Glutamine deficiency promotes recurrence and metastasis in colorectal cancer through enhancing epithelial–mesenchymal transition

Abstract

BACKGROUND: Glutamine is the most abundant amino acid in the body and plays a vital role in colorectal cancer (CRC) cell metabolism. However, limited studies have investigated the clinical and prognostic significance of preoperative serum glutamine levels in patients with colorectal cancer, and the underlying mechanism has not been explored. METHODS: A total of 121 newly diagnosed CRC patients between 2012 and 2016 were enrolled in this study. Serum glutamine levels were detected, and their associations with clinicopathological characteristics, systemic inflammation markers, carcinoembryonic antigen (CEA) and prognosis were analysed. In addition, the effect of glutamine depletion on recurrence and metastasis was examined in SW480 and DLD1 human CRC cell lines, and epithelial-mesenchymal transition (EMT)-related markers were detected to reveal the possible mechanism. RESULTS: A decreased preoperative serum level of glutamine was associated with a higher T-class and lymph node metastasis (P < 0.05). A higher serum level of glutamine correlated with a lower CEA level (r = - 0.25, P = 0.02). Low glutamine levels were correlated with shorter overall survival (OS) and disease-free survival (DFS). Multivariate Cox regression analysis showed that serum glutamine was an independent prognostic factor for DFS (P = 0.018), and a nomogram predicting the probability of 1-, 3- and 5-year DFS after radical surgery was built. In addition, glutamine deficiency promoted the migration and invasion of CRC cells. E-cadherin, a vital marker of EMT, was decreased, and EMT transcription factors, including zeb1and zeb2, were upregulated in this process. CONCLUSIONS: This study elucidated that preoperative serum glutamine is an independent prognostic biomarker to predict CRC progression and suggested that glutamine deprivation might promote migration and invasion in CRC cells by inducing the EMT process.