Abstract
BackgroundKrüppel-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.MethodsHEC-1-A sub-lines differing in relative levels of KLF9 were subjected to microarray analysis to identify differentially-regulated RNAs.ResultsKLF9 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), RXRα], 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: C12orf29 and C1orf186; KLF9-induced: C10orf38 and C9orf167) were altered by KLF9 expression. Human endometrial tumors of high tumor grade had decreased KLF9 mRNA abundance.ConclusionKLF9 influences the expression of uterine epithelial genes through mechanisms likely involving its transcriptional activator and repressor functions and which may underlie altered tumor biology with aberrant KLF9 expression.
Highlights
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 present study extended our initial characterization of HEC-1-A sub-lines which were genetically engineered to have enhanced or reduced expression of KLF9, relative to the parental HEC-1-A cell line [21]
We showed that the S lines with higher KLF9 expression and mitotic index grew as monolayers, whereas the AS lines with lower KLF9 expression and mitotic index tended to round up on plastic, formed multi-layers, and exhibited dome formation [21], the latter potentially indicative of enhanced tumor invasive capability and metastasis
Summary
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. Individual KLF proteins affect cell proliferation, differentiation, apoptosis, DNA damage, and stress responses [2]. Members of this family have been implicated in stem cell renewal, maintenance of pluripotency, lineage determination, organogenesis, and oncogenesis [2,3,4,5], underscoring their wide-ranging regulatory roles in development. Potential brain functions for KLF9 have been recently elucidated This transcription factor is induced in rat brain by 3, 5, 3'-triiodothyronine (T3) and mediates effects of T3 on neuronal process development [9,10,11]. KLF9 was shown to regulate crypt-villus cell renewal in mice [13] and secondary antibody responses of human splenic B cells [14]
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