Dynamic down-regulation of Krüppel-like factor 4 in colorectal adenoma-carcinoma sequence
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To explore the clinical significance of Krüppel-like factors 4 (KLF4) expression in colorectal cancer initiation and progression.
We used quantitative real-time PCR to detect KLF4 mRNA expression in 49 colorectal cancer samples with individual-matched normal mucosa and eight concurrent adenomas. We also analysed the immunostaining pattern of KLF4 in additional 129 colorectal cancers and 48 sporadic colorectal adenomas with matched normal mucosa and correlated KLF4 staining with clinicopathological parameters and prognosis. KLF4 expression change was detected in SW480, SW620 and RKO cell lines after treatment of 5-aza-dC (10 μM) or butyrate sodium (4 mM).
The large clinicopathlogical survey with combined methods confirmed a dynamic downregulation of KLF4 in individual-matched normal mucosa, adenoma and cancer (P < 0.05). The quantitative analysis of immunostaining pattern showed that KLF4 staining cells were more frequently seen in the upper zones than that in the lower zones of both normal mucosa and adenoma (P < 0.05). Survival analysis implied a trend toward better overall survival in KLF4-positive colorectal cancer patients with lymph node metastasis than that in KLF4-negative cancer with lymph node metastasis. In vitro study found elevated KLF4 mRNA expression in SW620 and RKO cells with 5-aza-dC treatment, implicating the underlying aberrant epigenetic modifications in regulating KLF4 expression at least in a subset of colorectal cancers.
KLF4 is associated with terminal differentiation in colorectal epithelium and drastically downregulated in colorectal adenomas and cancers via possible epigenetic modifications. Loss of KLF4 protein expression might contribute to assessing prognosis in colorectal cancer with lymph node metastasis.
KeywordsKrüppel-like factors 4 Colorectal tumour Prognosis DNA methylation
- Dang DT, Bachman KE, Mahatan CS, Dang LH, Giardiello FM, Yang VW (2000) Decreased expression of the gut-enriched Kruppel-like factor gene in intestinal adenomas of multiple intestinal neoplasia mice and in colonic adenomas of familial adenomatous polyposis patients. FEBS Lett 476:203–207PubMedCrossRefGoogle Scholar
- Garcia-Manero G, Kantarjian HM, Sanchez-Gonzalez B, Yang H, Rosner G, Verstovsek S, Rytting M, Wierda WG, Ravandi F, Koller C, Xiao L, Faderl S, Estrov Z, Cortes J, O’brien S, Estey E, Bueso-Ramos C, Fiorentino J, Jabbour E, Issa JP (2006) Phase 1/2 study of the combination of 5-aza-2’-deoxycytidine with valproic acid in patients with leukemia. Blood 108:3271–3279PubMedCrossRefGoogle Scholar
- Hamilton SR, Altonin LA (eds) (2000) World organization of tumours. Pathology and genetics: tumours of the digestive system. IARC Press, Lyon, pp 105–136Google Scholar
- Leake R, Barnes D, Pinder S, Ellis I, Anderson L, Anderson T, Adamson R, Rhodes T, Miller K, Walker R (2000) Immunohistochemical detection of steroid receptors in breast cancer: a working protocol. UK Receptor Group, UK NEQAS, The Scottish Breast Cancer Pathology Group, and The Receptor and Biomarker Study Group of the EORTC. J Clin Pathol 53:634–635PubMedCrossRefGoogle Scholar
- Ohnishi S, Ohnami S, Laub F, Aoki K, Suzuki K, Kanai Y, Haga K, Asaka M, Ramirez F, Yoshida T (2003) Downregulation and growth inhibitory effect of epithelial-type Krüppel-like transcription factor KLF4, but not KLF5, in bladder cancer. Biochem Biophys Res Commun 308:251–256PubMedCrossRefGoogle Scholar
- Shie JL, Chen ZY, O’Brien MJ, Pestell RG, Lee ME, Tseng CC (2000) Role of gut-enriched Kruppel-like factor in colonic cell growth and differentiation. Am J Physiol Gastrointest Liver Physiol 279:806–814Google Scholar