The Krüppel-like Factor 9 (KLF9) Network in HEC-1-A Endometrial Carcinoma Cells Suggests the Carcinogenic Potential of Dys-regulated KLF9 Expression

Overview

Journal Reprod Biol Endocrinol

Publisher Biomed Central

Specialties Endocrinology
Reproductive Medicine

Date 2008 Sep 12

PMID 18783612

Citations 46

Authors

Frank A Simmen

Ying Su

Rijin Xiao

Zhaoyang Zeng

Rosalia C M Simmen

Affiliations

Soon will be listed here.

Abstract

Background: 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.

Methods: HEC-1-A sub-lines differing in relative levels of KLF9 were subjected to microarray analysis to identify differentially-regulated RNAs.

Results: 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), RXRalpha], 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.

Conclusion: KLF9 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.

Citing Articles

TRα1 mutant suppresses KLF9 to cause endometrial metaplasia with ectopic IL-33 expression leading to uterine fibrosis and infertility.

Edmondson E, Kimura T, Hwang E, Kim M, Warner A, Zhu Y Sci Rep. 2025; 15(1):3892.

PMID: 39890871 PMC: 11785771. DOI: 10.1038/s41598-025-86848-5.

Prognostic value of KLFs family genes in renal clear cell carcinoma.

Fu M, Du Y, Liu F, Xiao J, Zhang L, Zeng Y Sci Rep. 2024; 14(1):20204.

PMID: 39215019 PMC: 11364764. DOI: 10.1038/s41598-024-69892-5.

Role of AMIGO2 in cancer progression: Novel insights (Review).

Tian Z, Zhou D, Jiang R, Zhou B Oncol Lett. 2024; 28(3):434.

PMID: 39049987 PMC: 11268087. DOI: 10.3892/ol.2024.14567.

A comprehensive analysis of the prognostic and immunological role of in pan-cancer.

Tan Y, Meng W, Jiang Z, Li N, Zhang T, Zhang J Transl Cancer Res. 2024; 13(2):1091-1113.

PMID: 38482441 PMC: 10928612. DOI: 10.21037/tcr-23-2379.

Krüppel-like Factor-9 and Krüppel-like Factor-13: Highly Related, Multi-Functional, Transcriptional Repressors and Activators of Oncogenesis.

Simmen F, Alhallak I, Simmen R Cancers (Basel). 2023; 15(23).

PMID: 38067370 PMC: 10705314. DOI: 10.3390/cancers15235667.

References

Yeaman G, Howell A, Weldon S, Demian D, Collins J, OConnell D . Human immunodeficiency virus receptor and coreceptor expression on human uterine epithelial cells: regulation of expression during the menstrual cycle and implications for human immunodeficiency virus infection. Immunology. 2003; 109(1):137-46. PMC: 1782948. DOI: 10.1046/j.1365-2567.2003.01623.x. View

Park I, Zhao R, West J, Yabuuchi A, Huo H, Ince T . Reprogramming of human somatic cells to pluripotency with defined factors. Nature. 2007; 451(7175):141-6. DOI: 10.1038/nature06534. View

Reed K, Blaeser L, Dantzer V, Green M, Simmen R . Control of secretory leukocyte protease inhibitor gene expression in the porcine periimplantation endometrium: a case of maternal-embryo communication. Biol Reprod. 1998; 58(2):448-57. DOI: 10.1095/biolreprod58.2.448. View

Talbi S, Hamilton A, Vo K, Tulac S, Overgaard M, Dosiou C . Molecular phenotyping of human endometrium distinguishes menstrual cycle phases and underlying biological processes in normo-ovulatory women. Endocrinology. 2005; 147(3):1097-121. DOI: 10.1210/en.2005-1076. View

Piccinni S, Bolcato-Bellemin A, Klein A, Yang V, Kedinger M, Simon-Assmann P . Kruppel-like factors regulate the Lama1 gene encoding the laminin alpha1 chain. J Biol Chem. 2003; 279(10):9103-14. PMC: 2225534. DOI: 10.1074/jbc.M305804200. View

McConnell B, Ghaleb A, Nandan M, Yang V . The diverse functions of Krüppel-like factors 4 and 5 in epithelial biology and pathobiology. Bioessays. 2007; 29(6):549-57. PMC: 2211634. DOI: 10.1002/bies.20581. View

