NFATc1 promotes epithelial-mesenchymal transition and facilitates colorectal cancer metastasis by targeting SNAI1.

Metastatic recurrence remains a major cause of colorectal cancer (CRC) mortality. In this study, we investigated the mechanistic role of nuclear factor of activated T cells 1 (NFATc1) in CRC metastasis. First, we explored the potential role of NFATc1 in CRC using bioinformatics and hypothesized that NFATc1 might play different roles at different stages of CRC development. Then, we examined the relative expression of NFATc1 in 25 CRC tissues and adjacent normal tissues, and further analyzed the correlation between NFATc1 expression levels and clinical stages in 120 CRC patients. The role of NFATc1 in CRC metastasis and the molecular mechanisms were investigated in both in vitro and in vivo models. Our results showed that the expression of NFATc1 was increased in metastatic CRC tissues and positively associated with clinical stages (stage I vs. stage II, III or IV) of CRC. Overexpression of NFATc1 promoted CRC cell migration, invasion, and epithelial-mesenchymal transition (EMT). Moreover, SNAI1 was verified as the direct transcriptional target of NFATc1 and interacted with SLUG to promote EMT. Remarkably, our lung and liver metastasis mouse model demonstrated that NFATc1 overexpression accelerated CRC metastasis, and treatment with FK506, a calcineurin-NFAT pathway inhibitor, could suppress CRC metastasis in vivo. Taken together, our findings suggest that NFATc1 could transcriptionally activate SNAI1, which in turn interacts with SLUG to mediate EMT to promote CRC metastasis. Thus, making NFATc1 a promising therapeutic target in the treatment of metastatic CRC.

Shen T ，Yue C ，Wang X ，Wang Z ，Wu Y ，Zhao C ，Chang P ，Sun X ，Wang W ... -  《-》

RANK promotes colorectal cancer migration and invasion by activating the Ca(2+)-calcineurin/NFATC1-ACP5 axis.

Liang Q ，Wang Y ，Lu Y ，Zhu Q ，Xie W ，Tang N ，Huang L ，An T ，Zhang D ，Yan A ，Liu S ，Ye L ，Zhu C ... -  《Cell Death & Disease》

FOXF1 Induces Epithelial-Mesenchymal Transition in Colorectal Cancer Metastasis by Transcriptionally Activating SNAI1.

Forkhead Box F1 (FOXF1) has been recently implicated in cancer progression and metastasis of lung cancer and breast cancer. However, the biological functions and underlying mechanisms of FOXF1 in the regulation of the progression of colorectal cancer (CRC) are largely unknown. We showed that FOXF1 was up-regulated in 93 paraffin-embedded archived human CRC tissue, and both high expression and nuclear location of FOXF1 were significantly associated with the aggressive characteristics and poorer survival of CRC patients. The GSEA analysis showed that the higher level of FOXF1 was positively associated with an enrichment of EMT gene signatures, and exogenous overexpression of FOXF1 induced EMT by transcriptionally activating SNAI1. Exogenous overexpression FOXF1 functionally promoted invasion and metastasis features of CRC cells, and inhibition of SNAI1 attenuates the invasive phenotype and metastatic potential of FOXF1-overexpressing CRC cells. Furthermore, the results of the tissue chip showed that the expression of FOXF1 was positively correlated with SNAI1 in CRC tissues chip. These results suggested that FOXF1 plays a critical role in CRC metastasis by inducing EMT via transcriptional activation of SNAI1, highlighting a potential new therapeutic strategy for CRC.

Wang S ，Yan S ，Zhu S ，Zhao Y ，Yan J ，Xiao Z ，Bi J ，Qiu J ，Zhang D ，Hong Z ，Zhang L ，Huang C ，Li T ，Liang L ，Liao W ，Jiao H ，Ding Y ，Ye Y ... -  《NEOPLASIA》

CAPS1 promotes colorectal cancer metastasis via Snail mediated epithelial mesenchymal transformation.

Zhao GX ，Xu YY ，Weng SQ ，Zhang S ，Chen Y ，Shen XZ ，Dong L ，Chen S ... -  《-》

Snail/FOXK1/Cyr61 Signaling Axis Regulates the Epithelial-Mesenchymal Transition and Metastasis in Colorectal Cancer.

Metastasis is the primary cause of colorectal cancer (CRC)-related death. However, the molecular mechanisms underlying metastasis in CRC remain unclear. We evaluated mRNA and protein expression levels by quantitative real-time reverse transcription PCR, western blotting, immunofluorescence, tissue microarrays, and immunohistochemistry assays. We also assessed the migration and invasion abilities of CRC cells in vitro by wound healing assays, invasion and migration assays, western blot analysis, and immunofluorescence. Tumor metastasis was evaluated in nude mice in vivo. A positive correlation was observed between the expression patterns of Forkhead box k1 (FOXK1) and Snail in CRC. Luciferase reporter and chromatin immunoprecipitation assays demonstrated that Snail directly bound to and activated the human FOXK1 gene promoter. Moreover, the Snail-FOXK1 axis promote epithelial mesenchymal transition (EMT)-mediated CRC cell invasion and metastasis. FOXK1 and Snail expression levels were correlated with tumor progression and served as significant predictors of overall survival in patients with CRC. Furthermore, overexpression of FOXK1 induced the EMT by upregulating the expression of cysteine-rich angiogenic inducer 61 (Cyr61). Luciferase assays showed that Cyr61 was a direct transcriptional target of FOXK1. Down regulation of Cyr61 decreased FOXK1-enhanced "CRC cell" migration, invasion, and metastasis. Additionally, FOXK1 expression was positively correlated with Cyr61 expression and was associated with poor prognosis. The Snail/FOXK1/Cyr61 signaling axis regulates the EMT and metastasis of CRC.

Huang X ，Xiang L ，Li Y ，Zhao Y ，Zhu H ，Xiao Y ，Liu M ，Wu X ，Wang Z ，Jiang P ，Qing H ，Zhang Q ，Liu G ，Zhang W ，Li A ，Chen Y ，Liu S ，Wang J ... -  《-》