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Abstract

Purpose: 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 18F-fluorodeoxyglucose (18F-FDG) is an effective method for predicting postoperative outcome in hepatocellular carcinoma. Herein, we examined whether K19+ HCC-CSCs can be tracked using 18F-FDG-PET.Experimental Design: K19 and glucose transporter-1 (GLUT1) expression was evaluated by IHC in 98 hepatocellular carcinoma patients who underwent 18F-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, 18F-FDG uptake and GLUT1 expression were examined in FACS-isolated K19+/K19- cells.Results: 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 18F-FDG uptake than K19- cells. Moreover, gain/loss-of-function experiments confirmed that K19 regulates 18F-FDG uptake through TGFβ/Smad signaling, including Sp1 and its downstream target GLUT1.Conclusions:18F-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. 

Author information​

Kawai T1,2, Yasuchika K3, Seo S1, Higashi T4, Ishii T1, Miyauchi Y1, Kojima H1, Yamaoka R1, Katayama H1, Yoshitoshi EY1,5, Ogiso S1, Kita S1, Yasuda K1,5, Fukumitsu K1, Nakamoto Y4, Hatano E1, Uemoto S1.

1 Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.

2 Department of Hepatobiliary Surgery and Liver Transplantation, Pitié-Salpétrière Hospital, University of Pierre and Marie Curie (UPMC), Paris, France.

3 Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan. kent@kuhp.kyoto-u.ac.jp.

4 Department of Diagnostic Radiology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.

5 Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto, Japan.