EMT and Stem Cell–Like Properties Associated with miR-205 and miR-200 Epigenetic Silencing Are Early Manifestations during Carcinogen-Induced Transformation of Human Lung Epithelial Cells

Abstract

Epithelial-to-mesenchymal transition (EMT) is strongly associated with cancer progression, but its potential role during premalignant development has not been studied. Here, we show that a 4-week exposure of immortalized human bronchial epithelial cells (HBEC) to tobacco carcinogens can induce a persistent, irreversible, and multifaceted dedifferentiation program marked by EMT and the emergence of stem cell-like properties. EMT induction was epigenetically driven, initially by chromatin remodeling through H3K27me3 enrichment and later by ensuing DNA methylation to sustain silencing of tumor-suppressive microRNAs (miRNA), miR-200b, miR-200c, and miR-205, which were implicated in the dedifferentiation program in HBECs and also in primary lung tumors. Carcinogen-treated HBECs acquired stem cell-like features characterized by their ability to form spheroids with branching tubules and enrichment of the CD44 high /CD24 low , CD133, and ALDH1 stem cell-like markers. miRNA overexpression studies indicated that regulation of the EMT, stem-like, and transformed phenotypes in HBECs were distinct events. Our findings extend present concepts of how EMT participates in cancer pathophysiology by showing that EMT induction can participate in cancer initiation to promote the clonal expansion of premalignant lung epithelial cells. Cancer Res; 71(8);

The Inflammatory Tumor Microenvironment, Epithelial Mesenchymal Transition and Lung Carcinogenesis

“…MiR-200 essentially counteracts classical EMT properties such as cell motility, and suppresses translation of stem cells factors, including Bmi1. Similarly, Tellez et al used tobacco carcinogen exposure of immortalized human bronchial epithelial cells to induce EMT and stemness phenotypes [158]. The observed induction of EMT was driven initially by epigenetic silencing of miR-200 and miR-205 that included chromatin remodeling with subsequent promoter methylation.…”

Cancer cells in epithelial-to-mesenchymal transition and tumor-propagating–cancer stem cells: distinct, overlapping or same populations

“…The emerging field of the role of micro RNAs in the mechanisms of the CSC-TPC state and the EMT is not considered as such in this review (Shi et al, 2010). See recent specific articles (Gunaratne, 2009;Kong et al, 2010;Mongroo and Rustgi, 2010;Castilla et al, 2011;Tellez et al, 2011).…”

Deciphering the Key Features of Malignant Tumor Microenvironment for Anti-cancer Therapy

“…The CSCs can be produced from precancerous stem cells [59][60][61][62][63][64], cell de-differentiation [65], or an epithelial-mesenchymal transition [66][67][68]. Malignant mesenchymal stem cells have been found in the niche of cancers [66,67], and an epithelial-mesenchymal transition may be an early key step in the initiation of TME and tumorigenesis [68]. The CSCs may expand by symmetric division, produce progenitor cells by asymmetric division, and differentiate to multiple lineages of tumor cells, resulting in a rapid increase in tumor mass (Figs.…”

“…First, CSCs actively participate in the development of the CSC niche [11]. Second, CSCs may trans-differentiate into cancer-associated stromal cells [58][59][60][61][62][65][66][67][68][69], such as cancer-associated fibroblasts and tumor endothelial cells [70,71]. The CSC-differentiated tumor endothelial cells are important in tumor neovascularization and the genesis of TME [72][73][74][75].…”

“…First, precancerous cells are reversible and may be induced to regress to normal cells, depending on the environmental cue [59][60][61]. Second, oncogenic mesenchymal stem cells could be reversed to normal epithelial cells using the approach of mesenchymalepithelial transition, because epithelial-mesenchymal transition may be reversible [65][66][67][68]. Furthermore, differentiation of CSCs and inhibition of the proliferation of these cells by changes in environmental cues may be additional options to normalize malignant TME.…”