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Oncogenic lncrna downregulates cancer cell antigen presentation and intrinsic tumor suppression

NATURE IMMUNOLOGY 2019年第7期20卷 835-+页

作者： Hu, Qingsong Ye, Youqiong Chan, Li-Chuan Li, Yajuan Liang, Ke Lin, Aifu Egranov, Sergey D. Zhang, Yaohua Xia, Weiya Gong, Jing Pan, Yinghong Chatterjee, Sujash S. Yao, Jun Evans, Kurt W. Nguyen, Tina K. Park, Peter K. Liu, Jiewei Coarfa, Cristian Donepudi, Sri Ramya Putluri, Vasanta Putluri, Nagireddy Sreekumar, Arun Ambati, Chandrashekar R. Hawke, David H. Marks, Jeffrey R. Gunaratne, Preethi H. Caudle, Abigail S. Sahin, Aysegul A. Hortobagyi, Gabriel N. Meric-Bernstam, Funda Chen, Lieping Yu, Dihua Hung, Mien-Chie Curran, Michael A. Han, Leng Lin, Chunru Yang, Liuqing Univ Texas MD Anderson Canc Ctr Dept Mol & Cellular Oncol Houston TX 77030 USA Univ Texas Hlth Sci Ctr Houston McGovern Med Sch Dept Biochem & Mol Biol Houston TX 77030 USA Univ Texas MD Anderson Canc Ctr Grad Sch Biomed Sci Houston TX 77030 USA Univ Houston Dept Biochem & Biol Houston TX USA Univ Texas MD Anderson Canc Ctr Div Canc Med Dept Invest Canc Therapeut Houston TX 77030 USA Baylor Coll Med Dept Mol & Cell Biol Houston TX 77030 USA Baylor Coll Med Alkek Ctr Mol Discovery Adv Technol Core Dan L Duncan Canc Ctr Houston TX 77030 USA Univ Texas MD Anderson Canc Ctr Dept Syst Biol Houston TX 77030 USA Duke Univ Sch Med Div Surg Sci Dept Surg Durham NC USA Univ Texas MD Anderson Canc Ctr Div Surg Dept Breast Surg Oncol Houston TX 77030 USA Univ Texas MD Anderson Canc Ctr Div Pathol & Lab Med Dept Pathol Houston TX 77030 USA Univ Texas MD Anderson Canc Ctr Div Canc Med Dept Breast Med Oncol Houston TX 77030 USA Yale Univ Sch Med Dept Immunobiol New Haven CT USA China Med Univ Taichung Taiwan Univ Texas MD Anderson Canc Ctr Div Basic Sci Dept Immunol Houston TX 77030 USA Univ Texas MD Anderson Canc Ctr Ctr RNA Interference & Non Coding RNAs Houston TX 77030 USA Zhejiang Univ Coll Life Sci Hangzhou Zhejiang Peoples R China UPMC Genome Ctr Pittsburgh PA USA

How tumor cells genetically lose antigenicity and evade immune checkpoints remains largely elusive. We report that tissue-specific expression of the human long noncoding rna LINK-A in mouse mammary glands initiates metastatic mammary gland tumors, which phenotypically resemble human triple-negative breast cancer (TNBC). LINK-A expression facilitated crosstalk between phosphatidylinositol-(3,4,5)-trisphosphate and inhibitory G-protein-coupled receptor (GPCR) pathways, attenuating protein kinase A-mediated phosphorylation of the E3 ubiquitin ligase TRIM71. Consequently, LINK-A expression enhanced K48-polyubiquitination-mediated degradation of the antigen peptide-loading complex (PLC) and intrinsic tumor suppressors Rb and p53. Treatment with LINK-A locked nucleic acids or GPCR antagonists stabilized the PLC components, Rb and p53, and sensitized mammary gland tumors to immune checkpoint blockers. Patients with programmed ccll death protein-1(PD-1) blockade-resistant TNBC exhibited elevated LINK-A levels and downregulated PLC components. Hence we demonstrate lncrna-dependent downregulation of antigenicity and intrinsic tumor suppression, which provides the basis for developing combinational immunotherapy treatment regimens and early TNBC prevention.

