The Long Noncoding MALAT-1 RNA Indicates a Poor Prognosis in Non-small Cell Lung Cancer and Induces Migration and Tumor Growth Lars Henning Schmidt,

Slides:

Advertisements

Similar presentations

Volume 342, Issue 1, Pages (January 2014)

Advertisements

Nicotinamide Phosphoribosyltransferase: A Potent Therapeutic Target in Non-small Cell Lung Cancer with Epidermal Growth Factor Receptor-Gene Mutation

Naomi Fujioka, MD, Christopher A. French, MD, Michael J

Aldehyde Dehydrogenase 1A1 Possesses Stem-Like Properties and Predicts Lung Cancer Patient Outcome Xiao Li, MD, Liyan Wan, MD, Jian Geng, MD, Chin-Lee.

Overexpression of CRM1: A Characteristic Feature in a Transformed Phenotype of Lung Carcinogenesis and a Molecular Target for Lung Cancer Adjuvant Therapy

Elevated FOXC2 Expression Promotes Invasion of HCC Cell Lines and is Associated with Poor Prognosis in Hepatocellular Carcinoma Cell Physiol Biochem 2017;44:99–109.

Silencing NKD2 by Promoter Region Hypermethylation Promotes Esophageal Cancer Progression by Activating Wnt Signaling Baoping Cao, MD, PhD, Weili Yang,

NDRG1/Cap43/Drg-1 may Predict Tumor Angiogenesis and Poor Outcome in Patients with Lung Cancer Koichi Azuma, MD, PhD, Akihiko Kawahara, PhD, Satoshi.

Group IIa secretory phospholipase expression correlates with group IIa secretory phospholipase inhibition–mediated cell death in K-ras mutant lung cancer.

WT1 Promotes Invasion of NSCLC via Suppression of CDH1

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

Jasmine George, Minakshi Nihal, Chandra K

Nicotine Induces Resistance to Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor by α1 Nicotinic Acetylcholine Receptor–Mediated Activation in.

Knockdown of secretory phospholipase A2 IIa reduces lung cancer growth in vitro and in vivo Jessica A. Yu, MD, David Mauchley, MD, Howard Li, MD, Xianzhong.

Detection of Rearrangements and Transcriptional Up-Regulation of ALK in FFPE Lung Cancer Specimens Using a Novel, Sensitive, Quantitative Reverse Transcription.

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,

Research Techniques Made Simple: Identification and Characterization of Long Noncoding RNA in Dermatological Research Dario Antonini, Maria Rosaria Mollo,

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,

ITPKA Gene Body Methylation Regulates Gene Expression and Serves as an Early Diagnostic Marker in Lung and Other Cancers Yi-Wei Wang, PhD, Xiaotu Ma,

MET Tyrosine Kinase Inhibitor Crizotinib (PF ) Shows Differential Antitumor Effects in Non-small Cell Lung Cancer According to MET Alterations

Volume 136, Issue 2, Pages e1 (February 2009)

MicroRNA-489 Plays an Anti-Metastatic Role in Human Hepatocellular Carcinoma by Targeting Matrix Metalloproteinase-7 Yixiong Lin, Jianjun Liu, Yuqi Huang,

Characterization of microRNA transcriptome in tumor, adjacent, and normal tissues of lung squamous cell carcinoma Jun Wang, MD, PhD, Zhi Li, MD, PhD,

Chandra M.V. Goparaju, PhD Journal of Thoracic Oncology

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

Volume 16, Issue 1, Pages (January 2008)

Molecular Analysis-Based Treatment Strategies for the Management of Non-small Cell Lung Cancer Howard West, MD, Rogerio Lilenbaum, MD, David Harpole,

Sunny Guin, PhD, Yuanbin Ru, PhD, Murry W

Prognostic Impact of Bcl-2 Depends on Tumor Histology and Expression of MALAT-1 lncRNA in Non–Small-Cell Lung Cancer Lars Henning Schmidt, Dennis Görlich,

Aldehyde Dehydrogenase 1A1 Possesses Stem-Like Properties and Predicts Lung Cancer Patient Outcome Xiao Li, MD, Liyan Wan, MD, Jian Geng, MD, Chin-Lee.

