Disease relevance of SNAI2

• SNAI2 mRNA was expressed in placenta, melanocyte, embryonic stem (ES) cells, leiomyosarcoma, neuroblastoma, and glioblastoma [1].
• A statistically significant association was found between Slug up-regulation and the expression of SIP1 in intestinal (p = 0.0014) and Snail in diffuse (p = 0.0067) carcinomas [2].
• We therefore investigated the role of Slug as a possible candidate contributing to the aetiology of neural tube defects (NTD) in humans [3].
• The SNAIL-related zinc-finger transcription factor, SLUG (SNAI2), is critical for the normal development of neural crest-derived cells and loss-of-function SLUG mutations have been proven to contribute to piebaldism and Waardenburg syndrome type 2 in a dose-dependent fashion [4].
• The Snail-related zinc-finger transcription factor, SLUG (SNAI2), is critical for the normal development of neural crest-derived cells and loss-of-function SLUG mutations have been proven to cause piebaldism and Waardenburg syndrome type 2 in a dose-dependent fashion [5].

High impact information on SNAI2

• Control of cell behavior during vertebrate development by Slug, a zinc finger gene [6].
• In presence of Ln-5, cells undergo partial EMT, Snail, and Slug are up-regulated, E-cadherin is down-regulated but cells do not scatter [7].
• In such cells, beta-catenin signaling, ErbB-1/2 levels, and ERK activation were reduced and Slug was undetectable [8].
• In human cancer, aberrant expression of Snail and/or Slug has been correlated with invasive growth potential, a property primarily attributed to their ability to directly repress transcription of genes whose products are involved in cell-cell adhesion, such as E-cadherin, occludin, and claudins [9].
• Snail or Slug expression also promoted resistance to programmed cell death elicited by DNA damage [9].

Biological context of SNAI2

• Phylogenetic analysis of human zinc finger proteins with SNAG domain revealed that SNAI1, SNAI2 and SNAI3 were more closely related [10].
• Comparative genomics on SNAI1, SNAI2, and SNAI3 orthologs [1].
• Thus, aberrant expression of Snail or Slug may promote tumorigenesis through increased resistance to programmed cell death [9].
• When we compared gene expression profiles between five MM cells and their multidrug-resistant (MM DX) sublines, we found that MM DX cells expressed both SCF and c-Kit and had higher mRNA levels of Slug [11].
• Transfection of c-Kit in parental MM cells in the presence of SCF up-regulated Slug and increased resistance to the chemotherapeutic agents [11].

Anatomical context of SNAI2

• SNAI2 induces the first phase of EMT, including desmosome dissociation, cell spreading, and initiation of cell separation [1].
• To investigate the molecular mechanisms of alterations in epithelial cell fate mediated by aberrant expression of Snail or Slug, we analyzed the consequences of exogenous expression of these factors in human cancer cells [9].
• Here, we identified a pathway that involves stem cell factor (SCF)/c-Kit/Slug in mediating multidrug resistance of MM cells [11].
• We do, however, find that activation of Slug results in a significant reduction in keratinocyte proliferation [12].
• They emphasize a link between Snail, Slug, and lymph node metastasis in a large sampling of mammary carcinomas, and suggest a role for Slug in the maintenance of semidifferentiated structures [13].

Associations of SNAI2 with chemical compounds

• Knockdown of c-Kit or Slug expression with their respective small interfering RNA sensitized MM DX cells to the induction of apoptosis by different chemotherapeutic agents, including doxorubicin, paclitaxel, and vincristine [11].
• Microarray analysis revealed that several genes, including Slug, were down-regulated by imatinib mesylate [14].

Physical interactions of SNAI2

• Here, we provide evidence through yeast two-hybrid and in vitro co-immunoprecipitation analyses that hSLUG does not directly interacts with hCtBP1 [15].
• We also demonstrate by band-shift assay that Snail and Slug bind to the E-box motifs present in the human Claudin-1 promoter [16].

Co-localisations of SNAI2

• RESULTS: In contrast with transformed cell lines, Slug was found to colocalize with E-cadherin at the cellular level in normal mammary epithelial cells and all tested carcinomas [13].

Regulatory relationships of SNAI2

• The transient activation of c-Src is involved in cytoskeleton remodeling whereas the Ras pathway controls the transcription of genes such as the transcription factor Slug which is involved in the internalization of desmosomes [17].
• In addition, Snail and Slug are able to effectively repress human Claudin-1-driven reporter gene constructs containing the wild-type promoter sequence, but not those with mutations in two proximal E-box elements [16].

Other interactions of SNAI2

• Based on the integromics analyses, SNAI2 orthologs were found to be more conserved than SNAI1 and SNAI3 orthologs [1].
• These results indicate that induction of Slug by autocrine production of SCF and c-Kit activation plays a key role in conferring a broad spectrum chemoresistance on MM cells and reveal a novel signal transduction pathway for pharmacological or genetic intervention of MM patients [11].
• Multivariate analysis indicated that E-cadherin expression and Slug expression were not independent prognostic factors [18].
• VEGFR-1 activation led to an increase in expression of the EMT-associated transcription factors Snail, Twist, and Slug [19].
• Snail, Slug, and Smad-interacting protein 1 as novel parameters of disease aggressiveness in metastatic ovarian and breast carcinoma [20].

Analytical, diagnostic and therapeutic context of SNAI2

• EXPERIMENTAL DESIGN: Immunohistochemistry was used to investigate the expression of E-cadherin and Slug proteins in 203 patients with ESCC [18].
• To investigate the possibility that some cases of human piebaldism might result from abnormalities of the human SLUG (SNAI2) gene, we carried out Southern blot analysis of the SLUG gene in 17 unrelated patients with piebaldism, who lack apparent KIT mutations [21].
• METHODS: Frozen sections from breast cancer primary tumors (tumor, n = 114; background, n = 30) were immunostained with Slug, Snail, and Twist antibodies [22].
• High E-cadherin mRNA expression predicted better disease-free survival (P = 0.023), with a similar trend for a low Slug/E-cadherin ratio (P = 0.07) [20].
• By reporter assay of the promoter of the Slug gene, gel shift and chromatin immunoprecipitation analyses showed AhR directly binds to xenobiotic responsive element 5 at -0.7 kb of the gene [23].

References