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Xiang R.,Scripps Research Institute | Xiang R.,Nankai University | Liao D.,Scripps Research Institute | Cheng T.,Scripps Research Institute | And 6 more authors.
British Journal of Cancer | Year: 2011

Background:The cancer stem cell hypothesis suggests that neoplastic clones are maintained exclusively by a small subpopulation of cells, which have indefinite proliferation and differentiation potentials and give rise to phenotypically diverse cancer cells. Cancer stem cells have been isolated by their ability to efflux Hoechst 33342 dye and are referred to as the side population (SP).Methods and results:The Hoechst efflux assay was used to isolate and characterize the SP from murine D121 lung carcinoma cells. Here, we demonstrated that D121-SP cells contain cancer stem cell characteristics, that is, upregulation of the transcription factors SOX2 and Oct 4 in D121-SP cells. In addition, the migration of D121-SP was decreased, and apoptosis of D121-SP was upregulated following knocking down of SOX2 in D121 cells. Importantly, downregulation of SOX2 in D121 cells markedly suppressed their metastatic potential in syngeneic mice.Conclusions:These results suggest that the SP is an enriched source of lung tumour cells with stem cell properties and that SOX2 has an important role in maintaining stem cell properties and functions that may be a potential target for effective lung cancer therapy. © 2011 Cancer Research UK All rights reserved.

Bai N.,Nankai University | Zhang C.,Nankai University | Liang N.,Nankai University | Zhang Z.,Nankai University | And 14 more authors.
Cancer Biology and Therapy | Year: 2013

The yes-associated protein (Yap) transcription co-activator has been reported either as an oncogene candidate or a tumor suppressor. Liver tissue chips revealed that about 51.4% human hepatocellular carcinoma (hCC) samples express Yap and 32.9% hCC samples express phosphorylated Yap. In this study, we found that chemotherapy increased Yap protein expression and nuclear translocation in hepG2 cells, as well as p53 protein expression and nuclear translocation. however, little is known about Yap functions during chemotherapy. Our results show that overexpression of Yap increases chemosensitivity of hepG2 cells during chemotherapy. Dominant negative transfection of Flag-s94a (TeaD binding domain mutant) or Flag-W1W2 (WW domain mutant) to hepG2 cells decreases p53 expression/nuclear translocation and chemosensitivity when compared with control hepG2 cells. Furthermore, rescue transfection of Flag-5sa-s94a or Flag-5sa-W1W2, respectively to hepG2 cells regains p53 expression/nuclear translocation and chemosensitivity. These results indicate that Yap promotes chemosensitivity by modulating p53 during chemotherapy and both TeaD and WW binding domains are required for Yap-mediated p53 function. ChIp assay results also indicated that Yap binds directly to the p53 promoter to improve its expression. In addition, p53 could positively feedback Yap expression through binding to the Yap promoter. Taken together, our current data indicate that Yap functions as a tumor suppressor that enhances apoptosis by modulating p53 during chemotherapy. © 2013 Landes Bioscience.

Yang J.,Nankai University | Liao D.,Scripps Research Institute | Chen C.,Beijing Union Medical School | Liu Y.,National Health Research Institute | And 5 more authors.
Stem Cells | Year: 2013

The cancer stem cell (CSC) hypothesis has gained significant recognition as a descriptor of tumorigenesis. Additionally, tumor-associated macrophages (TAMs) are known to promote growth and metastasis of breast cancer. However, it is not known whether TAMs mediate tumorigenesis through regulation of breast CSCs. Here, we report that TAMs promote CSC-like phenotypes in murine breast cancer cells by upregulating their expression of Sox-2. These CSC-like phenotypes were characterized by increased Sox-2, Oct-4, Nanog, AbcG2, and Sca-1 gene expression, in addition to increased drug-efflux capacity, resistance to chemotherapy, and increased tumorigenicity in vivo. Downregulation of Sox-2 in tumor cells by siRNA blocked the ability of TAMs to induce these CSC-like phenotypes and inhibited tumor growth in vivo. Furthermore, we identified a novel epidermal growth factor receptor (EGFR)/signal transducers and activators of transcription 3 (Stat3)/Sox-2 paracrine signaling pathway between macrophages and mouse breast cancer cells that is required for macrophage-induced upregulation of Sox-2 and CSC phenotypes in tumor cells. We showed that this crosstalk was effectively blocked by the small molecule inhibitors AG1478 or CDDO-Im against EGFR and Stat3, respectively. Therefore, our report identifies a novel role for TAMs in breast CSC regulation and establishes a rationale for targeting the EGFR/Stat3/Sox-2 signaling pathway for CSC therapy. © 2012 AlphaMed Press.

