SummaryIκB kinase/nuclear factor κB (IKK/NF-κB) signaling exhibits important yet opposing functions in hepatocarcinogenesis. Mice lacking NEMO in liver parenchymal cells (LPC) spontaneously develop steatohepatitis and hepatocellular carcinoma (HCC) suggesting that NF-κB prevents liver disease and cancer. Here, we show that complete NF-κB inhibition by combined LPC-specific ablation of RelA, c-Rel, and RelB did not phenocopy NEMO deficiency, but constitutively active IKK2-mediated NF-κB activation prevented hepatocellular damage and HCC in NEMOLPC-KO mice. Knock-in expression of kinase inactive receptor-interacting protein kinase 1 (RIPK1) prevented hepatocyte apoptosis and HCC, while RIPK1 ablation induced TNFR1-associated death domain protein (TRADD)-dependent hepatocyte apoptosis and liver tumors in NEMOLPC-KO mice, revealing distinct kinase-dependent and scaffolding functions of RIPK1. Collectively, these results show that NEMO prevents hepatocarcinogenesis by inhibiting RIPK1 kinase activity-driven hepatocyte apoptosis through NF-κB-dependent and -independent functions.

The abbreviated term NF-kB was incorrectly defined as ''necrosis factor kB'' instead of the correct definition, ''nuclear factor kB,'' on three occasions in the manuscript: in the Summary (pp. 582), Significance (pp. 582), and Introduction (pp. 584) sections. This has now been corrected in the article online. We apologize for the error and any confusion it may have caused.

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 ...

Hp eradication has no discernible effect on CSU beyond that of standard CSU therapy. Therefore, Hp eradication should only be initiated in accordance with currently accepted indications of Hp treatment guidelines.