Disclosures: The following people have nothing to disclose: Hirayuki Enomoto, Hideji Nakamura, Hiroyasu Imanishi, Noriko Ishii, Yukihisa Yuri, Tomoko Aoki,
Kazunori Yoh, Akio Ishii, Tomoyuki Takashima, Nobuhiro Aizawa, Yoshiyuki Sakai, Kazunari Iwata, Naoto Ikeda, Hironori Tanaka, Yoshinori Iwata, Masaki Saito, Hiroko Iijima, Shuhei Nishiguchi Background Stemness in cancer is currently of great interest as it can be used to predict prognosis of hepatocellular carcinoma (HCC). We recently proposed an HCC classification system defined by the stem cell markers epithelial cell adhesion molecule (EpCAM) and α-fetoprotein (AFP) to identify HCC subtypes closely related to certain liver lineages with distinct prognosis (Yamashita et al, Gastroenterology 2009). Here, we evaluated the utility Sirolimus purchase of determining serum Dickkopf-1 (DKK-1) levels, encoded by DKK1, a gene activated by Wnt signaling and co-regulated with EPCAM, for the diagnosis of HCC with stem cell features. Material and Methods Patients diagnosed with HCC at the Liver Center, Kanazawa University Hospital, Japan from 2005 to 2012 were enrolled. We measured serum DKK-1 levels using the human DKK-1 ELISA kit (Uscn Life Science Inc.). Hepatic stem cell-like (HpSC-) and mature hepatocyte-like
find more (MH-) HCCs were defined as previously described (Yamashita et al, Cancer Research 2008). Clinicopathological characteristics were determined and analyzed statistically in relation to serum DKK-1 concentrations using Kaplan-Meier survival analyses with log-rank tests, Cox proportional hazards models, Fisher’s exact tests,
and logistic regression models. Results The study included 357 HCC patients, 60 and 205 cases of whom had hepatitis B (HBV) or hepatitis C (HCV) infections, respectively. Mean serum DKK-1 levels were 209.3 pg/ml (range, 43.0–5556.3 pg/ml), and 54.4% of HCC patients showed elevated DKK-1 levels (DKK-1 high HCC) when a cut-off value of 200 pg/ml was used. Serum DKK-1 levels did not correlate with those of AFP learn more or des-γ-carboxy prothrombin (DCP), and tended to be higher in HBV-related (mean, 248.3 pg/ml) compared with HCV-related HCCs (mean, 182.1 pg/ml). Fifty-eight percent of HCC patients who were negative for AFP and DCP were DKK-1 high. HpSC-HCCs showed poor prognosis with high serum DKK-1 levels compared with MH-HCCs who received surgery, and DKK-1 high HCCs showed a significantly high frequency of portal vein invasion (p < 0.001). Among Barcelona Clinic Liver Cancer (BCLC) stage C patients treated with sorafenib or hepatic arterial infusion chemotherapy using interferon-alpha/5-FU/cisplatin, DKK-1 high HCCs showed a significantly poor prognosis compared with DKK-1 low HCCs (median overall survival 10.6 vs. 13.2 months: p=0.031, and 3.4 vs. 26.7 months: p=0.0005, respectively). Conclusions Serum DKK-1 is elevated in HCC with stem cell features.