Background & Aims: The molecular pathogenesis of human hepatocellular carcinoma (HCC) is understood poorly. In some tumors, activation of the Wnt/β-catenin pathway as a result of β-catenin gene mutations has been found. However, in many other HCCs, activation of the Wnt/β-catenin pathway has been shown in the absence of such mutations. Methods: We previously have identified the upstream human Frizzled-7 receptor (FZD7) gene of this pathway. In the present study, a quantitative real-time reverse-transcription polymerase chain reaction (RT-PCR) assay for FZD7 was developed and overexpression of FZD7 was detected in 90% of tumors, most of which were related to chronic hepatitis B virus infection. FZD7 also was overexpressed in the 6 HCC cell lines tested and functional analysis showed that FZD7 messenger RNA (mRNA) levels correlated with enhanced cellular motility. Results: Transfection of HCC cells with dominant-negative mutant constructs encoding a C-terminally truncated FZD7 protein decreased wild-type β-catenin protein accumulation and reduced cell motility. More importantly, we observed β-catenin accumulation in human HCC tumors containing the wild-type β-catenin gene in the context of high-level FZD7 expression. Conclusions: These observations suggest that the Wnt/β-catenin signal transduction pathway is involved much more commonly in the molecular pathogenesis of HCC than previously recognized because FZD7 overexpression occurred early in the disease process, stabilized wild-type β-catenin levels, and contributed to enhanced tumor cell migration.

Alcohol abuse causes progressive toxicity and degeneration in liver and brain due to insulin resistance, which exacerbates oxidative stress and pro-inflammatory cytokine activation. Alcohol-induced steatohepatitis promotes synthesis and accumulation of ceramides and other toxic lipids that cause insulin resistance. Ceramides can readily cross the blood-brain barrier, and ceramide exposure causes neurodegeneration with insulin resistance and oxidative stress, similar to the effects of alcohol. Therefore, in addition to its direct neurotoxic effects, alcohol misuse establishes a liver-brain axis of neurodegeneration mediated by toxic lipid trafficking across the blood-brain barrier, leading to progressive white matter degeneration and cognitive impairment.