关键词： Animal disease models Antigen processing and presentation Immune evasion Immunosurveillance Ubiquitylation

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Author Correction: Hypoxia-mediated downregulation of mirna biogenesis promotes tumour progression

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Nature communications 2020年第1期11卷 2867页

作者： Rajesha Rupaimoole Sherry Y Wu Sunila Pradeep Cristina Ivan Chad V Pecot Kshipra M Gharpure Archana S Nagaraja Guillermo N Armaiz-Pena Michael McGuire Behrouz Zand Heather J Dalton Justyna Filant Justin Bottsford Miller Chunhua Lu Nouara C Sadaoui Lingegowda S Mangala Morgan Taylor Twan van den Beucken Elizabeth Koch Cristian Rodriguez-Aguayo Li Huang Menashe Bar-Eli Bradly G Wouters Milan Radovich Mircea Ivan George A Calin Wei Zhang Gabriel Lopez-Berestein Anil K Sood Department of Gynecologic Oncology The University of Texas MD Anderson Cancer Center 1515 Holcombe Boulevard Houston TX 77030 USA. Graduate School of Biomedical Sciences The University of Texas MD Anderson Cancer Center 1515 Holcombe Boulevard Houston TX 77030 USA. Center for RNA Interference and Non-Coding RNA The University of Texas MD Anderson Cancer Center 1515 Holcombe Boulevard Houston TX 77030 USA. Department of Molecular Therapeutics University of North Carolina Lineberger Comprehensive Cancer Center 101 Manning Drive Chapel Hill NC 27599 USA. Department of Medical Biophysics University of Toronto Toronto ON Canada M5G 1L7. Princess Margaret Cancer Centre and Campbell Family Institute for Cancer Research University Health Network Toronto ON Canada M5G 1L7. Department of Experimental Therapeutics The University of Texas MD Anderson Cancer Center 1515 Holcombe Boulevard Houston TX 77030 USA. Department of Cancer Biology The University of Texas MD Anderson Cancer Center 1515 Holcombe Boulevard Houston TX 77030 USA. Department of Surgery Microbiology and Immunology Indiana University 980W Walnut Street Indianapolis IN 46202 USA. Department of Medicine Microbiology and Immunology Indiana University 980W Walnut Street Indianapolis IN 46202 USA. Department of Pathology The University of Texas MD Anderson Cancer Center 1515 Holcombe Boulevard Houston TX 77030 USA. Department of Gynecologic Oncology The University of Texas MD Anderson Cancer Center 1515 Holcombe Boulevard Houston TX 77030 USA. asood@***. Center for RNA Interference and Non-Coding RNA The University of Texas MD Anderson Cancer Center 1515 Holcombe Boulevard Houston TX 77030 USA. asood@***. Department of Cancer Biology The University of Texas MD Anderson Cancer Center 1515 Holcombe Boulevard Houston TX 77030 USA. asood@***.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

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Stem cell and neurogenic gene-expression profiles link prostate basal cells to aggressive prostate cancer

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NATURE COMMUNICATIONS 2016年第1期7卷 10798-10812页