Molecular Therapy - Nucleic Acids

Oncogenic Potential of CYP24A1 in Lung Adenocarcinoma

Learning More from Microarrays: Insights from Modules and Networks

Functional and Clinical Characterization of the Putative Tumor Suppressor WWOX in Non-small Cell Lung Cancer Silvan Becker, MD, Boyka Markova, PhD, Rainer.

Activated Leukocyte Cell-Adhesion Molecule (ALCAM) Promotes Malignant Phenotypes of Malignant Mesothelioma Futoshi Ishiguro, MD, Hideki Murakami, MD,

Chandra Goparaju, PhD, Jessica S

Frequent Coamplification and Cooperation between C-MYC and PVT1 Oncogenes Promote Malignant Pleural Mesothelioma Erick Riquelme, PhD, Milind B. Suraokar,

Thyroid Transcription Factor-1 Amplification and Expressions in Lung Adenocarcinoma Tissues and Pleural Effusions Predict Patient Survival and Prognosis

Nicotine Induces Resistance to Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor by α1 Nicotinic Acetylcholine Receptor–Mediated Activation in.

Molecular Therapy - Nucleic Acids

Volume 25, Issue 3, Pages (March 2017)

Serum miR-16: A Potential Biomarker for Predicting Melanoma Prognosis

Inhibition of KLF4 by Statins Reverses Adriamycin-Induced Metastasis and Cancer Stemness in Osteosarcoma Cells Yangling Li, Miao Xian, Bo Yang, Meidan.

Apelin Expression in Human Non-small Cell Lung Cancer: Role in Angiogenesis and Prognosis Judit Berta, MS, Istvan Kenessey, MD, Judit Dobos, PhD, Jozsef.

MiR-135b Stimulates Osteosarcoma Recurrence and Lung Metastasis via Notch and Wnt/β-Catenin Signaling Hua Jin, Song Luo, Yun Wang, Chang Liu, Zhenghao.

Christina I. Selinger, PhD, Wendy A

Increased Vascular-Endothelial Growth Factor (VEGF) Tumor Expression and Response to Epidermal Growth Factor Receptor (EGF-R) Inhibitor Erlotinib in Non-small.

Role of Chromosome 3q Amplification in Lung Cancer

miR-124 Inhibits Lung Tumorigenesis Induced by K-ras Mutation and NNK

Tumor-Infiltrating Foxp3+ Regulatory T Cells are Correlated with Cyclooxygenase-2 Expression and are Associated with Recurrence in Resected Non-small.

Extratumoral Vascular Invasion Is a Significant Prognostic Indicator and a Predicting Factor of Distant Metastasis in Non-small Cell Lung Cancer Yoshihisa.

High MET Gene Copy Number Leads to Shorter Survival in Patients with Non-small Cell Lung Cancer Heounjeong Go, MD, Yoon Kyung Jeon, MD, PhD, Hyo Jin.

Clinical Significance of Epidermal Growth Factor Receptors in Non-small Cell Lung Cancer and a Prognostic Role for HER2 Gene Copy Number in Female Patients

A Comprehensive Analysis of p16 Expression, Gene Status, and Promoter Hypermethylation In Surgically Resected Non-small Cell Lung Carcinomas William.

Kun-Peng Zhu, Xiao-Long Ma, Chun-Lin Zhang Molecular Therapy

Prognostic Impact of Node Involvement Pattern in Pulmonary pN1 Squamous Cell Carcinoma Patients Masayuki Nakao, MD, Junji Yoshida, MD, PhD, Genichiro.

