Identification of Keratin 19-Positive Cancer Stem Cells Associating Human Hepatocellular Carcinoma Using 18 F-Fluorodeoxyglucose Positron Emission Tomography

The current lack of tools for easy assessment of cancer stem cells (CSC) prevents the development of therapeutic strategies for hepatocellular carcinoma (HCC). We previously reported that keratin 19 (K19) is a novel HCC-CSC marker and that PET with F-fluorodeoxyglucose ( F-FDG) is an effective method for predicting postoperative outcome in hepatocellular carcinoma. Herein, we examined whether K19 HCC-CSCs can be tracked using F-FDG-PET. K19 and glucose transporter-1 (GLUT1) expression was evaluated by IHC in 98 hepatocellular carcinoma patients who underwent F-FDG-PET scans before primary tumor resection. Standardized uptake values (SUV) for primary tumors and tumor-to-nontumor SUV ratios (TNR) were calculated using FDG accumulation levels, and values were compared among K19 /K19 patients. Using hepatocellular carcinoma cell lines encoding with a K19 promoter-driven enhanced GFP, F-FDG uptake and GLUT1 expression were examined in FACS-isolated K19 /K19 cells. In hepatocellular carcinoma patients, K19 expression was significantly correlated with GLUT1 expression and FDG accumulation. ROC analyses revealed that among preoperative clinical factors, TNR was the most sensitive indicator of K19 expression in hepatocellular carcinoma tumors. In hepatocellular carcinoma cells, FACS-isolated K19 cells displayed significantly higher F-FDG uptake than K19 cells. Moreover, gain/loss-of-function experiments confirmed that K19 regulates F-FDG uptake through TGFβ/Smad signaling, including Sp1 and its downstream target GLUT1. F-FDG-PET can be used to predict K19 expression in hepatocellular carcinoma and should thereby aid in the development of novel therapeutic strategies targeting K19 HCC-CSCs. .