The biological implications of PDCD6 dysregulation in colorectal cancer

Abstract

Background: Programmed cell death protein 6 (PDCD6) mediates apoptosis via p53 dependent and independent pathways and is implicated in many cancer hallmarks. A multi-omics analysis of colorectal cancer (CRC) cell lines identified PDCD6 as a candidate prognostic and predictive biomarker. PDCD6 is dysregulated in different cancers, but the role of PDCD6 in CRC is still poorly understood. Methods: The clinicopathological data on 483 CRC patients treated at Mater Dei Hospital Malta between January 2008 and December 2011 were collated and tissue microarrays constructed in triplicate to represent central and peripheral tumour areas. PDCD6 protein expression was quantified by multiplex immunofluorescence (mIF; QuPath) along with fifteen other protein targets representing important cancer signalling and immune pathways. Expression of 770 genes was assessed using the NanoString nCounterVR PanCancer Pathways Panel in a subset of 34 patients with low/high PDCD6 expression. Associations with clinicopathological parameters including disease-free survival and overall survival (OS) were calculated. Results: Intra-tumoural PDCD6 protein expression was heterogeneous, having a higher expression at the tumour edge (p¼0.001). Invasive edge PDCD6 protein expression was significantly associated with TNMstage and tumour grade (p¼0.04 and<0.001, respectively), with lower PDCD6 expression in higher stage and poorly differentiated CRCs. PDCD6 expression was also associated with 5-year OS (p¼0.003), and higher PDCD6 expression revealed a trend towards longer OS. PDCD6 and Ki67