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Table 2 Genes involved in the epithelial-mesenchymal transition in CRC

From: Upregulation of NETO2 gene in colorectal cancer

Gene Description References
TWIST1 TWIST1 is a highly conserved basic helix-loop-helix (bHLH) transcription factor that regulates the EMT required for neural crest migration during vertebrate embryonic development. TWIST1 expression is positively associated with patient survival after curative CRC resection, and thus is a promising candidate biomarker of the disease progression. [33]
SNAIL1 SNAIL1 is a transcriptional regulator of E-cadherin, which suppression is critical to facilitate the EMT process. SNAIL1 mRNA level is not detectable in the normal colon mucosa, but is upregulated in 60–70% of CRC. Importantly, aberrant SNAIL1 expression in CRC has been shown to be associated not only with poor patient prognosis, but also with a reduced relapse-free survival time. [36]
SNAIL2 SNAIL2 has been implicated as an anti-apoptotic factor, and is thought to mediate the EMT process by repressing E-cadherin transcription. Accordingly, SNAIL2 expression in human CRC cell lines has been shown to be correlated with critical EMT properties, including the loss of E-cadherin expression and an increase in both cell migration and invasion. [41]
ZEB1 ZEB1 mediates the EMT pathway, and in fact has been shown to be not only sufficient to induce the EMT, but also necessary for maintaining the adapted mesenchymal phenotype. ZEB1 contains zinc finger clusters in both its N- and C-terminal regions, and a homeodomain in the central region. In CRC cells, ZEB1 has been shown to critically mediate the EMT, and thus may be an important regulator of CRC metastasis. [43]
ZEB2 ZEB2 is a member of the Zfh1 family of two-handed zinc-finger transcription factors. It is frequently expressed in colon cancer, and has been shown by several previous studies to induce the EMT, and to facilitate cancer-cell metastasis, possibly via the repression and upregulation of E-cadherin and vimentin respectively. [46]
LEF1 LEF1 is critical for tumor-cell adhesion and/or migration, and thus, also for tumor invasion and metastasis. In addition, it plays a pivotal role in carcinogenesis and CRC progression, partly via its function in the LEF1/β-catenin complex, which is a crucial effector of the Wnt signaling pathway. Increased LEF1 expression has been shown to be correlated with node and distant metastasis, and with an advanced tumor stage. Furthermore, LEF1 was shown to be involved in CRC invasion and metastasis. [49]
FOXA1 and FOXA2 Forkhead box (FOX) protein A1 (FOXA1) is a transcription factor belonging to the FOX gene superfamily that mediates fundamental developmental and differentiation processes. Specifically, it modulates transcriptional programs in a tissue-dependent manner by inducing nucleosomal rearrangement, and by altering chromatin accessibility to the transcriptional machinery. FOXA1 has been shown to be overexpressed in CRC, and furthermore, to be positively associated with poor clinicopathological features. This suggests that its expression may be a promising candidate prognostic biomarker for patients with CRC. FOXA2 is a known key regulator of CRC metastasis to the liver. [52]
CDH1 CDH1 gene encodes a classical cadherin. The E-cadherin-mediated cell adhesion system is required for both the EMT, and for cellular invasion, angiogenesis, and metastatic/tumor progression in many cancers, including CRC. [56]
STAT1 STAT1 is a signal mediator that controls cell-death functions in the context of both pro-apoptotic and anti-proliferative interferon-dependent signaling. It appears to exhibit tumor suppressive functions, and its activity has been shown to be associated with a favorable patient prognosis in some cancers. [57]
BMP2 and BMP5 Bone morphogenetic proteins (BMPs) are the secreted ligands of the proteins belonging to the transforming growth factor beta superfamily (TGFβ), and are important regulators of body-axis patterning during embryogenesis. In adult tissues, they regulate cell growth, apoptosis, and differentiation. The biological effects of BMPs have been predominantly studied in mesoderm-derived cells and tissues, and to a lesser degree, in epithelial cells and tissues. In general, BMPs are involved in the regulation of cancer progression and metastasis possibly through TGF-β-induced SMAD3-dependent EMT. Inactivation of BMP signaling increases the tumorigenicity of normal colon stem cells. [59]
VIM VIM is a Wnt-targeted gene that is expressed in normal mesenchymal cells, and that encodes the intermediate filament protein, vimentin. Previous studies have shown that vimentin mediates both cellular structure and integrity. Furthermore, vimentin has also been demonstrated to mediate cell shape and motility during the EMT process, which is required for cancer-cell metastasis. [62]
SMAD2, SMAD3, SMAD4, and SMAD7 The SMADs are a family of structurally related signaling proteins that can be divided into three subgroups according to their respective functions in TGFβ signaling. Specifically, the receptor-activated SMADs, including SMAD2 and SMAD3, are serine-phosphorylated following TGF-receptor complex formation. The unique SMAD4 co-SMAD (which is common to both TGFβ and BMP signaling), then interacts with the phosphorylated SMAD2/SMAD3. The resulting heteropolymer migrates to the nucleus and complexes with tissue-specific transcription factors, thereby inducing the transcription of TGFβ target genes, including SMAD7. Finally, SMAD7, which is the only TGFβ-specific anti-SMAD, prevents SMAD2/3 activation, thereby providing a transient TGFβ response in the form of a negative feedback loop. Immunohistochemical analysis has revealed the expression of SMADs during EMT process in CRC. [66]