作者： Zhang, Dingxiao Park, Daechan Zhong, Yi Lu, Yue Rycaj, Kiera Gong, Shuai Chen, Xin Liu, Xin Chao, Hsueh-Ping Whitney, Pamela Calhoun-Davis, Tammy Takata, Yoko Shen, Jianjun Iyer, Vishwanath R. Tang, Dean G. Univ Texas MD Anderson Canc Ctr Dept Epigenet & Mol Carcinogenesis Smithville TX 78957 USA Univ Texas Austin Ctr Syst & Synthet Biol Inst Cellular & Mol Biol Dept Mol Biosci Austin TX 78712 USA Tongji Univ Sch Med East Hosp Res Ctr Translat MedCanc Stem Cell Inst Shanghai 2001120 Peoples R China Univ Texas MD Anderson Canc Ctr RNA Interference & Non Coding RNAs & Mol Carcinog Ctr Canc Epigenet Houston TX 77030 USA Univ Texas MD Anderson Canc Ctr RNA Interference & Non Coding RNAs & Mol Carcinog Ctr Stem Cell Houston TX 77030 USA Univ Texas MD Anderson Canc Ctr RNA Interference & Non Coding RNAs & Mol Carcinog Ctr Dev Biol Houston TX 77030 USA Univ Texas Austin Dept Chem Engn Austin TX 78712 USA

The prostate gland mainly contains basal and luminal cells constructed as a pseudostratified epithelium. Annotation of prostate epithelial transcriptomes provides a foundation for discoveries that can impact disease understanding and treatment. Here we describe a genome-wide transcriptome analysis of human benign prostatic basal and luminal epithelial populations using deep rna sequencing. Through molecular and biological characterizations, we show that the differential gene-expression profiles account for their distinct functional properties. Strikingly, basal cells preferentially express gene categories associated with stem cells, neurogenesis and ribosomal rna (rrna) biogenesis. Consistent with this profile, basal cells functionally exhibit intrinsic stem-like and neurogenic properties with enhanced rrna transcription activity. Of clinical relevance, the basal cell gene-expression profile is enriched in advanced, anaplastic, castration-resistant and metastatic prostate cancers. Therefore, we link the cell-type-specific gene signatures to aggressive subtypes of prostate cancer and identify gene signatures associated with adverse clinical features.

关键词： Gene expression Prostate cancer

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Targeting 17q23 amplicon to overcome the resistance to anti-HER2 therapy in HER2+breast cancer

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NATURE COMMUNICATIONS 2018年第1期9卷 1页

作者： Liu, Yunhua Xu, Jiangsheng Choi, Hyun Ho Han, Cecil Fang, Yuanzhang Li, Yujing Van der Jeught, Kevin Xu, Hanchen Zhang, Lu Frieden, Michael Wang, Lifei Eyvani, Haniyeh Sun, Yifan Zhao, Gang Zhang, Yuntian Liu, Sheng Wan, Jun Huang, Cheng Ji, Guang Lu, Xiongbin He, Xiaoming Zhang, Xinna Indiana Univ Sch Med Dept Med & Mol Genet Indianapolis IN 46202 USA Univ Texas MD Anderson Canc Ctr Dept Canc Biol Houston TX 77030 USA Shanghai Univ Tradit Chinese Med Longhua Hosp Inst Digest Dis Shanghai 200032 Peoples R China Ohio State Univ Dept Biomed Engn Columbus OH 43210 USA Ohio State Univ Comprehens Canc Ctr Columbus OH 43210 USA Univ Maryland Fischell Dept Bioengn College Pk MD 20742 USA Univ Sci & Technol China Sch Informat Sci & Technol Dept Elect Sci & Technol Hefei 230027 Anhui Peoples R China Shanghai Univ Tradit Chinese Med Sch Pharm Drug Discovery Lab Shanghai 201203 Peoples R China Indiana Univ Sch Med Indiana Univ Melvin & Bren Simon Canc Ctr Indianapolis IN 46202 USA Univ Maryland Robert E Fischell Inst Biomed Devices College Pk MD 20742 USA Univ Maryland Marlene & Stewart Greenebaum Comprehens Canc Ctr Baltimore MD 21201 USA Univ Texas MD Anderson Canc Ctr Ctr RNA Interference & Non Coding RNAs Houston TX 77030 USA Univ Texas MD Anderson Canc Ctr Dept Gynecol Oncol & Reprod Med Houston TX 77030 USA

