Snail overexpression induces an epithelial to mesenchymal transition and cancer stem cell-like properties in SCC9 cells

Abstract

Local invasiveness and distant metastasis are critical factors that contribute to oral squamous cell carcinoma-related deaths. Increasing evidence has shown that the epithelial to mesenchymal transition (EMT) is involved in cancer progression and is associated with the 'stemness' of cancer cells. Snail is a transcriptional factor that can induce EMT and preserve stem-cell function, which may induce resistance to radio-and chemotherapies in the cells. In the present study, SCC9 cells were transfected with an empty vector or a vector encoding human Snail (SCC9-S). Overexpression of Snail induced SCC9 cells to undergo EMT, in which the cells presented a fibroblast-like appearance, downregulated the epithelial markers E-cadherin and b-catenin, upregulated the mesenchymal marker vimentin, and associated with highly invasive and metastatic properties. Furthermore, the induction of EMT promoted cancer stem cell (CSC)-like characteristics in the SCC9-S cells, such as low proliferation, self-renewal, and CSC-like markers expression. These results indicate that overexpression of Snail induces EMT and promotes CSC-like traits in the SCC9 cells. Further understanding the role of Snail in cancer progression may reveal new targets for the prevention or therapy of oral cancers. Oral squamous cell carcinoma (OSCC) is the most frequent type of cancer in the oral cavity and is associated with high morbidity and poor prognosis. 1,2 Despite progress in surgery, chemotherapy, and radiotherapy, the 5-year survival rate has remained at 50-55% over the past several decades. 3 Local or regional recurrences and distant metastases have a critical role in this process, and the mechanism underlying their occurrence remains poorly understood. 2,4 During metastatic progression, tumour cells lose cell-cell adhesion, detach from the primary site, invade the basement membrane, survive and circulate in the blood vessels, leave the bloodstream, and finally colonise in a new host environment to form micrometastases. 2,5-7 A growing body of research strongly suggests that the epithelial to mesenchymal transition (EMT), which occurs normally during embryonic development, tissue remodelling, and wound healing, is a critical early event in tumour invasion and metastasis. [8][9][10] It is characterised by downregulation of epithelial markers, such as E-cadherin, and upregulation of mesenchymal markers, such as vimentin. During the process of EMT, epithelial cells acquire mesenchymal cell properties and show reduced intercellular adhesion and increased invasion. 11 The transcriptional repressor Snail, which is a zinc finger protein, first described in Drosophila melanogaster, can bind to the E-boxes in the human E-cadherin promoter and suppress its transcription. 12,13 Snail has previously been implicated in triggering EMT during embryonic development, fibrosis, and tumour progression. 14 This process also occurs in the progression of carcinomas (including oral carcinoma cells), following the downregulation of E-cadherin expression or co-expression of NB...

Establishment of a highly metastatic model with a newly isolated lung adenocarcinoma cell line

“…Not only the doubling time and soft agar colony formation assays in vitro but also the growth rate of s.c. tumors in vivo suggested that XL-2sci cell line had a decreased proliferation ability, indicating its enhanced invasion and metastatic activity was not facilitated by a faster growth rate. An inverse correlation between proliferation and metastasis was demonstrated in our study, which was consistent with previous reports (31,54).…”

Radiotherapy-induced plasticity of prostate cancer mobilizes stem-like non-adherent, Erk signaling-dependent cells

“…Epithelial cancer cells undergoing EMT exhibit also features of stemness, 50,51 and Snail induces both EMT and stem cell-like features in squamous cell carcinoma. 52 We show that besides elevated Snail, radiation-surviving non-adherent CaP cells featured enhanced expression of stem cell-associated genes CD133, 53 Oct-4, Sox2 and Nanog, the latter three capable of reprogramming various differentiated cells toward stemness. 54,55 Besides these stem cell markers, radiation-surviving non-adherent CaP cells showed increased activity of Notch signaling, a characteristics of diverse progenitor cells.…”

“…The radiationinduced phenotypic heterogeneity, we report, might reflect transient cellular plasticity as well as stress-evoked responses of preexistent subsets cells seen in the parental DU145 and PC-3 cell populations. [40][41][42][43][44][45][46][47][48][49][50][51][52] Ionizing radiation can promote traits of EMT in normal human mammary epithelium, 41 lung carcinoma 42,43 and colorectal cancer cells. 44 Furthermore, besides their role in E-cadherin repression, 45,46 Slug and Snail have been implicated in radioresistance-associated EMT.…”

Mechanisms of Invasion in Head and Neck Cancer

“…77 In addition to inducing EMT and increased invasiveness, Snail has also been shown to induce stem-like properties in OSCC. 224 Adhesion-related signaling molecules that are important for EMT and invasion include ILK 149 and FAK. 152 For proteases, MT1-MMP has been shown to induce EMT and stemlike properties in OSCC, as well as invasion, in parallel with increased levels of Twist and ZEB.…”