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Inhaltsbereich

Cell Invasion of Liver Cancer

Changes in the epithelial phenotype are of outmost relevance for the progression and metastasis of carcinoma. We focus on the molecular mechanisms underlying the epithelial to mesenchymal transition (EMT) of hepatocellular carcinoma (HCC). This report summarizes recent findings on the role of the receptor tyrosine kinase Axl and the extracellular matrix protein Laminin B1 in EMT and HCC progression.
 

Invasion of carcinoma cells by EMT

Cancer cells invade other tissues either by moving collectively or as single cells via mesenchymal or amoeboid cell types. During carcinoma progression, tumor cells show changes in their epithelial plasticity by phenotypical conversions including EMT (Fig. 1). EMT represents a highly conserved process occurring during embryogenesis, wound healing and cancer progression.

Fig. 1: Collective and individual cell invasion by EMT, CAT (collective to amoeboid transition) and MAT (mesenchymal to amoeboid transition). ECM, extracellular matrix; MMP, matrix metalloproteinase.

Axl activates autocrine Transforming Growth Factor (TGF)-beta signaling

Fig. 2: Cooperation between Axl/14-3-3zeta
and TGF-beta signaling.

We found upregulation and activation of Axl in EMT-transformed HCC cells. Loss of Axl expression abrogates invasive abilities of mesenchymal HCC cells. Axl binds to 14-3-3zeta which is required for Axl-mediated cell invasion and TGF-beta resistance. Axl/14-3-3zeta signaling phosphorylates the Smad3 linker region (Smad3L), resulting in the upregulation of tumor-progressive TGF-beta target genes such as PAI1, MMP9, Snail and TGF-beta1 (Fig. 2). In HCC patient samples, high Axl expression correlates with elevated vessel invasion of HCC cells, strong phosphorylation of Smad3L and lower survival. Thus, Axl/14-3-3zeta signaling is central for TGF-beta-mediated HCC progression and a promising target for HCC therapy. A multicenter study further showed that the release of soluble Axl, a cleavage product of Axl, represents a biomarker to detect HCC with high diagnostic accuracy in blood.

IRES-mediated translational control of Laminin B1 (LamB1) upon EMT

Most of cellular mRNAs harboring an internal ribosome entry site (IRES) in the 5’-untranslated region (5’-UTR) are involved in cancer development via corresponding proteins. We identified a novel IRES motif in the 5’-UTR of the ECM component LamB1. RNA binding assays showed that La protein interacts with the IRES upon EMT, which is regulated by TGF-beta/PDGFR-alpha (Fig. 3). La activates the LamB1 IRES leading to translational upregulation during hepatocellular EMT. LamB1 essentially maintains the invasive EMT phenotype as ablation of LamB1 expression results in re-expression of E-cadherin and reversal from to a mesenchymal to an epithelial phenotype (MET).

Fig. 3: Translational control of LamB1 IRES during EMT.
 
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