Evidence has accumulated in support of the critical impact of cancer stem cells (CSCs) behind the chemotherapeutic failure, cancer metastasis and subsequent disease recurrence and relapse, but how CSCs are regulated is still limited. Redox status of the cells has been shown to dramatically influence on cell signaling and CSC-like aggressive behaviors. Here, we investigated how subtoxic concentrations of iron, which found to specifically induce cellular hydroxyl radical, affected CSC-like subpopulation of human non-small cell lung carcinoma (NSCLC). We revealed for the first time that subchronic iron exposure and higher level of hydroxyl radical correlated well with increased CSC-like phenotypes. The iron-exposed NSCLC H460 and H292 cells exhibited a remarkable increase in propensities to form CSC spheroids and to proliferate, migrate and invade in parallel with an increase in level of a well-known CSC marker ABCG2. We further observed that such phenotypic changes induced by iron were not related to an epithelial-to-mesenchymal transition (EMT). Instead, the sex-determining region Y (SRY)-box 9 protein (SOX9) was substantially linked to iron treatment and hydroxyl radical level. Using gene manipulations, including ectopic SOX9 overexpression and SOX9 short hairpin RNA knockdown, we have verified that SOX9 is responsible for CSC enrichment mediated by iron. These findings indicate a novel role of iron via hydroxyl radical in CSC regulation and its importance in aggressive cancer behaviors and likely metastasis through SOX9 upregulation.
- Cancer Stem Cells
- Lung Cancer
- Hydroxyl Radical
- Copyright © 2016, American Journal of Physiology - Cell Physiology