Deregulation of SLIT2-Mediated Cdc42 Activity Is Associated with Esophageal Cancer Metastasis and Poor Prognosis  Ruo-Chia Tseng, PhD, Jia-Ming Chang,

Slides:



Advertisements
Similar presentations
Alpha-Actinin 4 Is Associated with Cancer Cell Motility and Is a Potential Biomarker in Non–Small Cell Lung Cancer  Ming-Chuan Wang, PhD, Ying-Hua Chang,
Advertisements

Genome-Wide Analysis of DNA Methylation and the Gene Expression Change in Lung Cancer  Yong-Jae Kwon, PhD, Seog Joo Lee, MSc, Jae Soo Koh, MD, PhD, Sung.
Pathobiological Implications of MUC4 in Non–Small-Cell Lung Cancer
Aldehyde Dehydrogenase 1A1 Possesses Stem-Like Properties and Predicts Lung Cancer Patient Outcome  Xiao Li, MD, Liyan Wan, MD, Jian Geng, MD, Chin-Lee.
Volume 15, Issue 6, Pages (June 2009)
Antitumor Efficacy of the Anti-Interleukin-6 (IL-6) Antibody Siltuximab in Mouse Xenograft Models of Lung Cancer  Lanxi Song, MS, Matthew A. Smith, PhD,
Volume 145, Issue 4, Pages e9 (October 2013)
Phosphorylated mammalian target of rapamycin expression is associated with the response to chemoradiotherapy in patients with esophageal squamous cell.
Integrin αvβ6 Promotes Lung Cancer Proliferation and Metastasis through Upregulation of IL-8–Mediated MAPK/ERK Signaling  Pengwei Yan, Huanfeng Zhu, Li.
WT1 Promotes Invasion of NSCLC via Suppression of CDH1
DNMT3B Overexpression by Deregulation of FOXO3a-Mediated Transcription Repression and MDM2 Overexpression in Lung Cancer  Yi-Chieh Yang, MS, Yen-An Tang,
Microsomal Prostaglandin E Synthase-1 Inhibits PTEN and Promotes Experimental Cholangiocarcinogenesis and Tumor Progression  Dongdong Lu, Chang Han, Tong.
Sp1 Suppresses miR-3178 to Promote the Metastasis Invasion Cascade via Upregulation of TRIOBP  Hui Wang, Kai Li, Yu Mei, Xuemei Huang, Zhenglin Li, Qingzhu.
High Expression of PHGDH Predicts Poor Prognosis in Non–Small Cell Lung Cancer  Jinhong Zhu, Jianqun Ma, Xudong Wang, Tianjiao Ma, Shu Zhang, Wei Wang,
Genome-Wide Analysis of DNA Methylation and the Gene Expression Change in Lung Cancer  Yong-Jae Kwon, PhD, Seog Joo Lee, MSc, Jae Soo Koh, MD, PhD, Sung.
AZGP1 Autoantibody Predicts Survival and Histone Deacetylase Inhibitors Increase Expression in Lung Adenocarcinoma  Daniel L. Albertus, BS, Christopher.
Up-Regulation of RFC3 Promotes Triple Negative Breast Cancer Metastasis and is Associated With Poor Prognosis Via EMT  Zhen-Yu He, San-Gang Wu, Fang Peng,
IFN-γ Induces Gastric Cancer Cell Proliferation and Metastasis Through Upregulation of Integrin β3-Mediated NF-κB Signaling  Yuan-Hua Xu, Zheng-Li Li,
Interaction between neoplastic cells and cancer-associated fibroblasts through the CXCL12/CXCR4 axis: Role in non–small cell lung cancer tumor proliferation 
Hydrogen Sulfide Demonstrates Promising Antitumor Efficacy in Gastric Carcinoma by Targeting MGAT5  Rui Wang, Qilin Fan, Junjie Zhang, Xunan Zhang, Yuqi.
TGM2: A Cell Surface Marker in Esophageal Adenocarcinomas
Epigenetic Inhibition of Nuclear Receptor Small Heterodimer Partner Is Associated With and Regulates Hepatocellular Carcinoma Growth  Nan He, Kyungtae.
Interleukin-17 and Prostaglandin E2 Are Involved in Formation of an M2 Macrophage- Dominant Microenvironment in Lung Cancer  Lunxu Liu, MD, PhD, Dongxia.
