Targeting Signalling Pathways in Hepatocellular Carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) represents the most common malignant liver tumor in humans, which incidence and mortality have increased in Europe and United States in the last years. Most patients are diagnosed at an advanced stage, when it is not amenable to curative therapies, so there is an urgent need for new, more effective therapeutic tools and strategies. The molecular mechanisms of hepatocarinogenesis and HCC progression have been increasingly understood with intense research in recent years. METHODS: The goal of this work is to discuss the different signalling pathways as important potential therapeutic targets. RESULTS: Disruption of pathways known to play roles in HCC, such as Wnt/ß-catenin, Hedgehog, RAF/MEK/ERK, tryosine kinase receptor-related pathway, Met-HGF, VEGF/ VEGF and ROR signalling pathways may be seminal for liver oncogenesis. CONCLUSION: This review reveals that oncogenes, especially microRNAs that are conserved across species and interfere with signalling pathways might be used as promising strategies for halting or reversing the progression of HCC.

The Conserved Arginine Cluster in the Insert of the Third Cytoplasmic Loop of the Long Form of the D2 Dopamine Receptor (D2L-R) Acts as an Intracellular Retention Signal.

This study examined whether the conserved arginine cluster present within the 29-amino acid insert of the long form of the D2 dopamine receptor (D2L-R) confers its predominant intracellular localization. We hypothesized that the conserved arginine cluster (RRR) located within the insert could act as an RXR-type endoplasmic reticulum (ER) retention signal. Arginine residues (R) within the cluster at positions 267, 268, and 269 were charge-reserved to glutamic acids (E), either individually or in clusters, thus generating single, double, and triple D2L-R mutants. Through analyses of cellular localization by confocal microscopy and enzyme-linked immunosorbent assay (ELISA), radioligand binding assay, bioluminescence resonance energy transfer (BRET²) ß-arrestin 2 (ßarr2) recruitment assay, and cAMP signaling, it was revealed that charge reversal of the R residues at all three positions within the motif impaired their colocalization with ER marker calnexin and led to significantly improved cell surface expression. Additionally, these data demonstrate that an R to glutamic acid (E) substitution at position 2 within the RXR motif is not functionally permissible. Furthermore, all generated D2L-R mutants preserved their functional integrity regarding ligand binding, agonist-induced ßarr2 recruitment and Gαi-mediated signaling. In summary, our results show that the conserved arginine cluster within the 29-amino acid insert of third cytoplasmic loop (IC3) of the D2L-R appears to be the ER retention signal.