Submitted to: Reproductive Biology and Endocrinology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 9/2/2008
Publication Date: 9/10/2008
Citation: Simmen, F.A., Su, Y., Xiao, R., Zeng, Z., Simmen, R.C. 2008. The Kruppel-like factor 9 (KLF9) network in HEC-1-A endometrial carcinoma cells suggests the carcinogenic potential of dys-regulated KLF9 expression. Reproductive Biology and Endocrinology. 6(9):41-52.
Interpretive Summary: We identified families of genes whose activities in human endometrial cancer cells are affected by the protein, Krüppel-like factor 9 (KLF9). These genes, in turn, define important pathways that determine the biology of endometrial cancer cells and which ultimately may be used for designing strategies to retard endometrial cancer growth. Our results suggest the over-expression of KLF9 as one potential means to retard tumor development.
Technical Abstract: Krüppel-like factor 9 (KLF9) is a transcriptional regulator of uterine endometrial cell proliferation, adhesion and differentiation; processes essential for pregnancy success and which are subverted during tumorigenesis. The network of endometrial genes controlled by KLF9 is largely unknown. Over-expression of KLF9 in the human endometrial cancer cell line HEC-1-A alters cell morphology, proliferative indices, and differentiation, when compared to KLF9 under-expressing HEC-1-A cells. This cell line provides a unique model for identifying KLF9 downstream gene targets and signaling pathways. HEC-1-A sub-lines differing in relative levels of KLF9 were subjected to microarray analysis to identify differentially-regulated RNAs. KLF9 under-expression induced twenty four genes. The KLF9-suppressed mRNAs encode protein participants in: aldehyde metabolism (AKR7A2, ALDH1A1); regulation of the actin cytoskeleton and cell motility (e.g., ANK3, ITGB8); cellular detoxification (SULT1A1, ABCC4); cellular signaling (e.g., ACBD3, FZD5, RAB25, CALB1); and transcriptional regulation (PAX2, STAT1). Sixty mRNAs were more abundant in KLF9 over-expressing sub-lines. The KLF9-induced mRNAs encode proteins which participate in: regulation and function of the actin cytoskeleton (COTL1, FSCN1, FXYD5, MYO10); cell adhesion, extracellular matrix and basement membrane formation (e.g., AMIGO2, COL4A1, COL4A2, LAMC2, NID2); transport (CLIC4); cellular signaling (e.g., BCAR3, MAPKAPK3); transcriptional regulation [e.g., KLF4, NR3C1 (glucocorticoid receptor), RXRa], growth factor/cytokine actions (SLPI, BDNF); and membrane-associated proteins and receptors (e.g., CXCR4, PTCH1). In addition, the abundance of mRNAs that encode hypothetical proteins (KLF9-inhibited: open reading frames C12orf29 and C1orf186; KLF9-induced: open reading frames C10orf38 and C9orf167) were altered by KLF9 expression. Human endometrial tumors showed decreased KLF9 gene expression with increased tumor grade. KLF9 influences the expression of uterine epithelial genes through mechanisms likely involving its transcriptional activator and repressor functions and which may underlie altered tumor states with aberrant KLF9 expression.