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ASXL3 Is a Novel Pluripotency Factor in Human Respiratory Epithelial Cells and a Potential Therapeutic Target in Small Cell Lung Cancer.

ABSTRACT: In this study, we generated induced pluripotent stem cells (iPSC) from normal human small airway epithelial cells (SAEC) to investigate epigenetic mechanisms of stemness and pluripotency in lung cancers. We documented key hallmarks of reprogramming in lung iPSCs (Lu-iPSC) that coincided with modulation of more than 15,000 genes relative to parental SAECs. Of particular novelty, we identified the PRC2-associated protein, ASXL3, which was markedly upregulated in Lu-iPSCs and small cell lung cancer (SCLC) lines and clinical specimens. ASXL3 overexpression correlated with increased genomic copy number in SCLC lines. ASXL3 silencing inhibited proliferation, clonogenicity, and teratoma formation by Lu-iPSCs, and diminished clonogenicity and malignant growth of SCLC cells in vivo Collectively, our studies validate the utility of the Lu-iPSC model for elucidating epigenetic mechanisms contributing to pulmonary carcinogenesis and highlight ASXL3 as a novel candidate target for SCLC therapy. Cancer Res; 77(22); 6267-81. ©2017 AACR.

SUBMITTER: Shukla V

PROVIDER: S-EPMC5690859 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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ASXL3 Is a Novel Pluripotency Factor in Human Respiratory Epithelial Cells and a Potential Therapeutic Target in Small Cell Lung Cancer.

Shukla Vivek V Rao Mahadev M Zhang Hongen H Beers Jeanette J Wangsa Darawalee D Wangsa Danny D Buishand Floryne O FO Wang Yonghong Y Yu Zhiya Z Stevenson Holly S HS Reardon Emily S ES McLoughlin Kaitlin C KC Kaufman Andrew S AS Payabyab Eden C EC Hong Julie A JA Zhang Mary M Davis Sean S Edelman Daniel D Chen Guokai G Miettinen Markku M MM Restifo Nicholas P NP Ried Thomas T Meltzer Paul A PA Schrump David S DS

Cancer research 20170921 22

In this study, we generated induced pluripotent stem cells (iPSC) from normal human small airway epithelial cells (SAEC) to investigate epigenetic mechanisms of stemness and pluripotency in lung cancers. We documented key hallmarks of reprogramming in lung iPSCs (Lu-iPSC) that coincided with modulation of more than 15,000 genes relative to parental SAECs. Of particular novelty, we identified the PRC2-associated protein, ASXL3, which was markedly upregulated in Lu-iPSCs and small cell lung cancer ...[more]

PMID: 28935813

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Project description:Previously we reported that mithramycin represses multiple pathways critical for stem cell signaling and pluripotency in lung cancer cells. This phenomenon coincided with decreased side population fraction and dramatic dose-dependent growth arrest of lung cancer cells in vitro and in vivo. In the present study, microarray, quantitative reverse transcriptase polymerase chain reaction and immunoblot experiments were performed to further examine the effects of mithramycin on stem cell gene expression in lung cancer cells. This analysis revealed that mithramycin significantly inhibited expression of musashi-2 (MSI2), which encodes a RNA binding protein that mediates self-renewal and pluripotency in normal stem cells and has been implicated in mediating aggressive phenotype of a variety of human malignancies. MSI2 expression levels were significantly increased in non–small cell lung cancer lines and were even more dramatically elevated in small-cell lung cancer lines relative to cultured normal human respiratory epithelial cells (small airway epithelial cells / normal human bronchial epithelia / human bronchial epithelial cells; P < 0.001). MSI2 expression levels in primary lung cancers were significantly higher than those detected in adjacent paired normal lung parenchyma (P < 0.0003). Consistent with its putative role as a pluripotency factor, MSI2 messenger RNA as well as protein levels were significantly increased in induced pluripotent stem cells derived from normal human small airway epithelial cells, as well as side population fractions of lung cancer cells. Transient knock-down of MSI2 significantly inhibited proliferation of lung cancer cells; this phenomenon coincided with downregulation of octamer-binding transcription factor 4 (Oct4), Nanog, and MYC. To date, we have been unable to stably knock-down MSI2 in lung cancer cells in vitro or in vivo, suggesting a strong selection pressure to maintain expression of this pluripotency factor during pulmonary carcinogenesis. Under conditions potentially achievable in clinical settings, mithramycin significantly inhibited MSI2 expression in lung cancer cells in vitro and in vivo in a time- and dose-dependent manner. Collectively, these finding suggest MSI2 is a potential master regulator of stem cell gene expression and pluripotency in lung cancer cells, and a novel target for lung cancer therapy.

Dataset Information

ASXL3 Is a Novel Pluripotency Factor in Human Respiratory Epithelial Cells and a Potential Therapeutic Target in Small Cell Lung Cancer.

Publications

ASXL3 Is a Novel Pluripotency Factor in Human Respiratory Epithelial Cells and a Potential Therapeutic Target in Small Cell Lung Cancer.

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