KLF4-Mediated Negative Regulation of IFITM3 Expression Plays a Critical Role in Colon Cancer Pathogenesis

Abstract

Purpose IFITM3, an interferon-inducible gene, is overexpressed in human colorectal cancer. In this study, we sought to determine the clinical significance and underlying mechanisms of its dysregulated expression in human colon tumor specimens and murine models of this disease. Experimental Design IFITM3 expression in a tissue microarray of tumor and matched normal colon tissue specimens and lymph node metastasis specimens obtained from 203 patients with colon cancer was measured immunohistochemically. Results IFITM3 was expressed at higher levels in colon tumors and, particularly, nodal metastases than in normal colon tissue. A Cox proportional hazards model showed that IFITM3 expression was an independent prognostic factor for disease-free survival in patients with colon cancer. Knockdown of IFITM3 expression by a specific small interfering RNA significantly suppressed the proliferation, colony formation, migration, and invasion of colon cancer cells in vitro and tumor growth and metastasis in a xenograft model. Restored expression of KLF4, a putative tumor suppressor, downregulated IFITM3 expression in colon cancer cells in vitro. Two KLF4-binding sites in the IFITM3 promoter bound specifically to KLF4 protein in a chromatin immunoprecipitation assay and promoter mutagenesis analyses. Specific deletion of KLF4 led to IFITM3 overexpression in colon mucosa in Villin-Cre+;Klf4fl/fl mice. An inverse correlation between loss of KLF4 expression and IFITM3 overexpression was evident in human colon tumors. Conclusion these clinical and mechanistic findings indicate that IFITM3 is a direct transcriptional target of KLF4 and that dysregulated KLF4 expression leads to aberrant IFITM3 expression, thus contributing to colon cancer progression and metastasis.

Krüppel-Like Factor 7 is a Marker of Aggressive Gastric Cancer and Poor Prognosis

“…IHC staining was performed as described previously [17, 18]. KLF7 anti-human rabbit antibody was used at a dilution of 1: 100 (ab197690, Abcam); PBS was used as a negative control.…”

Gas1 Inhibits Metastatic and Metabolic Phenotypes in Colorectal Carcinoma

“…Construction of the TMA and IHC staining were performed as described previously (9,10). Gas1 and FOXM1 anti-human rabbit polyclonal antibodies were used at a dilution of 1:100 (AP11869a; Abgent) and 1:50 (sr-500; Santa Cruz Biotechnology), respectively; PBS was used alternately as negative control.…”

RETRACTED ARTICLE: Regulation of estrogen receptor signaling in breast carcinogenesis and breast cancer therapy

“…Current studies in carcinogen-esis have revealed that KLF4 can function as both tumor promoter and tumor suppressor depending on tissue type and cellular context [241]. The oncogenic effect of KLF4 has been reported in breast and squamous cell carcinoma [243][244][245][246][247], while its tumor suppression role was reported in various types of cancers such as colon cancer [248,249]. It was demonstrated that KLF4 is a fast turnover protein, whose turnover-half life is governed by the ubiquitin-proteasome system [250,251].…”