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      Klf4 reduces stemness phenotype, triggers mesenchymal-epithelial transition (MET)-like molecular changes, and prevents tumor progression in nasopharygeal carcinoma

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          Abstract

          The reprogramming factor Krüppel-like factor 4 (Klf4), one of the Yamanaka's reprogramming factors, plays an essential role in reprogramming somatic cells into induced pluripotent stem cells (iPSCs). Klf4 is dysregulated and displays divergent functions in multiple malignancies, but the biological roles of Klf4 in nasopharyngeal carcinoma (NPC) remain unknown. The present study revealed that Klf4 downregulation in a cohort of human NPC biopsies is significantly associated with invasive and metastatic phenotypes of NPC. Our results showed exogenous expression of Klf4 significantly inhibited cell proliferation, decreased stemness, triggered mesenchymal-epithelial transition (MET)-like molecular changes, and suppressed migration and invasion of NPC cells, whereas depletion of endogeneous Klf4 by RNAi reversed the aforementioned biological behaviors and characheristics. Klf4 silencing significantly enhanced the metastatic ability of NPC cells in vivo. In addition, CHIP assay confirmed that E-cadherin is a transcriptional target of Klf4 in NPC cells. Additional studies demonstrated that Klf4-induced MET-like cellular marker alterations, and reduced motility and invasion of NPC cells were mediated by E-cadherin. This study revealed the clinical correlation between Klf4 expression and epithelial-mesenchymal transition (EMT) biomarkers (including its target gene E-cadherin) in a cohort of NPC biopsies. Taken together, our findings suggest, for what we believe is the first time, that Klf4 functions as a tumor suppressor in NPC to decrease stemness phenotype, inhibit EMT and prevent tumor progression, suggesting that restoring Klf4 function may provide therapeutic benefits in NPC.

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          Most cited references43

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          The polycomb group protein Bmi-1 represses the tumor suppressor PTEN and induces epithelial-mesenchymal transition in human nasopharyngeal epithelial cells.

          The polycomb group protein B lymphoma Mo-MLV insertion region 1 homolog (Bmi-1) is dysregulated in various cancers, and its upregulation strongly correlates with an invasive phenotype and poor prognosis in patients with nasopharyngeal carcinomas. However, the underlying mechanism of Bmi-1-mediated invasiveness remains unknown. In the current study, we found that upregulation of Bmi-1 induced epithelial-mesenchymal transition (EMT) and enhanced the motility and invasiveness of human nasopharyngeal epithelial cells, whereas silencing endogenous Bmi-1 expression reversed EMT and reduced motility. Furthermore, upregulation of Bmi-1 led to the stabilization of Snail, a transcriptional repressor associated with EMT, via modulation of PI3K/Akt/GSK-3beta signaling. Chromatin immunoprecipitation assays revealed that Bmi-1 transcriptionally downregulated expression of the tumor suppressor PTEN in tumor cells through direct association with the PTEN locus. This in vitro analysis was consistent with the statistical inverse correlation detected between Bmi-1 and PTEN expression in a cohort of human nasopharyngeal carcinoma biopsies. Moreover, ablation of PTEN expression partially rescued the migratory/invasive phenotype of Bmi-1-silenced cells, indicating that PTEN might be a major mediator of Bmi-1-induced EMT. Our results provide functional and mechanistic links between the oncoprotein Bmi-1 and the tumor suppressor PTEN in the development and progression of cancer.
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            Activation of PKA leads to mesenchymal-to-epithelial transition and loss of tumor-initiating ability.

            The epithelial-to-mesenchymal transition enables carcinoma cells to acquire malignancy-associated traits and the properties of tumor-initiating cells (TICs). TICs have emerged in recent years as important targets for cancer therapy, owing to their ability to drive clinical relapse and enable metastasis. Here, we propose a strategy to eliminate mesenchymal TICs by inducing their conversion to more epithelial counterparts that have lost tumor-initiating ability. We report that increases in intracellular levels of the second messenger, adenosine 3',5'-monophosphate, and the subsequent activation of protein kinase A (PKA) induce a mesenchymal-to-epithelial transition (MET) in mesenchymal human mammary epithelial cells. PKA activation triggers epigenetic reprogramming of TICs by the histone demethylase PHF2, which promotes their differentiation and loss of tumor-initiating ability. This study provides proof-of-principle for inducing an MET as differentiation therapy for TICs and uncovers a role for PKA in enforcing and maintaining the epithelial state.
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              Identification and characterization of a gene encoding a gut-enriched Krüppel-like factor expressed during growth arrest.

              A cDNA clone, named gut-enriched Krüppel-like factor (GKLF), was isolated from an NIH 3T3 library using a probe encoding the zinc finger region of the immediate-early transcription factor zif/268. The deduced GKLF amino acid sequence contains three tandem zinc fingers that are related to members of the Krüppel family of transcription factors. By indirect immunofluorescence, GKLF is localized to the cell nucleus. In cultured fibroblasts, GKLF mRNA is found in high levels in growth-arrested cells and is nearly undetectable in cells that are in the exponential phase of proliferation. The growth-arresting nature of GKLF is demonstrated by an inhibition of DNA synthesis in cells transfected with a GKLF-expressing plasmid construct. In the mouse, GKLF mRNA is present in select tissues and is most abundant in the colon, followed by the testis, lung, and small intestine. In situ hybridization experiments indicate that GKLF mRNA is enriched in epithelial cells located in the middle to upper crypt region of the colonic mucosa. Taken together, these results suggest that GKLF is potentially a negative regulator of cell growth in tissues such as the gut mucosa, where cell proliferation is intimately coupled to growth arrest and differentiation.
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                Author and article information

                Journal
                Oncotarget
                Oncotarget
                Oncotarget
                ImpactJ
                Oncotarget
                Impact Journals LLC
                1949-2553
                7 November 2017
                27 September 2017
                : 8
                : 55
                : 93924-93941
                Affiliations
                1 Guangdong Provincial Key Laboratory of Cancer Immunotherapy Research and Guangzhou Key Laboratory of Tumor Immunology Research, Cancer Research Institute, Southern Medical University, Guangzhou 510515, China
                2 Institute of Comparative Medicine & Laboratory Animal Center, Southern Medical University, Guangzhou 510515, China
                3 Department of Oncology, The People’s Hosptial of Zhengzhou University, Zhengzhou 450003, China
                4 Department of Physiology, Faculty of Basic Medical Sciences, Guilin Medical University, Guilin 541004, China
                5 Department of Pathology, The Second Affiliated Hospital, Guilin Medical University, Guilin 541199, China
                6 Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China
                7 Department of Gastroenterology, The First Affiliated Hospital of Jinan University, Guangzhou 510630, China
                8 The Third People's Hospital of Shenzhen, Guangdong Medical University, Shenzhen 518112, China
                Author notes
                Correspondence to: Dong Xiao, xiao_d@ 123456hotmail.com
                Junshuang Jia, Jiajsh4@ 123456126.com
                [*]

                These authors have contributed equally to this work

                Article
                21370
                10.18632/oncotarget.21370
                5706845
                29212199
                d72d2f1a-69fc-4742-bbc7-6edfa4bc18a2
                Copyright: © 2017 Li et al.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 31 March 2017
                : 29 June 2017
                Categories
                Research Paper

                Oncology & Radiotherapy
                klf4,nasopharyngeal carcinoma (npc),stemness,epithelial-mesenchymal transition (emt),cancer invasion and metastasis

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