| Affiliation: | 1. Laboratoire EA3842 Contrôle de l’Activation Cellulaire, Progression Tumorale et Résistances thérapeutiques «CAPTuR», Faculté de médecine, Limoges, France Contribution: Conceptualization (equal), Formal analysis (equal), Methodology (equal), Writing - original draft (equal);2. Laboratoire EA3842 Contrôle de l’Activation Cellulaire, Progression Tumorale et Résistances thérapeutiques «CAPTuR», Faculté de médecine, Limoges, France;3. IGF, Université Montpellier, CNRS, INSERM, Montpellier Cedex 5, France |
| Abstract: | Colorectal cancer (CRC) is the third most common cancer worldwide. Even if 5-fluorouracil (5-FU) is used as the first-line chemotherapeutic drug, responsiveness is only 20-30%. Acquired resistance to 5-FU contributes to both poor patient prognosis and relapse, emphasizing the need to identify biomarkers. Sortilin, a vacuolar protein sorting 10 protein (Vps10p), implicated in protein trafficking, is over expressed in CRC cell lines cultured 72 hours in presence of 5-FU. This overexpression was also observed in 5-FU-resistant cells derived from these cell lines as well as in CRC primary cultures (or patients derived cell lines). A significantly higher expression of sortilin was observed in vivo, in 5-FU-treated tumours engrafted in Nude mice, as compared with non-treated tumour. A study of transcriptional regulation allowed identifying a decrease in ATF3 expression, as an explanation of sortilin overexpression following 5-FU treatment. In silico analysis revealed SORT1 expression correlation with poor prognosis. Moreover, sortilin expression was found to be positively correlated with CRC tumour grades. Collectively, our findings identify sortilin as a potential biomarker of 5-FU resistance associated with poor clinical outcomes and aggressiveness in CRC. As a new prognostic factor, sortilin expression could be used to fight against CRC. |
