The role of Krüppel-Like Factor 4 in Human Gastric Cancer Development and Progression and Comparison of the context dependent role of KLF4 and KLF5 in carcinogenesis

Abstract

The work presented in this thesis, which is based on our publication in Cancer Research in 2005: “Drastic Down-regulation of Krüppel-Like Factor 4 Expression Is Critical in Human Gastric Cancer Development and Progression” provides new insights of the role of KLF4 in human gastric cancer. First, we discovered the distinct KLF4 expression patterns in normal gastric and gastric tumor tissues. Specifically, we found that KLF4 protein was expressed in the cytoplasm and nuclei of cells localized predominantly in the glandular epithelium (glandular differentiation), suggesting that KLF4 plays an important role in the homeostasis and maintenance of gastric mucosa. In contrast, we observed a substantially decreased or lost KLF4 expression in both gastric tumor specimens and tumor cell lines. Second, restored expression of KLF4 significantly inhibited gastric cancer growth in vitro and tumorigenicity in animal models. Third, mechanism study showed that promoter hypermethylation and hemizygous deletion were found in a subset of gastric cancer tissues and cell lines and restoration of KLF4 expression induced typical apoptosis in gastric cancer cells. Finally, we observed an inverse correlation between decreased KLF4 expression and survival, and the expression of KLF4 was an independent prognostic factor to predict the outcome of patients. These results show that KLF4 plays an important role in the regulation of homeostasis and maintenance of gastric mucosa and functions as a tumor suppressor in gastric carcinogenesis and progression and that KLF4 pathway is both prognostic marker and potential therapeutic target for human gastric cancer treatment. Comparison with KLF5 revealed that both, KLF4 and KLF5 can act as either tumor suppressor or as promoter of tumorigenesis, depending on the cellular, tissue and genetic context. Further investigations of KLF4 and KLF5 may advance the understanding of the physiological and pathophysiological roles of KLF4 and KLF5 in regulating cellular proliferation and tumor formation in diverse tissues.

Der Transkriptionsfaktor Krüppel-Like Factor 4 (KLF 4) spielt eine wichtige Rolle in der Differenzierung und Aufrechterhaltung der gesunden Magenschleimhaut. KLF 4 zeigt unterschiedliche Expressionsmuster in gesunder Magenschleimhaut bzw. im Magenkarzinom. KLF4 ist in Proben von Magenkarzinomen bzw. in unterschiedlichen Magenkarzinomzelllinien geringer oder nicht exprimiert. Durch Wiedereinbringung des Transkriptionsfaktors KLF4 über einen Adenovirus in die Karzinomzellen wurde in vitro wie in vivo das Tumorwachstum unterdrückt. Hypermethylation des Promoters sowie hemizygote Deletion sind Ursache der verminderten Expression in einer Untergruppe von Karzinomgeweben- bzw. Zelllinien.Zudem konnte gezeigt werden, dass eine verminderte KLF-4 Expression bei Magenkarzinomen mit einer verminderten Überlebensrate einherging. Vergleiche zwischen KLF-4 und KLF-5 zeigen das beide Transkriptionsfaktoren abhängig von unterschiedlichen Faktoren sowohl begünstigend bezüglich der Karzinogenese wie auch hemmend auf diese einwirken können.