Zhong L.,Chongqing Medical University | Luo Y.,Beijing Union Medical School | Huang C.,Chengdu Railway Central Hospital | Liu L.,Chongqing Medical University
Diabetes and Metabolism | Year: 2011

Aim: This study aimed to investigate whether NF-κB contributes to insulin resistance in type 2 diabetes (T2DM). Methods: Subcutaneous abdominal adipose tissue was obtained from T2DM patients and non-diabetic control subjects. Pre-adipocytes were cultured and differentiated into adipocytes in vitro. Upon insulin stimulation, IRS-1 tyrosine and AKT (Ser473) phosphorylation were examined by immunoprecipitation and immunoblotting, while levels of inflammatory mediators IL-6 and MCP-1, and the DNA-binding activity of NF-κB, were examined by ELISA and electrophoretic mobility shift assay (EMSA), respectively. NF-κB decoy molecules were introduced into T2DM adipocytes, and their effects on all these molecular events evaluated. Results: Compared with cells from non-diabetic subjects, adipocytes from T2DM patients showed signs of insulin resistance, with significantly reduced IRS-1 tyrosine and AKT (Ser 473) phosphorylation levels in response to insulin stimulation. At the same time, T2DM cells displayed elevated levels of IL-6 and MCP-1, and NF-κB activity. Introduction of NF-κB decoy molecules significantly inhibited both IL-6 secretion and NF-κB activity, while enhancing insulin-stimulated IRS-1 tyrosine and AKT (Ser473) phosphorylation in T2DM adipocytes. Conclusion: Abdominal subcutaneous fat cells from T2DM patients display signs of insulin resistance and microinflammatory status. NF-κB decoy molecules inhibited NF-κB overactivation and also partly reversed insulin resistance. These results provide evidence of a link between inflammation and insulin resistance in T2DM cells, suggesting a potential contribution of inflammation to the mechanism of insulin resistance. © 2011 Elsevier Masson SAS.

Shen L.,Nankai University | Qin K.,Nankai University | Wang D.,Nankai University | Zhang Y.,Nankai University | And 5 more authors.
Biochimica et Biophysica Acta - Molecular Basis of Disease | Year: 2014

Although Oct4 is known as a critical transcription factor involved in maintaining "stemness", its role in tumor metastasis is still controversial. Herein, we overexpressed and silenced Oct4 expression in two breast cancer cell lines, MDA-MB-231 and 4T1, separately. Our data showed that ectopic overexpression of Oct4 suppressed cell migration and invasion in vitro and the formation of metastatic lung nodules in vivo. Conversely, Oct4 downregulation increased the metastatic potential of breast cancer cells both in vitro and in vivo. Furthermore, we identified Rnd1 as the downstream target of Oct4 by ribonucleic acid sequencing (RNA-seq) analysis, which was significantly downregulated upon Oct4 overexpression. Chromatin immunoprecipitation assays revealed the binding of Oct4 to the promoter region of Rnd1 by ectopic overexpression of Oct4. Dual luciferase assays indicated that Oct4 overexpression suppressed transcriptional activity of the Rnd1 promoter. Moreover, overexpression of Rnd1 partially rescued the inhibitory effects of Oct4 on the migration and invasion of breast cancer cells. Overexpression of Rnd1 counteracted the influence of Oct4 on the formation of cell adhesion and lamellipodia, which implied a potential underlying mechanism involving Rnd1. In addition, we also found that overexpression of Oct4 led to an elevation of E-cadherin expression, even in 4T1 cells that possess a relatively high basal level of E-cadherin. Rnd1 overexpression impaired the promoting effects of Oct4 on E-cadherin expression in MDA-MB-231 cells. These results suggest that Oct4 affects the metastatic potential of breast cancer cells through Rnd1-mediated effects that influence cell motility and E-cadherin expression. © 2014 Elsevier B.V.

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