Zeng Z, Velarde M, Simmen F, Simmen R . Delayed parturition and altered myometrial progesterone receptor isoform A expression in mice null for Krüppel-like factor 9. Biol Reprod. 2008; 78(6):1029-37. DOI: 10.1095/biolreprod.107.065821. View

Dominguez F, Galan A, Martin J, Remohi J, Pellicer A, Simon C . Hormonal and embryonic regulation of chemokine receptors CXCR1, CXCR4, CCR5 and CCR2B in the human endometrium and the human blastocyst. Mol Hum Reprod. 2003; 9(4):189-98. DOI: 10.1093/molehr/gag024. View

Krizsan-Agbas D, Pedchenko T, Hasan W, Smith P . Oestrogen regulates sympathetic neurite outgrowth by modulating brain derived neurotrophic factor synthesis and release by the rodent uterus. Eur J Neurosci. 2003; 18(10):2760-8. DOI: 10.1111/j.1460-9568.2003.03029.x. View

10.

Schrecengost R, Riggins R, Thomas K, Guerrero M, Bouton A . Breast cancer antiestrogen resistance-3 expression regulates breast cancer cell migration through promotion of p130Cas membrane localization and membrane ruffling. Cancer Res. 2007; 67(13):6174-82. PMC: 4109708. DOI: 10.1158/0008-5472.CAN-06-3455. View

11.

Foti D, Stroup D, Chiang J . Basic transcription element binding protein (BTEB) transactivates the cholesterol 7 alpha-hydroxylase gene (CYP7A). Biochem Biophys Res Commun. 1999; 253(1):109-13. DOI: 10.1006/bbrc.1998.9759. View

12.

Velarde M, Geng Y, Eason R, Simmen F, Simmen R . Null mutation of Kruppel-like factor9/basic transcription element binding protein-1 alters peri-implantation uterine development in mice. Biol Reprod. 2005; 73(3):472-81. DOI: 10.1095/biolreprod.105.041855. View

13.

Dang D, Zhao W, Mahatan C, Geiman D, Yang V . Opposing effects of Krüppel-like factor 4 (gut-enriched Krüppel-like factor) and Krüppel-like factor 5 (intestinal-enriched Krüppel-like factor) on the promoter of the Krüppel-like factor 4 gene. Nucleic Acids Res. 2002; 30(13):2736-41. PMC: 117055. DOI: 10.1093/nar/gkf400. View

14.

Ioachim E, Kitsiou E, Carassavoglou C, Stefanaki S, Agnantis N . Immunohistochemical localization of metallothionein in endometrial lesions. J Pathol. 2000; 191(3):269-73. DOI: 10.1002/1096-9896(2000)9999:9999<::AID-PATH616>3.0.CO;2-Q. View

15.

Good K, Tangye S . Decreased expression of Kruppel-like factors in memory B cells induces the rapid response typical of secondary antibody responses. Proc Natl Acad Sci U S A. 2007; 104(33):13420-5. PMC: 1948953. DOI: 10.1073/pnas.0703872104. View

16.

Jiang J, Chan Y, Loh Y, Cai J, Tong G, Lim C . A core Klf circuitry regulates self-renewal of embryonic stem cells. Nat Cell Biol. 2008; 10(3):353-60. DOI: 10.1038/ncb1698. View

17.

King A, Morgan K, Sallenave J, Kelly R . Differential regulation of secretory leukocyte protease inhibitor and elafin by progesterone. Biochem Biophys Res Commun. 2003; 310(2):594-9. DOI: 10.1016/j.bbrc.2003.08.151. View

18.

Velarde M, Zeng Z, McQuown J, Simmen F, Simmen R . Kruppel-like factor 9 is a negative regulator of ligand-dependent estrogen receptor alpha signaling in Ishikawa endometrial adenocarcinoma cells. Mol Endocrinol. 2007; 21(12):2988-3001. DOI: 10.1210/me.2007-0242. View

19.

Yaegashi N, Fujita N, Yajima A, Nakamura M . Menstrual cycle dependent expression of CD44 in normal human endometrium. Hum Pathol. 1995; 26(8):862-5. DOI: 10.1016/0046-8177(95)90008-x. View

20.

Imataka H, Mizuno A, Fujii-Kuriyama Y, Hayami M . Activation of the human immunodeficiency virus type 1 long terminal repeat by BTEB, a GC box-binding transcription factor. AIDS Res Hum Retroviruses. 1993; 9(9):825-31. DOI: 10.1089/aid.1993.9.825. View