Krüppel-like Factor 4 Suppresses Serine/Threonine Kinase 33 Activation and Metastasis of Gastric Cancer through Reversing Epithelial-Mesenchymal Transition

Abstract

Purpose: Cancers with aberrant expression of Serine/threonine kinase 33 (STK33) is particularly aggressive. However, its expression, clinical significance and biological functions in gastric cancer remain largely unknown. In the present study, we determined the expression and function of STK33 in gastric cancer and delineated the clinical significance of Krüppel-like factor 4 (KLF4) /STK33 signaling pathway. Experimental Design: STK33 expression and its association with multiple clinicopathologic characteristics were analyzed immunohistochemically in human gastric cancer specimens. STK33 knockdown and overexpression were used to dissect the underlying mechanism of its functions in gastric cancer cells. Regulation and underlying mechanisms of STK33 expression by KLF4 in gastric cancer cells were studied using cell and molecular biological methods. Results: Drastically higher expression of STK33 was observed in gastric cancer and gastric intraepithelial neoplasia tissues compared to adjacent normal gastric tissues. Increased STK33 expression correlated directly with tumor size, lymph node and distant metastasis; and patients with low STK33 expression gastric cancer were predicted to have a favorable prognosis. Enforced expression of STK33 promoted gastric cancer cell proliferation, migration, and invasion in vitro and in vivo, whereas reduced STK33 did the opposite. Moreover, STK33 promoted epithelial-mesenchymal transition (EMT) in vitro. Mechanistically, KLF4 transcriptionally inhibited STK33 expression in gastric cancer cells. KLF4-mediated inhibition of gastric cancer cell invasion was reversed by upregulation of STK33 expression. Conclusions: STK33 has pro-tumor function and is a critical downstream mediator of KLF4 in gastric cancer. STK33 may serve as a potential prognostic marker and therapeutic target for gastric cancer.