Abstract
Hyperactivation of Wnt and Ras-MAPK signalling are common events in development of colorectal adenomas. Further progression from adenoma-to-carcinoma is frequently associated with 20q gain and overexpression of Aurora kinase A (AURKA). Interestingly, AURKA has been shown to further enhance Wnt and Ras-MAPK signalling. However, the molecular details of these interactions in driving colorectal carcinogenesis remain poorly understood. Here we first performed differential expression analysis (DEA) of AURKA knockdown in two colorectal cancer (CRC) cell lines with 20q gain and AURKA overexpression. Next, using an exact algorithm, Heinz, we computed the largest connected protein-protein interaction (PPI) network module of significantly deregulated genes in the two CRC cell lines. The DEA and the Heinz analyses suggest 20 Wnt and Ras-MAPK signalling genes being deregulated by AURKA, whereof β-catenin and KRAS occurred in both cell lines. Finally, shortest path analysis over the PPI network revealed eight ‘connecting genes’ between AURKA and these Wnt and Ras-MAPK signalling genes, of which UBE2D1, DICER1, CDK6 and RACGAP1 occurred in both cell lines. This study, first, confirms that AURKA influences deregulation of Wnt and Ras-MAPK signalling genes, and second, suggests mechanisms in CRC cell lines describing these interactions.
Highlights
Chromosomal arm 20q is frequently gained in CRC8,9 and has a strong association with the progression of colorectal adenoma to carcinoma[10]
The genetics differ between these cell lines, they originate from different individuals and have different germline variations, and they have progressed to carcinomas independently and differ in their somatic alterations, such as DNA mutations and DNA copy number alterations
The number of significantly expressed genes in response to Aurora kinase A (AURKA) downmodulation at a q-value less than 0.05 was 2,057 and 3,606 in SW480 and Caco[2], respectively. 924 genes were significantly deregulated in both cell lines, whereof 50 were deregulated in opposite directions
Summary
Chromosomal arm 20q is frequently gained in CRC8,9 and has a strong association with the progression of colorectal adenoma to carcinoma[10]. AURKA itself has been shown to be a target gene of both MAPK1/ERK2 signalling in pancreatic cancer cells[22] and Wnt/β-catenin signalling in multiple myeloma[23] These data suggest a positive feedback loop from hyperactive proliferative signalling to AURKA overexpression, further inducing proliferative signalling cells[21]. All this implies that there is interplay between AURKA and the Wnt and Ras-MAPK signalling pathways and vice versa in different cancer settings. We used two distinct cell lines, SW480 and Caco[2], both derived from colon carcinomas with 20q copy number gain and mutated TP53. Using SW480 and Caco[2], we set out to investigate which key players and molecular interactions are involved in the interplay between AURKA and the Wnt and Ras-MAPK pathways that may drive progression of CRC
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