Drastic Down-regulation of Krüppel-Like Factor 4 Expression Is Critical in Human Gastric Cancer Development and Progression

Abstract

Krüppel-like factor 4 (KLF4) is highly expressed in epithelial tissues such as the gut and skin. However, the role of KLF4 in human gastric cancer development and progression is unknown. Here we show that KLF4 protein expression was decreased or lost in primary tumors and, in particular, lymph node metastases when compared with that in normal gastric mucosa. Moreover, loss of KLF4 expression in the primary tumors was significantly associated with poor survival, and also an independent prognostic marker in a multivariate analysis. Consistently, most human gastric cancer cell lines exhibited loss of or a substantial decrease in KLF4 expression at both RNA and protein levels. Enforced restoration of KLF4 expression resulted in marked cell growth inhibition in vitro and significantly attenuated tumor growth and total abrogation of metastasis in an orthotopic animal model of gastric cancer. Mechanism studies indicated that promoter hypermethylation and hemizygous deletion contributed to the down-regulation of KLF4 expression and the induction of apoptosis contributed to the antitumor activity of KLF4. Collectively, our data provide first clinical and casual evidence and potential mechanism that the alteration of KLF4 expression plays a critical role in gastric cancer development and progression. (Cancer Res 2005; 65(7): 2746-54)

Krüppel-like factor 4 exhibits antiapoptotic activity following γ-radiation-induced DNA damage

“…KLF4 has a dual function -to synergistically induce the expression of p21 WAF1/CIP1 with p53, leading to cell cycle arrest (Zhang et al, 2000) and to suppress BAX expression, both directly and indirectly by inhibiting activation of BAX by p53, thus reducing apoptosis (this study). This model may explain the context-dependent nature by which KLF4 functions as either a tumor suppressor or an oncogene as reported by various groups (Foster et al, 1999(Foster et al, , 2005Zhao et al, 2004;Rowland et al, 2005;Wei et al, 2005;Rowland and Peeper, 2006). It may also explain the recent finding that inactivation of p21 WAF1/CIP1 by oncogenic RAS V12 neutralizes the cytostatic action of KLF4, converting the latter to a transforming protein owing to its antiapoptotic activity (Rowland et al, 2005) Materials and methods…”

“…These results indicate that KLF4 is an important factor in mediating the checkpoint functions of p53 following DNA damage. Accordingly, KLF4 has been shown to be a potential tumor suppressor in tumors of the gastrointestinal tract (Zhao et al, 2004;Katz et al, 2005;Wei et al, 2005).…”

The KLF4 tumour suppressor is a transcriptional repressor of p53 that acts as a context-dependent oncogene

“…In mice, ectopic expression of Klf4 accelerates terminal differentiation, leading to premature skin-barrier acquisition 7 , whereas Klf4 deficiency prevents the terminal differentiation of colonic goblet cells 8 and the skin epithelium 9 , which leads to neonatal death 9 . These observations establish KLF4 as a stress-and differentiation-associated inhibitor of proliferation 10 , raising the possibility that KLF4 may have tumour-suppressive functions 8,11,12 .Indeed, KLF4 expression is frequently lost in various human cancer types 11,[13][14][15][16][17][18][19] . Recently, KLF4 has been shown to undergo promoter methylation and loss of heterozygosity in gastrointestinal cancer 16,17 .…”

“…Indeed, KLF4 expression is frequently lost in various human cancer types 11,[13][14][15][16][17][18][19] . Recently, KLF4 has been shown to undergo promoter methylation and loss of heterozygosity in gastrointestinal cancer 16,17 .…”

“…Recently, KLF4 has been shown to undergo promoter methylation and loss of heterozygosity in gastrointestinal cancer 16,17 . Consistent with a tumour-suppressor function for KLF4, its overexpression reduces the tumorigenicity of colonic and gastric cancer cells in vivo 17,20 . These observations, taken together, indicate that KLF4 acts as a tumour suppressor.…”