EMT and stem cell–like properties associated with miR-205 and miR-200 epigenetic silencing are early manifestations during carcinogen-induced transformation of …

CS Tellez, DE Juri, K Do, AM Bernauer, CL Thomas… - Cancer research, 2011 - AACR
CS Tellez, DE Juri, K Do, AM Bernauer, CL Thomas, LA Damiani, M Tessema, S Leng
Cancer research, 2011AACR
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 …
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 CD44high/CD24low, 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); 3087–97. ©2011 AACR.
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