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Cold atmospheric plasma (CAP) is selective against many cancers with little side effect, yet its molecular mechanism remains unclear. Through whole transcriptome sequencing followed by assays in vitro , in vivo and using clinical samples, we propose CAP as a promising onco-therapy targeting cancer stemness via the AQP3/FOXO1 axis. CAP-generated reactive species penetrated cells via AQP3 and suppressed RPS6KA3, a shared kinase of AQP3 and FOXO1. Reduced AQP3-19Y phosphorylation suppressed SCAF11-mediated AQP3-5K K48-ubiquitination that led to sabotaged FOXO1 stability. Inhibited FOXO1 phosphorylation retarded its regulatory activities in maintaining cancer stemness including ALDH1 and IL6. Enhanced anti-cancer efficacy was observed through combining CAP with Atorvastatin in vitro and in vivo . We propose CAP as a 'selective' onco-therapeutic against cancer stemness, with the AQP3/FOXO1 axis being one molecular mechanism. We report SCAF11 as an E3 ubiquitin ligase of both AQP3 and FOXO1, identify AQP3-5K as an AQP3 K48-ubiquitination site, and emphasize the essential role of AQP3-19Y in this process. We reposition Atorvastatin into the onco-therapeutic portfolio by synergizing it with CAP towards enhanced efficacy. We anticipate the efficacy of CAP in targeting malignancies of high stemness alone or as an adjuvant therapy towards the hope of ultimate cancer cure., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

MicroRNAs (miRNAs) play an important role in regulating cancer stem cell (CSC). Previous studies have shown that microRNA-221/222 (miR-221/222) cluster are involved in the propagation of breast cancer stem cell (BCSC), however, the underlying molecular mechanisms are still not fully understood. In this study, we found that miR-221/222 were overexpressed in highly aggressive breast cancer MDA-MB-231 cells, that are enriched in markers for epithelial-mesenchymal transition (EMT) and BCSCs, than in MCF-7 cells. Phosphatase and tensin homolog (PTEN) was confirmed to be the target of miR-221/222 in breast cancer cells. MiR-221/222 enhanced breast cancer cell growth, migration and invasion by downregulating PTEN. Importantly, both ectopic expression of miR-221/222 and PTEN knockdown increased the mammosphere formation capacity and the expression of the stemness marker ALDH1. MiR-221/222 lentivirus vector infected MCF-7 cells produced larger subcutaneous tumors, while shRNA vector of PTEN showed similar trend. Along with the downregulation of PTEN caused by miR-221/222 in the breast cancer cells and the xenograft tumor tissues, Akt phosphorylation (p-Akt), NF-κB p65 and phosphorylated p65 (p-p65), and cyclooxygenase-2 (COX-2) were all overexpressed compared to the negative control. Taken together, our findings indicate that miR-221/222 play a critical role in the propagation of BCSCs and tumor growth possibly through targeting PTEN, which in turn activating the Akt/NF-κB/COX-2 pathway. MiR-221/222 might represent the potential target of breast cancer therapy., (Copyright © 2017 Elsevier B.V. All rights reserved.)

This article has been retracted: please see Elsevier Policy on Article Withdrawal (http://www.elsevier.com/locate/withdrawalpolicy). This article has been retracted at the request of the Editor-in-Chief. Concerns were raised in the public domain and also reported by the authors to the journal regarding the similarity between various panels from Figures 2 and 3. Given also the institutional investigation, the journal requested the authors to provide the raw data. However, the authors were not able to provide raw data of sufficient quality and detail for the journal to independently audit the provenance and validity of the data, and therefore the Editor-in-Chief decided to retract the article., (Copyright © 2016 Elsevier Masson SAS. All rights reserved.)