Characterisation of the Arachidonic Acid Metabolising Pathway in Colorectal Cancer


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Graeme Murray1,Abdo Alnalbulsi1,Rebecca Swan1,Beatriz Cash2,Ayahm Alnabulsi2
1University of Aberdeen,2Vertebrate Antibodies

Abstract

Background

Colorectal cancer is one of the most common type of cancer in the developed world. Arachidonic acid is converted by individual cytochrome P450 enzymes to epoxyeicosatrienoic acids which have been implicated in various cancer-associated biological processes. Thus, the aim of this study was to profile the expression of arachidonic acid metabolising enzymes in primary colorectal cancer and assess the association between their expression and prognosis.

Method

Monoclonal antibodies to CYP4A11, CYP4F11, CYP4V2 and CYP4Z1 were developed and successfully characterised by immunoblotting and immunohistochemistry. The antibodies were then used to profile the expression of those enzymes by immunohistochemistry on a large and well characterised colorectal cancer cohort (n=650) arrayed on a tissue microarray. The immunohistochemistry results were interpreted by light microscopy using a semi-quantitative scoring system.

Results

For each antibody, immunoblotting using lysate overexpressing the relevant protein resulted in a band migrating at the expected molecular weight. The expression of CYP4A11 (p<0.001), CYP4F11 (p<0.001) and CYP4V2 (p<0.001) were significantly higher in primary tumour when compared to normal mucosa. While, significant reduction in the expression of CYP4A11 (P=0.007), CYP4F11 (P<0.001), CYP4V2 (P<0.001) was observed in lymph node metastasis compared with their corresponding primary tumours. The presence of strong CYPA11 immunoreactivity was associated with significantly reduced survival in the whole patient cohort (χ2=7.234, p=0.007) and in mismatch repair (MMR) proficient tumours (χ2=9.404, p=0.002). CYP4F11 immunoreactivity was significantly associated with poor survival in MMR deficient tumours (χ2=4.684, p=0.03).

Conclusion

In conclusion, arachidonic acid metabolising enzymes CYP4A11, CYP4V2 and CYP4F11 are significantly overexpressed in patients with colorectal cancer. The high expression of CYP4A11 is significantly associated with poor survival.