Role of the epithelial-mesenchymal transition regulator Slug in primary human cancers

Abstract

Epithelial-mesenchymal-transition (EMT) is a crucial process during morphogenesis of multi-cellular organisms. EMT not only is a normal developmental process but also plays a role in tumor invasion and metastasis. Indeed, molecules involved in EMT, such as the transcription factor and E-cadherin repressor Slug (SNAI2), have recently been demonstrated to be important for cancer cells to down-regulate epithelial markers and up-regulate mesenchymal markers in order to become motile and invasive. Here we summarize major studies focusing on Slug expression in human tumor samples. We review a total of 13 studies involving 1150 cases from 9 different types of tumors. It is becoming clear that this transcription factor plays a role in the progression of some tumor types, including breast and gastric cancer. Interestingly, Slug expression is not always associated with down-regulation of E-cadherin. The mode of action, the signaling pathways involved in its regulation, and the interplay with other EMT regulators need to be addressed in future studies in order to fully understand Slug's role in tumor progression.

Epithelial-to-mesenchymal transition (EMT) confers primary resistance to trastuzumab (Herceptin)

“…1,16 It is well-established that some members of the SNAIL family (i.e., SLUG/SNAIL2) and TWIST can confer an EMT phenotype to breast epithelial cells, a phenomenon that generally correlates with the cells changing their phenotype from CD44 -CD24 + to CD44 + CD24 -/low . [58][59][60][61][62] We now confirm the possibility that the EMT drivers SLUG/SNAIL2 and TWIST can also participate in the conversion of CD44 + CD24 + basal epithelial cells into CD44 + CD24 -/low mesenchymal cells. More importantly, the fact that the HER2 + basal epithelial cells are susceptible to such EMTrelated phenotypic changes can explain the intrinsic ability of a breast CSCs, 3,54-56 we decided to establish primary mammospheres from CD44 + CD24 -/low -positive parental JIMT1 cells and their CD44 + CD24 -/low -negative derivatives, cells in which the expression of SLUG/SNAIL2 was stably knocked-down by a lentivirus-delivered shRNA.…”

Classification of epithelial–mesenchymal transition phenotypes in esophageal squamous cell carcinoma is strongly associated with patient prognosis

“…These E-cadherin ( þ ) and Slug ( þ ) cases may be related to the hybrid type of epithelial-mesenchymal transition because Slug is also an important transcription factor involved in epithelial-mesenchymal transition. 22 Furthermore, Natsugoe et al 23 also described that some epithelial-mesenchymal transition patients with preserved E-cadherin expression had a poor prognosis, and the overall survival rate was better in patients with negative Snail expression than in those with positive Snail expression in the preserved E-cadherin group. These results could be explained if the ones with poor prognosis in the group with preserved E-cadherin are associated with the cases that were classified as the hybrid type of epithelial-mesenchymal transition in our study.…”

Critical role for transcriptional repressor Snail2 in transformation by oncogenic RAS in colorectal carcinoma cells

“…Snail2 belongs to the Snail superfamily of zinc finger transcriptional repressors. It is an important regulator of EMT and has a significant role in the malignant progression of cancer (Cobaleda et al, 2007;Peinado et al, 2007;Alves et al, 2009). Snail2-overexpressing mice develop mesenchymal tumours, whereas Snail2-deficient mice are resistant to BCR-ABL-induced leukaemogenesis (Perez-Mancera et al, 2005).…”

“…Snail2-overexpressing mice develop mesenchymal tumours, whereas Snail2-deficient mice are resistant to BCR-ABL-induced leukaemogenesis (Perez-Mancera et al, 2005). Snail2 overexpression has been described in a wide spectrum of human cancers including breast cancer, colorectal cancer, gastric carcinoma, oesophageal carcinoma and other tumour types and seems to be important for tumour progression toward invasion and metastasis, in most cases involving E-cadherin downregulation (Cobaleda et al, 2007;Peinado et al, 2007;Alves et al, 2009). Snail2 expression has been reported to be important for the metastatic spread of RAS mutant melanoma cells in a mouse model (Gupta et al, 2005) and to be an independent prognostic marker for poor survival in colorectal cancer patients (Shioiri et al, 2006).…”