Molekulare Mechanismen der HCC-Entstehung

Zusammenfassung Die Ergebnisse der vorliegenden Arbeit zeigen neue Mechanismen auf, die bei der Entstehung und Entwicklung des HCCs von entscheidender Bedeutung sind. Es wurde leberspezifische Laborparameter identifiziert, die als prognostische Marker für die Tumorrekurrenz und das Überleben von HCC-Patienten nach einer Lebertransplantation verwendet werden können. Die Kombination der prä-operativen AP- bzw. GLDH-Werte der HCC-Patienten mit den AFP-Werten zum Zeitpunkt der Transplantation ermöglicht eine sehr genaue Vorhersage der Tumorrekurrenz. Die Kombination der AP- und AFP-Werte erlaubt zudem eine Prognose des post-operativen Überlebens der Patienten, sodass die Auswahl der Patienten, die für eine Lebertransplantation in Frage kommen möglicherweise in Zukunft noch stärker anhand ihrer medizinischen Vorteile ausgewählt werden könnten. Darüber hinaus ist auch das Expressionslevel des Tumorsuppressors TRAIL im HCC als prognostischer Marker für die post-operative Tumorrekurrenz und das Outcome der Patienten geeignet. Eine Verminderung der TRAIL-Expression erhöht zudem die Migrationsfähigkeit von Hepatomzellen, was die Entstehung und auch Entwicklung eines HCC maßgeblich beeinflussen kann. Die Verminderung der TRAIL-Expression im HCC ist auf die Sequenzvariation -1453T/C innerhalb des TRAIL-Promoters zurückzuführen. Die Nukleobase an dieser Position ist entscheidend für die Funktionalität der Bindungsstelle für den Transkriptionsfaktor GATA-1. Die TRAIL-Expression in HCC-Gewebe ist ohne diese GATA-1 Bindungsstelle signifikant geringer als in Patienten die diese Bindungsstelle besitzen. In nachfolgenden in vitro Untersuchungen konnten gezeigt werden, dass der Verlust der GATA-1 Bindungsstelle zu einer verminderten Funktionalität des TRAIL-Promotors führt, vor allem in Zusammenhang mit der IFN-vermittelten Induktion der TRAIL-Expression. Aus Vorarbeiten ist bekannt, dass die Expression des Tumorsuppressors PML über proteosomale Degradationsprozesse reguliert wird. Eine Verminderung der PML-Expression führt sowohl in der murinen Leber als auch in humanen Hepatomzellen zu einer Reduktion der TRAIL-Expression, was wiederum die Migrationsfähigkeit in humanen Hepatomzellen beeinflusst. Darüber hinaus führt eine PML-Defizienz mit gleichzeitiger Expression der HCV-Proteine zu einer verstärkten Lebertumorentstehung in Mäusen. Die Genarrayanalysen zeigen zudem weitere Ansatzpunkte auf, um die molekularen Mechanismen der HCV-assoziierten HCC-Entstehung weiter zu charakterisieren.The herein presented results reveal novel insights into mechanisms affecting the development and growth of human HCC. Clinical parameters were established with the potential to predict the risk of HCC recurrence as well as patients’ survival after liver transplantation. The combination of AP- and GLDH-values with AFP-levels at time of liver transplantation allowes an accurate prediction of tumor recurrence. Furthermore, the combination of AP- and AFP values enables the prognosis of HCC patients as to whether a patient would benefit from this treatment or rather not. In addition the expression level of the tumor suppressor protein TRAIL serve as a predictive marker for the risk of HCC recurrence and the outcome for HCC patients after liver transplantation. TRAIL-expression levels are a landmark feature of human HCC, significantly influencing the migration potential of hepatoma cells and the development and progression of HCC. Impairment of TRAIL-expression has been shown to be caused by a sequence variation between thymine and cytosine at position -1453 in the human TRAIL promoter. The functionality of the GATA-1 transcription factor binding site in this position depends on the presence of the nucleobase thymine. HCC tissue with this ‘loss of function’ GATA-1T/C sequence variation is characterized by a significantly lower TRAIL expression than tissue which comprises an intact GATA-1T/T binding site. In vitro analyses reveal an impaired function of the GATA-1T/C-containing human TRAIL promoter with respect to migration and responsiveness to cytokines. Supplementing previous work from our lab on the tumor suppressor protein PML, it became now apparent that PML-expression is intimately connected with the TRAIL-expression and, consecutively, with the migration potential of human hepatoma cells. Moreover, PML-deficiency does, in conjunction with hepatitis C viral proteins, sensitize liver cells in an oncogenic way to tumor development in mice. Further analyses by gene expression arrays identified additional indicators for the more detailed characterisation of molecular mechanisms involved in the development of HCV-associated hepatocarcinogenesis

Myoclonus dystonia and muscular dystrophy: ɛ-sarcoglycan is part of the dystrophin-associated protein complex in brain

BACKGROUND: Myoclonus-dystonia is a neurogenic movement disorder caused by mutations in the gene encoding ɛ-sarcoglycan. By contrast, mutations in the α-, β-, γ-, and δ-sarcoglycan genes cause limb girdle muscular dystrophies. The sarcoglycans are part of the dystrophin-associated protein complex in muscle that is disrupted in several types of muscular dystrophy. Intriguingly, patients with myoclonus-dystonia have no muscle pathology; conversely, limb-girdle muscular dystrophy patients have not been reported to have dystonia-associated features. To gain further insight into the molecular mechanisms underlying these differences, we searched for evidence of a sarcoglycan complex in the brain. METHODS: Immunoaffinity chromatography and mass spectrometry were used to purify ubiquitous and brain-specific ɛ-sarcoglycan directly from tissue. Cell models were used to determine the effect of mutations on the trafficking and assembly of the brain sarcoglycan complex. RESULTS: Ubiquitous and brain-specific ɛ-sarcoglycan isoforms copurify with β-, δ-, and ζ-sarcoglycan, β-dystroglycan, and dystrophin Dp71 from brain. Incorporation of a muscular dystrophy-associated β-sarcoglycan mutant into the brain sarcoglycan complex impairs the formation of the βδ-sarcoglycan core but fails to abrogate the association and membrane trafficking of ɛ- and ζ-sarcoglycan. CONCLUSIONS: ɛ-Sarcoglycan is part of the dystrophin-associated protein complex in brain. Partial preservation of ɛ- and ζ-sarcoglycan in brain may explain the absence of myoclonus dystonia-like features in muscular dystrophy patients. © 2016 International Parkinson and Movement Disorder Society

Publisher Correction: Variations in Dysbindin-1 are associated with cognitive response to antipsychotic drug treatment.

In the original version of this Article, references in the Methods section incorrectly referred to references in the Supplementary References section. The relevant references (now numbered 20, 27, 42, 47, 69-80) have been removed from the Supplementary References section of the Supplementary Information file and added to the References section of the main manuscript, in both the PDF and HTML versions of the Article

Erratum to: Variations in Dysbindin-1 are associated with cognitive response to antipsychotic drug treatment (Nature Communications, (2018), 9, 1, (2265), 10.1038/s41467-018-04711-w)

In the original version of this Article, references in the Methods section incorrectly referred to references in the Supplementary References section. The relevant references (now numbered 20, 27, 42, 47, 69–80) have been removed from the Supplementary References section of the Supplementary Information file and added to the References section of the main manuscript, in both the PDF and HTML versions of the Article