Expression of GLS1 in intrahepatic cholangiocarcinoma and its clinical significance

Abstract

Kidney-type glutaminase (GLS1) plays a significant role in tumor metabolism. Our recent studies demonstrated that GLS1 was aberrantly expressed in hepatocellular carcinoma (HCC) and facilitated tumor progression. However, the roles of GLS1 in intrahepatic cholangiocarcinoma (ICC) remain largely unknown. Thus, the aim of this study was to evaluate the expression and clinical significance of GLS1 in ICC. For this purpose, combined data from the Oncomine database with those of immunohistochemistry were used to determine the expression levels of GLS1 in cancerous and non-cancerous tissues. Second, a wound-healing assay and Transwell assay were used to observe the effects of the knockdown and overexpression of GLS1 on the invasion and migration of ICC cells. We examined the associations between the expression of GLS1 and epithelial-mesenchymal transition (EMT)-related markers by western blot analysis. Finally, we examined the associations between GLS1 levels and clinicopathological factors or patient prognosis. The results revealed that GLS1 was overexpressed in different digestive system tumors, including ICC, and that GLS1 expression in ICC tissue was higher than that in peritumoral tissue. The overexpression of GLS1 in RBE cells induced metastasis and invasion. Moreover, the EMT-related markers, E-cadherin and Vimentin, were regulated by GLS1 in ICC cells. By contrast, the knockdown of GLS1 expression in QBC939 cells yielded opposite results. Clinically, a high expression of GLS1 in ICC samples negatively correlated with E-cadherin expression and positively correlated with Vimentin expression. GLS1 protein expression was associated with tumor differentiation (P=0.001) and lymphatic metastasis (P=0.029). Importantly, patients with a high GLS1 expression had a poorer overall survival (OS) and a shorter time to recurrence than patients with a low GLS1 expression. Multivariate analysis indicated that GLS1 expression was an independent prognostic indicator. On the whole, the findings of this study demonstrated that GLS1 is an independent prognostic biomarker of ICC. GLS1 facilitates ICC progression and may thus prove to be a therapeutic target in ICC.

Targeting Glutaminolysis: New Perspectives to Understand Cancer Development and Novel Strategies for Potential Target Therapies

“…Xiang et al demonstrated that GLS1 expression was required for hypoxia-induced migration and invasion in vitro and for tumor growth and metastatic colonization in vivo in CRC cells (64). The important role of GLS1 also shows that the overexpression of GLS1 induced metastasis and invasion and promoted epithelial-mesenchymal transition (EMT) in intrahepatic cholangiocarcinoma (ICC) cells (86). In addition, Li et al demonstrated that targeting GLS1 not only reduced the expression of stemness-related genes including NANOG, OCT4, KLF4, SOX2 and c-Myc, but also suppressed CSC properties via ROS/Wnt/b-catenin signaling (81).…”

“…By transactivating GLS1 and GOT2 to enhance asparagine synthesis, SOX12 overexpression promotes CRC cell proliferation, migration, invasion, and metastasis (100). GLS1 was also reported to promote cell migration and invasion by regulating EMT in intrahepatic cholangiocarcinoma, in which GLS1 expression was higher in tumor tissues than in peritumoral tissues, and the higher expression of GLS1 independently predicted a poor survival (86). Besides, Ramirez-Peña et al found that experimentally induced EMT breast cancer cells showed a decreased GLS2 expression, which could be further restored by inhibiting the EMT transcription factor FOXC2 (101).…”

A comparative pharmaco-metabolomic study of glutaminase inhibitors in glioma stem-like cells confirms biological effectiveness but reveals differences in target-specificity

“…1b) and it is thought that these tumor compartments promote GSC enrichment through a mechanism called epithelial-mesenchymal (EMT)-like transition 35 . Concisely, GLS has been reported to regulate the expression of EMT markers in colorectal cancer 36,37 . To assess GLS expression in stem cell-enriched GBM Fig.…”

Evaluation of Glutaminase Expression in Prostate Adenocarcinoma and Correlation with Clinicopathologic Parameters

“…Several studies reported that increased GLS1 expression was associated with disease aggressiveness and could be used as a prognostic marker in select solid tumors [ 17 , 18 , 19 , 20 ]. However, there is a lack of high-quality studies analyzing GLS1 expression in PCa.…”