Prognostic Significance of TAZ Expression in Resected Non-Small Cell Lung Cancer  Mian Xie, MD, PhD, Li Zhang, MD, Chao-Sheng He, MD, Jin-Hui Hou, MD,
MicroRNA-381 Represses ID1 and is Deregulated in Lung Adenocarcinoma
Aldehyde Dehydrogenase 1A1 Possesses Stem-Like Properties and Predicts Lung Cancer Patient Outcome  Xiao Li, MD, Liyan Wan, MD, Jian Geng, MD, Chin-Lee.
Volume 145, Issue 2, Pages e6 (August 2013)
Alpha-Actinin 4 Is Associated with Cancer Cell Motility and Is a Potential Biomarker in Non–Small Cell Lung Cancer  Ming-Chuan Wang, PhD, Ying-Hua Chang,
Overexpression of Muscarinic Receptor 3 Promotes Metastasis and Predicts Poor Prognosis in Non–Small-Cell Lung Cancer  Gengpeng Lin, MD, Longhua Sun,
Activated Leukocyte Cell-Adhesion Molecule (ALCAM) Promotes Malignant Phenotypes of Malignant Mesothelioma  Futoshi Ishiguro, MD, Hideki Murakami, MD,
Yuen Yee Cheng, PhD, Michaela B
The C-terminus of Hsp70-Interacting Protein Promotes Met Receptor Degradation  Kang Won Jang, PhD, Jeong Eun Lee, MD, Sun Young Kim, MD, Min-Woong Kang,
The VEGF-C/Flt-4 axis promotes invasion and metastasis of cancer cells
Co-Overexpression of Cyclooxygenase-2 and Microsomal Prostaglandin E Synthase-1 Adversely Affects the Postoperative Survival in Non-small Cell Lung Cancer 
Volume 5, Issue 6, Pages (December 2013)
Uc.454 Inhibited Growth by Targeting Heat Shock Protein Family A Member 12B in Non- Small-Cell Lung Cancer  Jun Zhou, Chenghai Wang, Weijuan Gong, Yandan.
Volume 152, Issue 1, Pages (January 2019)
Inhibiting MDM2-p53 Interaction Suppresses Tumor Growth in Patient-Derived Non– Small Cell Lung Cancer Xenograft Models  Josephine Hai, PhD, Shingo Sakashita,
P16Ink4a Suppression of Lung Adenocarcinoma by Bmi-1 in the Presence of p38 Activation  Mi-Ok Lee, MSc, Hyeon-Jae Lee, MD, Mi-Ae Kim, MD, Eun-Kyung Kim,
Molecular Therapy - Nucleic Acids
Molecular Therapy - Nucleic Acids
Volume 140, Issue 3, Pages (March 2011)
Volume 11, Issue 2, Pages (February 2007)
MicroRNA-101 Exerts Tumor-Suppressive Functions in Non-small Cell Lung Cancer through Directly Targeting Enhancer of Zeste Homolog 2  Ji-guang Zhang,
Human Mitochondrial NAD(P)+–Dependent Malic Enzyme Participates in Cutaneous Melanoma Progression and Invasion  Yung-Lung Chang, Hong-Wei Gao, Chien-Ping.
MiR-135b Stimulates Osteosarcoma Recurrence and Lung Metastasis via Notch and Wnt/β-Catenin Signaling  Hua Jin, Song Luo, Yun Wang, Chang Liu, Zhenghao.
Pathobiological Implications of MUC4 in Non–Small-Cell Lung Cancer
Loss of CRNN expression is associated with advanced tumor stage and poor survival in patients with esophageal squamous cell carcinoma  Po-Kuei Hsu, MD,
Microsomal Prostaglandin E Synthase-1 Inhibits PTEN and Promotes Experimental Cholangiocarcinogenesis and Tumor Progression  Dongdong Lu, Chang Han, Tong.
Reduced membranous β-catenin protein expression is associated with metastasis and poor prognosis in squamous cell carcinoma of the esophagus  Po-Kuei.
Lu Zheng, Nan You, Xiaobing Huang, Huiying Gu, Ke Wu, Na Mi, Jing Li 
TROP-2 exhibits tumor suppressive functions in cervical cancer by dual inhibition of IGF-1R and ALK signaling  Sarah T.K. Sin, Yan Li, Ming Liu, Stephanie.
Volume 19, Issue 8, Pages (August 2011)
High Expression of p300 Has an Unfavorable Impact on Survival in Resectable Esophageal Squamous Cell Carcinoma  Yong Li, MD, Hao-Xian Yang, MD, Rong-Zhen.
Figure 1. RSPO3 expression is upregulated in bladder cancer
Figure 1. LOC is highly expressed in NPC and predicts unfavorable prognosis. (A) Differential gene expression ... Figure 1. LOC is highly expressed.
