Snail silencing effectively suppresses tumour growth and invasiveness

Abstract

The transcription factor Snail has been recently proposed as an important mediator of tumour invasion because of its role in downregulation of E-cadherin and induction of epithelial-mesenchymal transitions (EMT). This behaviour has led to the consideration of Snail as a potential therapeutic target to block tumour progression. In this report, we provide evidence for this hypothesis. We show that silencing of Snail by stable RNA interference in MDCK-Snail cells induces a complete mesenchymal to epithelial transition (MET), associated to the upregulation of E-cadherin, downregulation of mesenchymal markers and inhibition of invasion. More importantly, stable interference of endogenous Snail in two independent carcinoma cell lines leads to a dramatic reduction of in vivo tumour growth, accompanied by increased tumour differentiation and a significant decrease in the expression of MMP-9 and angiogenic markers and invasiveness. These results indicate that use of RNA interference can be an effective tool for blocking Snail function, opening the way for its application in new antiinvasive therapies.

Snai1 and Snai2 collaborate on tumor growth and metastasis properties of mouse skin carcinoma cell lines

“…Importantly, the effect of shSnai2 is specific as it did not influence Snai1-EGFP mediated repression of E-cadherin promoter (Supplementary Figure S1B). As previously reported, shSnai1 is specific for Snail1 repression (Supplementary Figure S1B; Olmeda et al, 2007a).…”

“…Previous studies on human breast carcinoma cells also suggested a differential involvement of Snai1 and Snai2 in E-cadherin repression or specific invasion patterns (Hajra et al, 2002;Come et al, 2006). We recently described an important role for Snai1 in tumor growth, differentiation and invasion of mouse skin (Olmeda et al, 2007a), and in lymph node metastasis of human breast carcinoma cells (Olmeda et al, 2007b). Now, we have investigated the interplay between Snai1 and Snai2 in tumorigenesis targeting each factor by stable RNA interference in two mouse skin carcinoma cell lines, analysing their effect in in vitro invasion, and tumorigenic and metastatic behaviour into nude mice.…”

“…We have recently reported that endogenous Snai1 silencing in HaCa4 and CarB cells leads to decreased expression of mesenchymal markers and invasiveness (Olmeda et al, 2007a). To answer whether Snai2 could collaborate with Snai1 in the phenotype and tumorigenic behaviour of both carcinoma cell lines, the shSnai2 vector was stably transfected in HaCa4 and CarB cells in the absence or presence of shSnai1.…”

“…Stable clones (5-10) were isolated and characterized from each cell line and transfection (named HaCa4-shSnai2 or CarB-shSnai2 for shSnai2, and HSS and CSS for shSnai1/shSnai2 double interference); two representative examples of each type are shown. Two selected clones of the recently described HaCa4-shSnai1 and CarB-shSnai1 cells (Olmeda et al, 2007a) were included. Cells stably transfected with shEGFP (HaCa4-shEGFP and CarB-shEGFP) were used as negative controls.…”

Oxazepine Derivative as an Antitumor Agent and Snail1 Inhibitor against Human Colorectal Adenocarcinoma

“…Snail 1 has recently been shown to revoke the inhibition of the Wnt/beta-Catenin pathway caused by the anti-tumoral compound 1α,25-dihydroxyvitamin D3 [16,17]. Snail 1 is upregulated and frequently associated with invasiveness, metastases and poor prognosis in several human cancers [18][19][20][21][22]. Snail 1 is upregulated (in tumor-stroma interphase) in 60-70 % of colorectal adenoma and colorectal cancers [23].…”