Chromosome 17q23 amplification occurs in similar to 11% of human breast cancers. Enriched in HER2+ breast cancers, the 17q23 amplification is significantly correlated with poor clinical outcomes. In addition to the previously identified oncogene WIP1, we uncover an oncogenic microrna gene, MIR21, in a majority of the WIP1-containing 17q23 amplicons. The 17q23 amplification results in aberrant expression of WIP1 and miR-21, which not only promotes breast tumorigenesis, but also leads to resistance to anti-HER2 therapies. Inhibiting WIP1 and miR-21 selectively inhibits the proliferation, survival and tumorigenic potential of the HER2+ breast cancer cells harboring 17q23 amplification. To overcome the resistance of trastuzumab-based therapies in vivo, we develop pH-sensitive nanoparticles for specific co-delivery of the WIP1 and miR-21 inhibitors into HER2+ breast tumors, leading to a profound reduction of tumor growth. These results demonstrate the great potential of the combined treatment of WIP1 and miR-21 inhibitors for the trastuzumab-resistant HER2+ breast cancers.

关键词： Breast cancer Cancer genomics Cancer therapy

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Corrigendum: FOXM1 mediates Dox resistance in breast cancer by enhancing DNA repair

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Carcinogenesis 2019年第7期40卷 936页

作者： Yun-Yong Park Sung Yun Jung Nicholas B Jennings Cristian Rodriguez-Aguayo Guang Peng Se-Ra Lee Sang Bae Kim Kyounghyun Kim Sun-Hee Leem Shiaw-Yih Lin Gabriel Lopez-Berestein Anil K Sood Ju-Seog Lee Department of Systems Biology The University of Texas MD Anderson Cancer Center Houston TX USA. Department of Biochemistry and Molecular Biology Baylor College of Medicine Houston TX USA. Department of Gynecologic Oncology Houston TX USA. Department of Experimental Therapeutics The University of Texas MD Anderson Cancer Center Houston TX USA. Department of Biology and Biomedical Science Dong-A University Busan Korea. Institute of Biosciences and Technology Texas A&M University Health Science Center Houston TX USA. Deparment of Cancer Biology The University of Texas MD Anderson Cancer Center Houston TX USA. Center for RNA Interference and Non-Coding RNA The University of Texas MD Anderson Cancer Center Houston TX USA.

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Role of YAP1 as a Marker of Sensitivity to Dual AKT and P70S6K Inhibition in Ovarian and Uterine Malignancies

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JNCI-JOUrnaL OF THE NATIONAL CANCER INSTITUTE 2017年第7期109卷 djw296-djw296页

作者： Previs, Rebecca A. Armaiz-Pena, Guillermo N. Ivan, Cristina Dalton, Heather J. Rupaimoole, Rajesha Hansen, Jean M. Lyons, Yasmin Huang, Jie Haemmerle, Monika Wagner, Michael J. Gharpure, Kshipra M. Nagaraja, Archana S. Filant, Justyna McGuire, Michael H. Noh, Kyunghee Dorniak, Piotr L. Linesch, Sarah L. Mangala, Lingegowda S. Pradeep, Sunila Wu, Sherry Y. Sood, Anil K. Univ Texas MD Anderson Canc Ctr Dept Gynecol Oncol & Reprod Med Houston TX 77030 USA Univ Texas MD Anderson Canc Ctr Dept Canc Biol Houston TX 77030 USA Univ Texas MD Anderson Canc Ctr Ctr RNA Interference & Non Coding RNAs Houston TX 77030 USA Ponce Hlth Sci Univ Dept Basic Sci Div Pharmacol Ponce PR USA Ponce Res Inst Div Canc Biol Ponce PR USA

