Abstract
We examined IL-6 effects on growth, epithelial-mesenchymal transition (EMT) process, and metastatic ability of CD133+ and CD133– cell subpopulations isolated from three non-small cell lung cancer (NSCLC) cell lines: A549, H157, and H1299. We developed IL-6 knocked-down and scramble (sc) control cells of A549 and H157 cell lines by lentiviral infection system, isolated CD133+ and CD133– sub-populations, and investigated the IL-6 role in self-renewal/growth of these cells. IL-6 showed either an inhibitory or lack of effect in modulating growth of CD133– cells depending on intracellular IL-6 levels, but there was higher self-renewal ability of IL-6 expressing CD133+ cells than IL-6 knocked down cells, confirming the promoter role of IL-6 in CD133+ cells growth. We then examined tumor growth of xenografts developed from CD133+ cells of A549IL-6si vs. A549sc cell lines. Consistently, there was retarded growth of tumors developed from A549IL-6si, CD133+ cells compared to tumors originating from A549sc, CD133+ cells. The effect of IL-6 in promoting CD133+ self-renewal was due to hedgehog (Hhg) and Erk signaling pathway activation and higher Bcl-2/Bcl-xL expression. We also investigated whether IL-6 regulates the EMT process of CD133− and CD133+ cells differently. Expression of the EMT/metastasis-associated molecules in IL-6 expressing cells was higher than in IL-6 knocked down cells. Together, we demonstrated dual roles of IL-6 in regulating growth of CD133– and CD133+ subpopulations of lung cancer cells and significant regulation of IL-6 on EMT/metastasis increase in CD133+ cells, not in CD133– cells.
Highlights
Lung cancer is the predominant cause of cancer deaths in both men and women [1]
The CD133 molecule is the most widely used surface marker for the non-small cell lung cancer (NSCLC) cancer stem cells (CSCs), and previous studies have shown that the CD133+ cells exhibited biological features of CSCs [27, 28]
We discovered differential roles of IL-6 in regulation of the growth/self-renewal of two subpopulation (CD133+ CSC-like, CD133–) cells of NSCLC cell lines
Summary
Lung cancer is the predominant cause of cancer deaths in both men and women [1]. While lung cancer is heterogeneous in cell types, it is generally divided into two major subtypes: small cell lung carcinomas (SCLCs) and non-small cell lung carcinomas (NSCLCs), with the latter comprising 85% of all lung cancer cases [2]. Despite decades of research and clinical trials testing different therapeutic interventions, the treatment outcome of lung cancer remains unsatisfactory. Recent evidence supports the hypothesis that tumors contain putative cancer stem cells (CSCs). The existence of CSCs in lung tumors and in established NSCLC cell lines has been reported [3, 4].
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