Overexpression of sortilin is associated with 5-FU resistance and poor prognosis in colorectal cancer.

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. © 2020 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.

Citation

Sabrina Blondy, Hugo Talbot, Sofiane Saada, Niki Christou, Serge Battu, Julie Pannequin, Marie-Odile Jauberteau, Fabrice Lalloué, Mireille Verdier, Muriel Mathonnet, Aurélie Perraud. Overexpression of sortilin is associated with 5-FU resistance and poor prognosis in colorectal cancer. Journal of cellular and molecular medicine. 2021 Jan;25(1):47-60

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PMID: 33325631

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