a substantial impact on m5C modifications of miRNA and scRNA, and genes associated with regulation of TNF signalling. Knockdown of IGF2BP3 expression in primary tumour organoid cultures suppressed proliferation and elicited apoptosis, indicating a critical requirement for IGF2BP3 within malignant stem cells. These data show that IGF2BP3 is expressed consistently in PDAC, plays a dominant role in regulation of RNA splicing and modification, and supports cancer stem cell proliferation and survival. IGF2BP3 therefore occupies a critical position within the RNA regulon of PDAC and represents an important therapeutic target in this tumour of unmet need.