SNAILs promote G1 phase in selected cancer cells

Abstract

Abstract. Cells can acquire a stem-like cell phenotype through epithelial-mesenchymal transition (EMT). However, it is not known which of the stem-like cancer cells are generated by these phenotype transitions. We studied the EMT-inducing roles of SNAILs (the key inducers for the onset of EMT) in selected cancer cells (lung cancer cell line with relatively stable genome), in order to provide more implications for the investigation of EMT-related phenotype transitions in cancer. However, SNAILs fail to induce completed EMT. In addition, we proved that Snail accelerates the early G1 phase whereas Slug accelerates the late G1 phase. Blocking G1 phase is one of the basic conditions for the onset of EMT-related phenotype transitions (e.g., metastasis, acquring stemness). The discovery of this unexpected phenomenon (promoting G1 phase) typically reveals the heterogeneity of cancer cells. The onset of EMT-related phenotype transitions in cancer needs not only the induction and activation of SNAILs, but also some particular heredity alterations (genetic or epigenetic alterations, which cause heterogeneity). The new connection between heredity alteration (heterogeneity) and phenotype transition suggests a novel treatment strategy, the heredity alteration-directed specific target therapy. Further investigations need to be conducted to study the relevant heredity alterations. IntroductionCancer stem cell (CSC) is a cell within a tumor that possesses the capacity to self-renew and to cause the heterogeneous lineages of cancer cells that comprise the tumor (1). Although it has been proven that epithelial-mesenchymal transition (EMT) can generate cells with stem cell properties (2), it is still unknown which of the stem-like cancer cells are generated by these phenotype transitions.The function of Snail genes is best known for induction of EMT. Both in development and during carcinoma progression, Snail1 (Snail) is expressed at the onset of the transition, whereas Snail2 (Slug), Zeb genes, E47 and Twist are subsequently induced to maintain the migratory mesenchymal state (3). As transcriptional repressors, Snail and Slug can regulate the expression of genes mediating therapeutic resistance and acquiring of stem-like phenotype in ovarian cancer cells (4).Snail and Slug have complicated interactions with many key molecules. Snail can cause functional deficiency of p53 in tumor cells with mutant KRAS (5). We know GSK3β, the downstream molecule of Akt (6), can phosphorylate Snail to cause the degradation or the nuclear export of Snail (7). However, KRAS can interact with the PI3K/Akt pathway (8), and then affect GSK3β. Slug can escape degradation when p53 is mutant in lung cancer (9). In addition, the experssion of Slug can be regulated by mutant KRAS in colon cancer cells (10). Snail and Slug are also connected to other key molecules (e.g., EGFR, ERCC1) (11-13).Certain key molecules, including KRAS, p53, EGFR, ERCC1, are all connected to EMT (11,[14][15][16] and stem cell biology (17)(18)(19)(20). This makes the SNAIL-related ph...