The Relationship Between Repetitive DNA & Radioresponse in Rectal Cancer

Colorectal cancer (CRC) is the third most common cancer worldwide with rectal cancer (RC) accounting for around 28% of cases. The current standard of care for rectal cancer involves pre-operative radiotherapy followed by surgery. Patient response to pre-operative treatment is unpredictable with around 20% of patients showing no response. The ability to predict patient response could prevent patients receiving unnecessary treatment. Ionising radiation is known to drive a global decrease in methylation which is most pronounced at Long Interspersed Nuclear Elements-1 (LINE1s). LINE1s are a family of retrotransposons which are heavily methylated and inactive in healthy cells. Hypomethylation of these elements is considered synonymous with their activation leading to genomic instability and drive the expression of coding & non-coding transcripts (e.g. LINE1 chimeric transcripts). The expression of LINE1s have not been thoroughly characterised in irradiated cells and how this correlates with radiosensitivity. This study aimed to uncover the relationship between these elements and radiosensitivity in addition to assessing the potential of resveratrol as a radiosensitiser. Resveratrol is a naturally occurring compound that has been shown to possess anti-cancer and antiinflammatory properties.

In this study, the expression profile of the L1-5’UTR and some known LCTs were characterised in two rectal cancer cell lines (SW837 & HT55) in response to radiation, resveratrol and combined treatment. Increased expression of the L1-5’UTR was observed in the sensitive SW837 cells compared with no increase in the resistant HT55 cells. Resveratrol treatment decreased survival when used alone however resulted in increased resistance when combined with radiation. SW837 clones stably expressing endo453 shRNA to knockdown the L1-5’UTR resulted in increased resistance however the control clones also showed some increased resistance. This study has shown possible links between LINE1 expression and radioresponse and further work is needed to validate whether this is the case.