Targeting the Thyroid Transcription Factor-1 Induces Phenotypic Differentiation of Human Lung Adenocarcinoma Stem Cells

Abstract: The cancer stem cells (CSC) have been characterized by their abilities to self-renew and to differentiate into heterogeneous lineages of cancer cells that compose the tumor. The molecular mechanisms regulating these properties， however， remain largely unknown. In this study， we explored the impact of targeting thyroid transcription factor-1(TTF-1) on the differentiation of CSC in human lung adenocarcinoma by using of nanoparticalmediated microRNA silencing technique. The results showed that CSC in lung adenocarcinoma belonged to the primitive， undifferentiated cells with phenotypic features of embryonic stem cells (ESC). These cancer cells expressed the core regulatory circuitry for self-renewal in ESC (i.e.， OCT4， Nanog and Sox2)， the phenotypic markers of bronchioalveolar stem cells (CCSP and SP-C)， and the lineage markers related to the type I pneumocytes AQP5 and the ciliated cells Foxj1. They also exhibited the lung development-related transcription factors (TTF-1 and GATA6). In contrast， the TTF-1-inactivated cells expressed SP-C and GATA6 only， indicating the loss of capacity to self-renew and the phenotypic differentiation into type II pneumocytes. After propagations in culture， these TTF-1- inactivated cells further differentiated into the type I-like pneumocytes with phenotype of SP-C-AQP5+. These data documented that TTF-1 played a critical role in maintaining the biological features of CSC in lung adenocarcinoma. Silencing this gene enforced the lung adenocarcinoma stem cells to differentiate phenotypically.

CSTR: 32200.14.cjcb.2011.02.0003