Volume 17, Issue 2, Pages (February 2009)
Tumor-Stroma Ratio Is an Independent Predictor for Survival in Esophageal Squamous Cell Carcinoma  kai Wang, MD, Wei Ma, MD, Jianbo Wang, MD, Liang Yu,
Volume 36, Issue 2, Pages (October 2009)
Shrimp miR-34 from Shrimp Stress Response to Virus Infection Suppresses Tumorigenesis of Breast Cancer  Yalei Cui, Xiaoyuan Yang, Xiaobo Zhang  Molecular.
MicroRNA-381 Represses ID1 and is Deregulated in Lung Adenocarcinoma
Overexpression of Fetuin-A Counteracts Ectopic Mineralization in a Mouse Model of Pseudoxanthoma Elasticum (Abcc6−/−)  Qiujie Jiang, Florian Dibra, Michael.
LncRNA TRERNA1 Function as an Enhancer of SNAI1 Promotes Gastric Cancer Metastasis by Regulating Epithelial-Mesenchymal Transition  Huazhang Wu, Ying.
Long Noncoding RNA BC as a Novel Therapeutic Target for Colorectal Cancer that Suppresses Metastasis by Upregulating TIMP3  Jiaxin Lin, Xin Tan,
MiR-409 Inhibits Human Non-Small-Cell Lung Cancer Progression by Directly Targeting SPIN1  Qi Song, Quanbo Ji, Jingbo Xiao, Fang Li, Lingxiong Wang, Yin.
Clinicopathologic significance of cyclooxygenase-2 overexpression in esophageal squamous cell carcinoma  Kuang-Tai Kuo, MD, Kuan-Chih Chow, PhD, Yu-Chung.
Overexpression of Muscarinic Receptor 3 Promotes Metastasis and Predicts Poor Prognosis in Non–Small-Cell Lung Cancer  Gengpeng Lin, MD, Longhua Sun,
Molecular Therapy - Nucleic Acids
Paracrine Apoptotic Effect of p53 Mediated by Tumor Suppressor Par-4
Signal Transducer and Activator of Transcription 3 as Molecular Therapy for Non–Small- Cell Lung Cancer  Cheng-Yi Wang, MD, Ting-Ting Chao, PhD, Wei-Tien.
Presentation transcript:

Deregulation of SLIT2-Mediated Cdc42 Activity Is Associated with Esophageal Cancer Metastasis and Poor Prognosis  Ruo-Chia Tseng, PhD, Jia-Ming Chang, MD, Jeng-Hung Chen, MS, Way-Ren Huang, PhD, Yen-An Tang, PhD, I-Ying Kuo, PhD, Jing- Jou Yan, MD, PhD, Wu-Wei Lai, MD, Yi-Ching Wang, PhD  Journal of Thoracic Oncology  Volume 10, Issue 1, Pages 189-198 (January 2015) DOI: 10.1097/JTO.0000000000000369 Copyright © 2015 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 1 Low SLIT2 protein expression correlates with poor survival in ESCC patients. A, Immunohistochemical analysis of three representative patients. SLIT2 normal expression was found in patient 1. Patients 2 and 3 showed low SLIT2. A 4× enlarged image of normal region is shown in the right panel of each patient, whereas an enlarged image of tumor region is shown in the left panel. Their original region is indicated by the dotted line in the middle panel (Original magnification: 100×). The staining was graded as “normal” or “low” expression as described in the Methods. B, Patients with low SLIT2 protein expression (−) or normal expression (+) show significant difference in overall survival and in disease-free survival. C, The overall survival curves with respect to low protein expression of SLIT2 in patients with locally advanced or tumor stage III. ESCC, esophageal squamous cell carcinoma SLIT2. Journal of Thoracic Oncology 2015 10, 189-198DOI: (10.1097/JTO.0000000000000369) Copyright © 2015 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 2 Low SLIT2 expression is associated with SLIT2 promoter hypermethylation in ESCC patients and cell lines. A, The promoter methylation analyses (upper panel) and mRNA (lower panel) of SLIT2 genes in four representative ESCC patients. The primer sets used for amplification are designated “U” for unmethylated or “M” for methylated genes. HET-1A is an unmethylated control, and SssI-treated HET-1A is a methylated control. B, An inverse correlation between DNA methylation and mRNA expression was found in tumor from 50 ESCC patients (p = 0.049 by linear regression analysis). C, A positive correlation between protein and mRNA expression and a negative correlation between protein expression and SLIT2 DNA methylation were found in tumor from ESCC patients (p = 0.024 and p = 0.040, by χ2 analysis). “+” indicates mRNA or protein normal expression or promoter hypermethylation as opposed to “−”, which is low expression or no promoter hypermethylation of the corresponding sample. The percentage of concordant group (white bar) and discordant group (gray bar) are indicated at the