Nicotinamide Phosphoribosyltransferase: A Potent Therapeutic Target in Non-small Cell Lung Cancer with Epidermal Growth Factor Receptor-Gene Mutation

Use of MicroRNA Expression Levels to Predict Outcomes in Resected Stage I Non- small Cell Lung Cancer Eric Duncavage, MD, Boone Goodgame, MD, Ananth Sezhiyan,

Volume 17, Issue 2, Pages (February 2009)

Pathologic N1 non-small cell lung cancer: Correlation between pattern of lymphatic spread and prognosis Alessandro Marra, MD, PhD, Ludger Hillejan, MD,

Volume 25, Issue 4, Pages (April 2017)

MicroRNA-381 Represses ID1 and is Deregulated in Lung Adenocarcinoma

Long Noncoding RNA BC as a Novel Therapeutic Target for Colorectal Cancer that Suppresses Metastasis by Upregulating TIMP3 Jiaxin Lin, Xin Tan,

Volume 15, Issue 12, Pages (June 2016)

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.

The lncRNA PDIA3P Interacts with miR-185-5p to Modulate Oral Squamous Cell Carcinoma Progression by Targeting Cyclin D2 Cheng-Cao Sun, Ling Zhang, Guang.

Thymidylate Synthase Protein Expression by IHC and Gene Copy Number by SISH Correlate and Show Great Variability in Non–Small Cell Lung Cancer Murry.

The Expression of MicroRNA-598 Inhibits Ovarian Cancer Cell Proliferation and Metastasis by Targeting URI Feng Xing, Shuo Wang, Jianhong Zhou Molecular.

Overexpression of CRM1: A Characteristic Feature in a Transformed Phenotype of Lung Carcinogenesis and a Molecular Target for Lung Cancer Adjuvant Therapy

Presentation transcript:

