Targeting the Wnt-Regulatory Protein CTNNBIP1 by microRNA-214 Enhances the Stemness and Self-Renewal of Cancer Stem-Like Cells in Lung Adenocarcinomas

Abstract

A novel hypothesis in cancer biology proposes that cancer growth is driven by cancer stem-like cells (CSLCs), also called tumor-initiating cells, which can self-renew and differentiate into multilineage progeny in a fashion similar to stem cells. However, the impact and underlying mechanisms of this process in lung adenocarcinoma (LAC) remain to be elucidated. Here, we report that microRNA-214 (miR-214) contributes to cell self-renewal by directly targeting catenin beta interacting protein 1 (CTNNBIP1), a member of the Wnt signaling pathway. We demonstrate that miR-214 overexpression enhances stem-like properties in LAC cells and that miR-214 shows increased expression in CSLCs derived from primary tumor tissue and from two LAC cell lines (A549 and NCI-H1650). Strikingly, downregulation of miR-214 expression in CSLCs resulted in a significant decrease in spheroid formation and the expression of the stem-cell markers Nanog, Oct-4, and Sox-2. Finally, CTNNBIP1 was identified as a target of miR-214. miR-214 expression in LAC was negatively correlated with CTNNBIP1 expression and positively correlated with differentiated cellular states. Moreover, CTNNBIP1 expression correlated with longer overall survival in LAC patients. This study reveals that miR-214 plays a critical role in CSLC self-renewal and stemness by targeting CTNNBIP1. The identification of this functional miR-214-CTNNBIP1 interaction that regulates self-renewal in CSLCs has the potential to direct the development of novel therapeutic strategies for LAC. STEM CELLS 2015;33:3423-3436 SIGNIFICANCE STATEMENTThis study is the first to investigate and identify the role of miR-214 in lung adenocarcinoma (LAC) from a perspective of CSLC regulation. We show that miR-214 inhibits CTNNBIP1 expression and thereby illuminate the mechanism of Wnt/b-catenin signal activation in CSLCs in LAC. Finally, we investigate the significance of CTNNBIP1 in clinical patients and find that CTNNBIP1 expression is positively correlated with differentiated cancer-cell grades and predicted prognosis in patients with LAC. The identification of the miR-214-CTNNBIP1 pathway that regulates selfrenewal and stemness in CSLCs has potential to facilitate the development of novel therapeutic strategies for the patients with LAC.

Integrated analysis of long non-coding RNA-associated ceRNA network reveals potential lncRNA biomarkers in human lung adenocarcinoma

“…Then, he found BMp9 can inhibit the growth and migration of LUAD A549 cells through the MApK/ERK and NF-κB pathways. It was also reported that Wnt signaling pathways were related with LUAD (53)(54)(55).…”

TWIST1 upregulates miR-214 to promote epithelial-to-mesenchymal transition and metastasis in lung adenocarcinoma

“…However, this is no way to fully define the function of one gene. For instance, a review of the literature reveals that TWIST1 overexpression in mammary epithelial and cancer cell lines has been shown to promote tumor stemness (25), and miR-214 enhances the stemness and self-renewal of cancer stem-like cells (CSLCs) in lung adenocarcinomas by targeting CTNNBIP1 (22). This indicates that TWIST1 may play a critical role in CSLCs self-renewal and stemness by upregulating miR-214 expression.…”

Functional roles of circular RNAs during epithelial-to-mesenchymal transition

“…Mechanistically, increasing evidence has shown that the CTNNBIP1/β-catenin interaction can prevent the formation of the β-catenin/TCF/ LEF complex. As a result, it prevents the activation of the Wnt/β-catenin signaling pathway [95][96][97][98]. The upregulated circRNA_102171 facilitates the malignant behavior of papillary thyroid cancer by regulating the CTNNBIP1-mediated activation of the Wnt/β-catenin pathway.…”