top. D, Methylation level of SLIT2 was significant lower in demethylation reagent (Aza) treated than DMSO treated ESCC CE48T and CE81T cell lines. E, mRNA expression level of SLIT2 was higher in Aza treated than DMSO treated cell lines. P values were calculated by two-tailed paired t test. Data represent mean ± SD (n = 3). *p < 0.05; **p < 0.01; ***p < 0.001. ESCC, esophageal squamous cell carcinoma. Journal of Thoracic Oncology 2015 10, 189-198DOI: (10.1097/JTO.0000000000000369) Copyright © 2015 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 3 SLIT2 negatively regulates cell migration ability in CE48T and CE81T ESCC cells. A, Migration ability decreased dramatically in CE48T stably overexpressing SLIT2 assessed by wound healing assay. B, SLIT2 knockdown (si-SLIT2) promoted cell motility in CE81T cells. C, Migration was inhibited in CE48T cells and CE81T cells after addition of CM from CE48T stably overexpressing SLIT2 cells (CM-SLIT2) than CE48T cells without ectopic SLIT2 expression (CM-Con). SLIT2 concentration in the medium was measured by Western blot and is indicated at the top. β-actin was used to quantify the total cellular protein in cells from which the CM were derived. P values were calculated by two-tailed paired t test. Data represent mean ± SD (n = 3) (Original magnification: 100×). CM, conditioned media. Journal of Thoracic Oncology 2015 10, 189-198DOI: (10.1097/JTO.0000000000000369) Copyright © 2015 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 4 Cdc42-related signaling pathways involve in SLIT2-mediated migration suppression in ESCC. A, Overexpression of SLIT2 down-regulated the Cdc42 activity manifested by decreasing the level of GTP-Cdc42 (left); knockdown of SLIT2 up-regulated Cdc42 activity (right). IP assay using the anti-srGAP1 antibody showed (B) an increased interaction of srGAP1 with Cdc42 in CE48T stably overexpressing SLIT2 and (C) a decreased interaction of srGAP1 with Cdc42 in SLIT2 knockdown CE81T cells. An immunoblot of long exposure for Cdc42 input is shown to justify the interaction of srGAP1 with Cdc42 observed. The immunofluorescence assay illustrated (D) a decrease of membrane localization of p-Paxillin and p-FAK staining in CE48T stably overexpressing SLIT2 compared with control cells and (E) an increase of membrane p-Paxillin and p-FAK staining in SLIT2 knockdown CE81T compared with control cells. 4',6-diamidino-2-phenylindole stains show the nuclear immunoreactivity. A 3× enlarged image is shown in the right panel of each group, and its original region is indicated by the dotted line in the left panel. Representative blots and images were selected from at least three independent experiments. ESCC, esophageal squamous cell carcinoma; IP, Immunoprecipitation. Journal of Thoracic Oncology 2015 10, 189-198DOI: (10.1097/JTO.0000000000000369) Copyright © 2015 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 5 Knock down of SLIT2 promotes tumor metastasis in vivo. SLIT2 knockdown CE81T cells (5 × 105) or control cells were intravenously injected into tail-vein of SCID mice. Mice were killed and lung tissues were collected after 18 weeks. A, The group of mice injected intravenously via the tail vein with SLIT2 knockdown CE81T showed more tumor nodules in lung tissue than the control group. B, Lung tissues were sectioned for hematoxylin and eosin staining examination (Original magnification: ×200). C, Quantitative results showed more tumor nodules in SLIT2 knockdown group than in control group. P values were calculated by two-tailed paired t test (n = 6 mice per group). D, Western blots of SLIT2 expression in SLIT2 knockdown CE81T cells as compared with control cells before tail-vein injection. E, Protein expression of p-Paxillin and p-FAK in vivo. Immunohistochemistry revealed that the protein expression level of membrane p-FAK and p-Paxillin was increased in tumor nodules from si-SLIT2 mice group as compared with control group. Enlarged images shown in insets of the original area indicated by the dashed lines. Original magnification ×200. SCID, severe combined immune-deficient mice. Journal of Thoracic Oncology 2015 10, 189-198DOI: (10.1097/JTO.0000000000000369) Copyright © 2015 International Association for the Study of Lung Cancer Terms and Conditions