Neighbor of punc E11, a novel oncofetal marker for hepatocellular carcinoma

Abstract

Hepatocellular carcinoma (HCC) is the 5th common malignancy worldwide, but established markers fail to detect up to one third of HCC. We have recently identified Neighbor of Punc E11 (Nope) as a surface marker for murine fetal liver stem cells. Similar to commonly used HCC markers such as a-Fetoprotein (Afp) and Glypican-3 (Gpc-3), we here establish Nope as an oncofetal marker of murine and human HCC and investigate its specific expression in hepatoma cell lines and primary HCC. Murine and human hepatoma cell lines and Cre-inducible SV40 T-antigen transgenic mice (Alb-SV40TAg ind ) were analyzed for Nope expression in comparison to common HCC markers by quantitative RT-PCR, Western blot analyses and immunohistochemistry. Nope expression in primary human HCC was investigated using Oncomine Microarray database. Nope expression was elevated in 8 of 10 investigated murine and human hepatoma cell lines and in all tumors of our oncogenic mouse model but remained undetectable in normal liver and at preneoplastic stages of murine hepatocarcinogenesis. Furthermore, a significant induction of Nope was detected in primary human cancers compared to corresponding normal or cirrhotic tissue. Nope expression in tumor specimens and murine cell lines correlated closely with expression levels of Gpc-3, whereas expression levels of Afp showed high variations. In conclusion, we identified Nope as a novel oncofetal surface marker for murine and human HCC. Nope is specifically expressed by epithelial tumor cells but not in preneoplastic stages and is a promising marker for clinical application because of its high detection rate in Afp-positive and Afp-negative tumors.Hepatocellular carcinoma (HCC) is the 5th common malignancy worldwide. The incidence in developed countries has almost doubled within the last 40 years and remains constantly increasing.1-4 The high mortality of HCC ranks it among the most common cause of cancer-related deaths together with colon and lung cancer. Although many novel therapeutic strategies have been developed in the past, the 5-year survival rate remains poor with approximately 5%.3 Because of the late diagnosis, more than 40% of the patients cannot be treated in a curative intention.5 Thus, early detection is considered the most important prognostic factor for survival.Clinically established screening methods for HCC such as ultrasound and elevated serum levels of a-fetoprotein (AFP) slightly improved the prognosis, but sensitivity and specificity are still limited especially in early stages of tumor development.6-8 Moreover, clinically established tumor markers fail to detect up to one third of HCC completely. Apart from high sensitivity and reliable detection of early stages in carcinogenesis, limited expression in normal tissue and independency of the underlying disease and its stage are further attributes of ideal tumor markers. Apart from AFP, other biomarkers (AFP-L3, Golgi protein 73, des-y-carboxy prothrombin (DCP) and Glypican-3 (GPC-3)) have been identified, and some show promising results for ...

Depolarized Hepatocytes Express the Stem/Progenitor Cell Marker Neighbor of Punc E11 After Bile Duct Ligation in Mice

“…In our previous work, we have demonstrated that Nope is a surface marker of murine fetal and adult liver stem/ progenitor cells 3,5 as well as a specific and sensitive marker of hepatocellular carcinoma (HCC). 4 In our present study, we describe for the first time the expression of Nope on adult hepatocytes. Although the expression of Nope is physiologically downregulated in the postnatal period and barely detectable thereafter, the expression of Nope was significantly induced in adult hepatocytes after BDL.…”

Network-Based Differential Analysis to Identify Molecular Features of Tumorigenesis for Esophageal Squamous Carcinoma

“…It implied the effectiveness of the way to identify cancer related molecular by local eigenvector centrality. A pervious study has identified IGDCC4 as a novel oncofetal surface marker for murine and human HCC and it is specifically expressed by epithelial tumor cells but not in preneoplastic stages and is a promising marker [ 52 ].…”

One Year Follow-Up Risk Assessment in SKH-1 Mice and Wounds Treated with an Argon Plasma Jet

“…Next, we performed quantitative PCR analysis of five tumor markers such as AFP , NOPE (neighbor of Punc 11 ), a novel TM of the liver [43], β2 microglobulin ( β2M ), carcinoembryonic antigen ( CEA ), or neuron-specific enolase ( NSE ). No changes were observed in, e.g., liver, brain, lung, or ear skin tissue relative to the controls and in contrast to organs of the HCC-bearing mouse (+ve ctrl).…”