Abstract

Background

Early detection of colorectal cancer (CRC) is critical, as >95% of people diagnosed at stage I will survive. While stage I CRC represents a small proportion of symptomatic CRC cases, within bowel cancer screening, 42-48% of cancers are diagnosed at stage I. Despite this good prognosis, a small proportion of T1 colorectal tumours go on to develop distant metastasis. This is contrary to the classical “linear progression” model of metastasis, as even in the absence of nodal disease, some T1’s disseminate to a secondary site such as the liver, suggesting a “born-to-be-bad” biology. Using a small pilot cohort enriched for these highly aggressive T1 tumours, our data suggests that an enrichment for Parkinson’s disease (PD) related genes are involved in driving early stage CRC progression.

Method

A case-controlled cohort of T1 CRC tumours (n=41) with known relapse (n=10) vs non-relapse (n=31) status were subject to transcriptional profiling, revealing a significant upregulation of PD gene sets in the relapsed samples, in particular PARK7 (DJ-1). In vitro studies, including stress signalling and phenotypic assays, were performed to assess the role of PARK7 in CRC. 

Results

In CRC models, we show that PARK7 is crucial for sensing and scavenging both intrinsic and treatment-induced reactive oxidation species (ROS). We highlight the importance of a key cysteine residue for PARK7 function and subcellular localisation during this stress response. We also find that PARK7 expression is positively correlated with a stem-like phenotype and explore its role in regulating an invasive phenotype in CRC.

Conclusion

Aberrant expression of PARK7 may be a potential biomarker of aggressive tumour biology, particularly at the earliest stages of CRC.