Abstract
Intrahepatic cholangiocarcinoma (ICC) is the second most common primary liver cancer, with a 5-year survival rate of <10%; effective drug treatment for ICC is currently lacking. Glucagon-like peptide-1 receptor (GLP-1R) is upregulated in ICC; however, the functions of GLP-1R in ICC remain unknown. In this study, the upregulation of GLP-1R was confirmed in ICC cells using reverse transcription-quantitative polymerase chain reaction and western blot analysis, and GLP-1R was determined to promote the migration and invasion of ICC cells using Transwell assays. This tumor-promoting effect depended on the upregulation of epithelial-mesenchymal transformation-associated proteins, which was mediated by the FoxO1 signaling pathway. It was also indicated that following oxaliplatin treatment, the effects of GLP-1R on EMT and invasion were reversed. This functional reversion was associated with the reduced phosphorylation of S256 in forkhead box O1 (FoxO1) and an increase in the levels of unphosphorylated FoxO1. These findings suggest that incretin-based therapies may increase the risk of ICC metastasis and should not be used solely for the treatment of patients with ICC.
Highlights
IntroductionIntrahepatic cholangiocarcinoma (ICC) is a form of liver cancer typically diagnosed at advanced stages and with poor
Intrahepatic cholangiocarcinoma (ICC) is a form of liver cancer typically diagnosed at advanced stages and with poorKey words: intrahepatic cholangiocarcinoma, glucagon‐like peptide‐1, forkhead box O1, epithelial‐mesenchymal transformation, oxaliplatin prognosis; in the United States its incidence has increased to 3,000 cases annually [1]
It was indicated that mRNA and protein expression levels of Glucagon‐like peptide‐1 (GLP‐1) receptor (GLP‐1R) were significantly higher in the ICC cell lines RBE and HCCC‐9810 compared with the extrahepatic cholangiocarcinoma (ECC) lines QBC939 and SSP‐25 (Fig. 1A and B)
Summary
Intrahepatic cholangiocarcinoma (ICC) is a form of liver cancer typically diagnosed at advanced stages and with poor. Due to its ability to regulate blood glucose levels, GLP‐1 is widely used in clinic for patients with diabetes [10]. In addition to its hypoglycemic effect, GLP‐1 alleviates inflammation in intraepithelial lymphocytes of intestinal mucosal epithelium, confers antioxidative and neurogenerative effects in the brain, and protects vascular functions in the cardiovascular system [11]. GLP‐1 and GLP‐1R‐associated signaling promote tumor progression. Exendin‐4 with regards to diabetes, a GLP‐1 analog that has similar functions as GLP‐1, enhanced oxaliplatin‐mediated tumor suppression in ICC [16]. These conflicting data call for an in‐depth study on the GLP‐1R underlying mechanism of action in ICC
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