β-Catenin Inhibitor ICAT Modulates the Invasive Motility of Melanoma Cells

Abstract

Inhibitor of b-catenin and TCF (ICAT) inhibits b-catenin transcriptional activity by competing with T-cell factor/ lymphoid enhancer factor. We documented high ICAT levels in human melanoma cells, in which b-catenin signaling is frequently deregulated, finding a correlation with the capacity to form metastases in nude mice. Ectopic expression of ICAT in melanoma cells did not affect their proliferation but increased cell motility and Matrigel invasion of metastatic cells in a manner relying upon stable ICAT-b-catenin interaction. This effect was associated with conversion of an elongated/mesenchymal phenotype to a round/amoeboid phenotype in the absence of similar effects on elongated morphology of nonmetastatic melanoma cells. Transition from mesenchymal to amoeboid movement was associated with decreased levels of NEDD9 and activated Rac1, a positive regulator of mesenchymal movement. Ectopic ICAT promoted colonization of melanoma cells in the lungs of nude mice, suggesting an increase in metastatic potential. Together, our results showed that by downregulating Rac signaling in metastatic melanoma cells, ICAT increased their invasive motility by promoting a morphologic variation that facilitates a favorable adaptation to their microenvironment. Cancer Res; 74(7); 1983-95. Ó2014 AACR.

The RhoE/ROCK/ARHGAP25 signaling pathway controls cell invasion by inhibition of Rac activity

“…These observations agree with previous studies demonstrating that amoeboid shape is correlated with the aggressive phenotype of several cancer cell lines. Cancer cells with a rounded morphology are more prone to invasion (Sanz-Moreno et al ., 2008; de Toledo et al ., 2012; Hager et al ., 2012; Domingues et al ., 2014; Liu et al ., 2015), whereas cells converting from the amoeboid to the mesenchymal type of migration are less efficient in invading the surrounding matrix (Saito et al ., 2012; Shao et al ., 2014). …”

ICAT inhibits glioblastoma cell proliferation by suppressing Wnt/β-catenin activity

“…Another study has shown that transient exogenous ICAT expression increases melanoma cell motility and invasion. Additionally, high ICAT expression was associated with reduced survival time for melanoma patients through regulating scaffold protein NEDD9 [15]. There have been no reports regarding the function of the ICAT gene in human glioma.…”

“…Previous studies have shown that the expression level of ICAT differs in human melanoma and colorectal cancer tissues compared with normal tissues [11,15,16]. To examine the expression profile of ICAT in glioma samples, we analyzed 305 tumor samples from patients with glioma in the CGGA (Chinese Glioma Genome Atlas, http://www.cgcg.org.cn) cohort.…”

Long Noncoding RNA NEAT1, Regulated by the EGFR Pathway, Contributes to Glioblastoma Progression Through the WNT/β-Catenin Pathway by Scaffolding EZH2

“…Abnormal activation of the canonical WNT/b-catenin pathway has been reported to participate in malignant progression and has been implicated in the poor prognosis of malignant tumors (18) by regulating multiple aspects of cancer formation and growth. Axin2, GSK3B, and ICAT (CTNNBIP1), as WNT/b-catenin negatively regulated factors, play an important part in the canonical WNT/b-catenin pathway by promoting the degradation of b-catenin and repressing T-cell factor/lymphoid enhancer factor (TCF/LEF)-b-catenin transcriptional activity in vitro (19)(20)(21). However, the relationship between NEAT1 and the WNT/b-catenin pathway is rarely reported.…”