Overexpression of ICAT Inhibits the Progression of Colorectal Cancer by Binding with β-Catenin in the Cytoplasm

Abstract

Inhibitor of β-catenin and T-cell factor (ICAT) was first found as a polypeptide that blocks β-catenin–TCF interaction. Abundant evidence has shown that ICAT has different functions in diverse cancers’ progression. Nevertheless, the roles it plays in colorectal cancer (CRC) have not been described. Here, we documented that ICAT expression was higher in CRC tissue than in the adjacent normal tissue and that prognosis was better in high-ICAT expression patients. The overexpression of ICAT inhibited CRC cell proliferation both in vitro and in vivo. Wnt pathway transcriptional activity was suppressed in the CRC cells with ICAT overexpression, where the CCND1 and MYC expression, which occurs downstream of the Wnt signaling pathway, was inhibited. Co-immunoprecipitation experiments showed that ICAT bound with β-catenin in stable overexpression cell lines; immunofluorescence showed the co-localization of ICAT and β-catenin in the cytoplasm. Overall, our study reveals that ICAT inhibits CRC cell proliferation by binding to cytoplasm-located β-catenin, and prevents its translocation, which results in Wnt signaling pathway inactivation. It may provide a scientific foundation for focusing on ICAT in treatments for CRC.

ICAT promotes colorectal cancer metastasis via binding to JUP and activating the NF‐κB signaling pathway

“…Our previous experiments showed that ICAT could inhibit the proliferation of CRC cells by binding to β-catenin in the cytoplasm. 13 However, in this study, we confirmed that ICAT could promote CRC invasion and migration, which is consistent with the premetastatic role on ICAT reported in studies of melanoma and cervical cancer. 10,12 The ICAT reflects the metastatic ability of CRC and can be developed as a potential diagnostic biomarker.…”

“…Stable cell lines overexpressing the protein of interest were developed as previously described. 13,18 Lentiviruses carrying ICAT cDNA and vector control (VC) packaged by Vigene Biosciences were transfected into the SW480 cell line following the manufacturer's instructions to construct ICAT-overexpressing cell lines and VC. Stable cell lines were selected after 2 weeks of puromycin (10 μg/ml) selection and were maintained in 1 μg/ml puromycin.…”

“…Our previous study demonstrated that ICAT is located in the cytoplasm of CRC cells and that the interaction of ICAT with the Wnt signaling pathway regulates the proliferation of CRC cells. 13 However, the role of ICAT in CRC metastasis and the proteins that interact with ICAT are not fully elucidated.…”

Blocking the Wnt/β‑catenin signaling pathway to treat colorectal cancer: Strategies to improve current therapies (Review)

“…ICAT was found to be a polypeptide that downregulates the expression of genes that are targeted by the Wnt pathway, such as cyclin D1 and Myc, by blocking the β-catenin-TCF interaction, which significantly reduces the growth of CRC cells and tumor formation (62). Furthermore, patients with CRC and high ICAT levels have a favorable prognosis.…”

Expression level and prognostic potential of beta-catenin–interacting protein in acute myeloid leukemia

“…Thus, we observed that catenin, beta-interacting protein 1 (inhibitor of beta-catenin and TCF [ ICAT ] or CTNNBIP1 ), an inhibitor of β-catenin is upregulated during monocyte differentiation, can enhance drug sensitivity of HL60 cells. [ 8 ] The ICAT molecule plays a crucial role in the Wnt/β-catenin signaling pathway, and in a competitive region with T-cell factor ( TCF )/lymphocyte enhancement factor ( LEF ), binds to the tandem protein and E-cadherin and inhibits Wnt signal transduction as well as intracellular adhesion, [ 9 , 10 ] which plays a critical role in tumorigenesis. Therefore, it has been observed in several studies that ICAT acts as a caner suppressor.…”