The Long Noncoding MALAT-1 RNA Indicates a Poor Prognosis in Non-small Cell Lung Cancer and Induces Migration and Tumor Growth Lars Henning Schmidt, MD, Tilmann Spieker, MD, Steffen Koschmieder, MD, Julia Humberg, Dominik Jungen, PhD, Etmar Bulk, PhD, Antje Hascher, PhD, Danielle Wittmer, Alessandro Marra, MD, Ludger Hillejan, MD, Karsten Wiebe, MD, Wolfgang E. Berdel, MD, Rainer Wiewrodt, MD, Carsten Muller-Tidow, MD Journal of Thoracic Oncology Volume 6, Issue 12, Pages 1984-1992 (December 2011) DOI: 10.1097/JTO.0b013e3182307eac Copyright © 2011 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 1. MALAT-1 transcript in human lung cancer. A, MALAT-1 transcript (8.7 kb) is located on chromosome 11q13, known for its strong impact on tumorigenesis and metastasis. To investigate the biological effect of MALAT-1, down-regulation was performed by four short hairpin RNA (shRNA) sequences at four positions (shRNA oligos—red color). A 61-nt RNA, referred to *mascRNA (*MALAT-1-associated small cytoplasmic RNA—blue color), reaches the cytoplasm.11 B, According to quantitative RNA analysis, established human NSCLC cell lines A549, HTB 58, and NSCLC tissues (surgical resected specimens from 10 individuals) express high levels of MALAT-1 transcript if compared with human GAPDH (housekeeping gene). All columns, mean of three independent experiments performed in triplicate; bars, SD. Journal of Thoracic Oncology 2011 6, 1984-1992DOI: (10.1097/JTO.0b013e3182307eac) Copyright © 2011 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 2. Transduction of MALAT-1 into NIH 3T3 cells increases the migratory potential. A, NIH 3T3 cells were transduced with MALAT-1 expression PINCO vector. MALAT-1 expression analysis by RT-PCR analysis revealed high expression of human MALAT-1 transcript in MALAT-1 transduced NIH 3T3 cells compared with control (NIH 3T3 cells transduced with empty vector, EV). B, On MALAT-1 transduction, NIH 3T3 cells showed reduced expression of murine MALAT-1 compared with EV transduced NIH 3T3 cells. C, Expression of human MALAT-1 transcript in NIH 3T3 cells was associated with increased migration potential (migration assay; p = 0.001, t test). All bars indicate the mean of three independent experiments performed in triplicate; bars, SD. Journal of Thoracic Oncology 2011 6, 1984-1992DOI: (10.1097/JTO.0b013e3182307eac) Copyright © 2011 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 3. Down-regulation of MALAT-1 expression in human A549 NSCLCs reduced migration. A, After transfection of A549 cells with shRNA (II; III; II, III, IV) against MALAT-1, expression of MALAT-1 is decreased, as demonstrated by reverse-transcriptase polymerase chain reaction (RT-PCR) analysis. Most effective down-regulation is achieved, if three shRNA (II, III, IV) are transfected at once in A549 cell. B, Significantly reduced transwell migration of A549 cells transfected with shRNA against MALAT-1 was found if either shRNA “III” (p < 0.001, t test) or “pooled” shRNA (II,III,IV; p < 0.001, t test) was used, compared with “scrambled.” C, Soft agar colony formation assay showed less colonies per well after 21 days growth of A549 cells transfected with three shRNA (II, III, IV), if compared with A549 cells (p < 0.001, t test control versus II, III, IV). All columns, mean of three independent experiments performed in triplicate; bars, SD. Journal of Thoracic Oncology 2011 6, 1984-1992DOI: (10.1097/JTO.0b013e3182307eac) Copyright © 2011 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 4. MALAT-1 gene knockdown suppresses tumor growth and metastasis in nude mice. A, A549 cells transfected with either scrambled control or pooled shRNA (II, III, IV) were injected subcutaneously into nude mice (n = 10) at three locations each. After 31 days, animals were killed for determination of tumor weights and immunohistochemistry. Injected cells transfected with shRNA against MALAT-1 demonstrated reduced tumor growth (volume) when compared with scrambled-transfected cells (*p < 0.05). B, According to tumor volume, tumor weight was significantly less in the “pooled” shRNA group compared with the “scrambled” shRNA group (p = 0.021). C, On day 31, murine MALAT-1 (mMALAT-1), human MALAT-1 (hMALAT-1), murine GAPDH (mGAPDH), and human GAPDH (hGAPDH) gene expression, respectively, were evaluated using RT-PCR. In all test sets, no difference between both tumor types (A 549 scrambled shRNA versus A 549 pooled shRNA) were found. Journal of Thoracic Oncology 2011 6, 1984-1992DOI: (10.1097/JTO.0b013e3182307eac) Copyright © 2011 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 5. Prognostic role of MALAT-1 expression evaluated by chromogenic in situ hybridization. To evaluate the sensitivity of the ISH probe, hybridization was first tested in A549 cells. A, Strong hybridization signal of MALAT-1 RNA after transfection of A549 cells with “scrambled” control shRNA (pRNAT-H1.1/Neo vector). If A549 cells were transfected with “scrambled” control shRNA (pRNAT-H1.1/Neo vector), a strong amplification signal was detected. B, After transfection of “pooled” shRNA, MALAT-1 amplification signal was weak, indicating gene knock-down. C, Strong MALAT-1 transcript hybridization signals were observed in 123 (35%) of the tested 352 NSCLC tissues. Representative MALAT-1 staining is shown for squamous cell carcinoma (blue, hematoxylin counterstaining of nuclei). D, In contrast to NSCLC tissues, nonmalignant lung tissue showed a weak amplification signal of MALAT-1 RNA. E, Kaplan-Meier curves were used to determine the survival probability, and the log-rank test was used to compare the survival curves between patients with and without MALAT-1 hybridization signals. Blue indicates weak expression of MALAT-1 transcript and the red line stands for positive expression. For pulmonary squamous cell carcinoma, positive MALAT-1 expression indicated poor prognosis (p = 0.012; log-rank test). Journal of Thoracic Oncology 2011 6, 1984-1992DOI: (10.1097/JTO.0b013e3182307eac) Copyright © 2011 International Association for the Study of Lung Cancer Terms and Conditions