The characterisation of SORT1A variants and their impact on lung cancer tumourigenesis

Abstract

With a global estimated 2.2 million diagnoses and 1.8 million deaths in 2020, lung cancer is the leading cause of cancer-related deaths. During the proliferation of lung cancer cells, Epidermal Growth Factor Receptor (EGFR) transmits signals from the microenvironment, allowing relevant signalling pathways to initiate cell proliferation. Sortilin (SORT1) is a member of the vacuolar protein sorting receptor 10 (VPS10) family and is a multifaceted receptor involved in many pathways; however, it can regulate EGFR internalisation. The decrease in SORT1 expression in cancerous lung cells is induced by EGFR signalling at the cell surface, thereby maintaining uncontrolled cell proliferation. Recently, two variants of SORT1 were discovered (SORT1A1 and SORT1A2), yet their individual functions remain unknown. Using a variety of in vitro methods in this investigation, that include immunofluorescence, Western blotting, cell death assay, and cellular metabolism assay, to provide preliminary insights into the differences between the variants. Through this study, distinct cellular localisations of SORT1A1 and SORT1A2 were identified: SORT1A1 was localised in the nucleus, whereas SORT1A2 was found at the cell membrane, as visualised by immunofluorescence. In addition, a potential difference in half-life between the SORT1 isoforms was observed, which may correspond with their distinct cellular localisations and provide valuable insight into the key functional differences between them. This finding suggests that the variants may play distinct roles within their respective pathways. More broadly, it could help address existing controversies in the literature by offering a clearer understanding of the roles of SORT1 isoforms in different disease.

Date of Award	2025
Original language	English
Awarding Institution	Canterbury Christ Church University