Dynamic down-regulation of Krüppel-like factor 4 in colorectal adenoma-carcinoma sequence

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 microM) or butyrate sodium (4 mM).

The large clinicopathological 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.