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      RhoC Regulates Cancer Stem Cells in Head and Neck Squamous Cell Carcinoma by Overexpressing IL-6 and Phosphorylation of STAT3

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          Abstract

          In this study we investigated the correlation between RhoC expression and cancer stem cells (CSCs) formation in head and neck squamous cell carcinoma (HNSCC). The inhibition of RhoC function was achieved using shRNA. The expression of stem cell surface markers, ALDH and CD44 were significantly low in two RhoC depleted HNSCC cell carcinoma cell lines. Furthermore, a striking reduction in tumorsphere formation was achieved in RhoC knockdown lines. The mRNA expression of RhoC in RhoC knockdown adherent and tumorspheres are dramatically down regulated as compared with the scrambled control. The mRNA expression of stem cell transcription factors; nanog, oct3/4 (Pouf1), and sox2 were significantly depleted in RhoC knockdown clones. Further, the phosphorylation of STAT3 ser727, and STAT3 tyr705 were significantly down regulated in RhoC knockdown clones. The overexpression of STAT3 in RhoC knockdown did not show any change in expression patterns of either-STAT3 tyr705 or stem cell transcription factors, signifying the role of RhoC in STAT3 activation and thus the expression of nanog, oct3/4 and sox2 in HNSCC. The expression of Inter leukin-6 (IL-6) in RhoC knockdown HNSCC cell lines was dramatically low as compared to the scrambled control. Further, we have shown a rescue in STAT3 phosphorylation by IL-6 stimulation in RhoC knockdown lines. This study is the first of its kind to establish the involvement of RhoC in STAT3 phosphorylation and hence in promoting the activation of core cancer stem cells (CSCs) transcription factors. These findings suggest that RhoC may be a novel target for HNSCC therapy.

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          Most cited references33

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          Global cancer statistics in the year 2000.

          D Parkin (2001)
          Estimation of the burden of cancer in terms of incidence, mortality, and prevalence is a first step to appreciating appropriate control measures in a global context. The latest results of such an exercise, based on the most recent available international data, show that there were 10 million new cases, 6 million deaths, and 22 million people living with cancer in 2000. The most common cancers in terms of new cases were lung (1.2 million), breast (1.05 million), colorectal (945,000), stomach (876,000), and liver (564,000). The profile varies greatly in different populations, and the evidence suggests that this variation is mainly a consequence of different lifestyle and environmental factors, which should be amenable to preventive interventions. World population growth and ageing imply a progressive increase in the cancer burden--15 million new cases and 10 million new deaths are expected in 2020, even if current rates remain unchanged.
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            Breast cancer stem cell markers CD44, CD24 and ALDH1: expression distribution within intrinsic molecular subtype.

            The study of CD44/CD24 and ALDH1 expression is the most accurate method to identify cancer stem cells (CSC) from breast cancer populations. However, the overlap between CD44(+)CD24(-/low) and ALDH1(high) CSC phenotypes in breast cancer seems to be very small, as well as their distribution among intrinsic breast cancer subtypes. Due to this discrepancy, it is imperative to improve the understanding of breast CSC marker distribution. 466 invasive breast carcinomas and eight breast cancer cell lines were analysed for the expression of CD44, CD24 and ALDH1, to evaluate their distribution among the distinct molecular subtypes. Basal-like tumours (76.5%) contained the higher percentage of cells with the CSC phenotype CD44(+)CD24(-/low) (p<0.0001). From ALDH1-positive cases, 39.4% were also basal-like tumours (p<0.0001). The analysis of breast cancer cell lines indicated that luminal cell lines are mainly enriched in a CD44(-/low)CD24(+) cell population, basal/mesenchymal breast cancer cell lines are enriched in the CD44(+)CD24(-/low) phenotype, whereas the remaining basal/epithelial cell lines are mainly positive for both markers. ALDH1 activity was mainly found in HER-OE and basal/epithelial breast cancer cell. CD44(+)CD24(-/low) and ALDH1(+) phenotypes seem to identify CSC with distinct levels of differentiation. It seems that the paramount method and biomarkers that identify breast CSC within the distinct molecular subtypes need to be better explored, because it is pivotal to translate the CSC concept to clinical practice. In the future, the recognition of reliable markers to distinguish the CSC pool in each molecular subtype will be decisive for the development of specific target therapies.
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              Distinct lineage specification roles for NANOG, OCT4, and SOX2 in human embryonic stem cells.

              Nanog, Oct4, and Sox2 are the core regulators of mouse (m)ESC pluripotency. Although their basic importance in human (h)ESCs has been demonstrated, the mechanistic functions are not well defined. Here, we identify general and cell-line-specific requirements for NANOG, OCT4, and SOX2 in hESCs. We show that OCT4 regulates, and interacts with, the BMP4 pathway to specify four developmental fates. High levels of OCT4 enable self-renewal in the absence of BMP4 but specify mesendoderm in the presence of BMP4. Low levels of OCT4 induce embryonic ectoderm differentiation in the absence of BMP4 but specify extraembryonic lineages in the presence of BMP4. NANOG represses embryonic ectoderm differentiation but has little effect on other lineages, whereas SOX2 and SOX3 are redundant and repress mesendoderm differentiation. Thus, instead of being panrepressors of differentiation, each factor controls specific cell fates. Our study revises the view of how self-renewal is orchestrated in hESCs. Copyright © 2012 Elsevier Inc. All rights reserved.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1932-6203
                2014
                12 February 2014
                : 9
                : 2
                : e88527
                Affiliations
                [1 ]Department of Otolaryngology-Head and Neck Surgery, The Ohio State University Wexner Medical Center, Columbus, Ohio, United States of America
                [2 ]Comprehensive Cancer Center, The Ohio State University Wexner Medical Center, Columbus, Ohio, United States of America
                Johns Hopkins University, United States of America
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Conceived and designed the experiments: MI. Performed the experiments: MI SS. Analyzed the data: MI SS. Wrote the paper: MI TNT.

                Article
                PONE-D-13-41994
                10.1371/journal.pone.0088527
                3922885
                24533098
                d44089a6-7217-492c-b245-2b820ed6da74
                Copyright @ 2014

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 14 October 2013
                : 7 January 2014
                Page count
                Pages: 11
                Funding
                This study was supported by The Ohio State University Comprehensive Cancer Center and the Slomin Family Foundation (Florida, USA) to Ted Teknos. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Biology
                Molecular Cell Biology
                Cytometry
                Flow Cytometry
                Signal Transduction
                Signaling in Cellular Processes
                STAT signaling family
                Medicine
                Clinical Immunology
                Immunologic Techniques
                Immunoassays
                Oncology
                Cancers and Neoplasms
                Head and Neck Tumors
                Head and Neck Squamous Cell Carcinoma
                Otorhinolaryngology

                Uncategorized
                Uncategorized

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