Nicotine-enhanced stemness and epithelial-mesenchymal transition of human umbilical cord mesenchymal stem cells promote tumor formation and growth in nude mice
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Tao Li1,*, Jun Zhang2,*, Jiahui Zhang1, Nannan Zhang1, Yang Zeng3, Shengnan Tang1, Zehua Tao1, Xiying Qu3, Jue Jia4, Wei Zhu1, Xiaochun Sun1 and Huabiao Chen1,3
1School of Medicine, Jiangsu University, Zhenjiang, Jiangsu 212001, P.R. China
2Department of Laboratory, The Affiliated Hospital of Yangzhou University, Yangzhou, Jiangsu 225001, P.R. China
3Vaccine and Immunotherapy Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
4The Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu 212001, P.R. China
*These authors contributed equally to this work
Huabiao Chen, email: [email protected]
Xiaochun Sun, email: [email protected]
Keywords: cancer; nicotine; mesenchymal stem cells; stemness; EMT
Received: March 21, 2017 Accepted: November 01, 2017 Published: November 27, 2017
Cigarette smoking is a well-known risk factor in the development and progression of malignant diseases. Nicotine, the major constituent in cigarette smoke, has also shown negative effects on stem cells. Mesenchymal stem cells (MSCs) have been widely demonstrated to migrate into tumors and play key roles in cancer progression. However, the mechanisms by which nicotine impacts MSCs and tumorigenesis of lung cancer are still undetermined. In this study we investigated the effects of nicotine on human umbilical cord mesenchymal stem cells (hUC-MSCs) and the impacts of nicotine-treated hUC-MSCs on tumor formation and progression. We found that nicotine has a toxic effect on hUC-MSCs and changes the morphology, inhibits proliferation and promotes apoptosis of hUC-MSCs in a dose-dependent manner. Nicotine-treated hUC-MSCs produce higher level of IL-6. Moreover, nicotine promotes migration, stemness and epithelial-mesenchymal transition (EMT) of hUC-MSCs by inhibiting E-cadherin expression and upregulating mesenchymal markers such as N-cadherin and Vimentin, leading to the induction of stem cell markers Sox2, Nanog, Sall4, Oct4 and CD44. Migration and proliferation of non-small cell lung cancer A549 cells and breast cancer MCF-7 cells are promoted after their coculture with nicotine-treated hUC-MSCs in a cell-cell contact-independent manner. Furthermore, nicotine-treated hUC-MSCs promote tumor formation and growth of A549 cells in nude mice. These studies demonstrated that the enhanced stemness and EMT of hUC-MSCs induced by nicotine are critical for the development of tobacco-related cancers.
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