Background: The PI3K/AKT/P70S6K pathway is an attractive therapeutic target in ovarian and uterine malignancies because of its high rate of deregulation and key roles in tumor growth. Here, we examined the biological effects of MSC2363318A, which is a novel inhibitor of AKT1, AKT3, and P70S6K. Methods: Orthotopic murine models of ovarian and uterine cancer were utilized to study the effect of MSC2363318A on survival and regression. For each cell line, 10 mice were treated in each of the experimental arms tested. Moreover, in vitro experiments in 21 cell lines (MTT, immunoblot analysis, plasmid transfection, reverse phase protein array [RPPA]) were carried out to characterize underlying mechanisms and potential biomarkers of response. All statistical tests were two-sided. Results: MSC2363318A decreased tumor growth and metastases in multiple murine orthotopic models of ovarian (SKOV3ip1, HeyA8, and Igrov1) and uterine (Hec1a) cancer by reducing proliferation and angiogenesis and increasing cell death. Statistically significant prolonged overall survival was achieved with combination MSC2363318A and paclitaxel in the SKUT2 (endometrioid) uterine cancer mouse model (P<.001). Mice treated with combination MSC2363318A and paclitaxel had the longest overall survival (mean = 104.2 days, 95% confidence interval [CI] = 97.0 to 111.4) compared with those treated with vehicle (mean = 61.9 days, 95% CI = 46.3 to 77.5), MSC2363318A alone (mean = 89.7 days, 95% CI = 83.0 to 96.4), and paclitaxel alone (mean = 73.6 days, 95% CI = 53.4 to 93.8). Regression and stabilization of established tumors in the Ishikawa (endometrioid) uterine cancer model was observed in mice treated with combination MSC2363318A and paclitaxel. Synergy between MSC2363318A and paclitaxel was observed in vitro in cell lines that had an IC50 of 5 mu M or greater. RPPA results identified YAP1 as a candidate marker to predict cell lines that were most sensitive to MSC2363318A (R = 0.54, P = .02). After establish

关键词： Adaptor Proteins Signal Transducing/*metabolism Biomarkers Tumor/*metabolism Ovarian Neoplasms/*metabolism Phosphoproteins/*metabolism Proto-Oncogene Proteins c-akt/*metabolism Ribosomal Protein S6 Kinases 70-kDa/*metabolism Uterine Neoplasms/*metabolism Angiogenesis Inhibitors/administration & dosage Angiogenesis Inhibitors/pharmacology Animals Antineoplastic Agents Phytogenic/administration & dosage Antineoplastic Agents Phytogenic/pharmacology Antineoplastic Combined Chemotherapy Protocols/pharmacology Apoptosis/drug effects Bevacizumab/administration & dosage Bevacizumab/pharmacology Cell Line Tumor Cell Proliferation/drug effects Female Humans Inhibitory Concentration 50 Kaplan-Meier Estimate Mice Nude Ovarian Neoplasms/drug therapy Paclitaxel/administration & dosage Paclitaxel/pharmacology Protein Kinase Inhibitors/administration & dosage Protein Kinase Inhibitors/pharmacology Proto-Oncogene Proteins c-akt/antagonists & inhibitors Ribosomal Protein S6 Kinases 70-kDa/antagonists & inhibitors Tumor Burden/drug effects Uterine Neoplasms/drug therapy Xenograft Model Antitumor Assays

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Publisher Correction: Regulation of cellular sterol homeostasis by the oxygen responsive noncoding rna lincNORS

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Nature communications 2020年第1期11卷 5737页

作者： Xue Wu Cristina M Niculite Mihai Bogdan Preda Annalisa Rossi Toma Tebaldi Elena Butoi Mattie K White Oana M Tudoran Daniela N Petrusca Amber S Jannasch William P Bone Xingyue Zong Fang Fang Alexandrina Burlacu Michelle T Paulsen Brad A Hancock George E Sandusky Sumegha Mitra Melissa L Fishel Aaron Buechlein Cristina Ivan Spyros Oikonomopoulos Myriam Gorospe Amber Mosley Milan Radovich Utpal P Davé Jiannis Ragoussis Kenneth P Nephew Bernard Mari Alan McIntyre Heiko Konig Mats Ljungman Diana L Cousminer Paolo Macchi Mircea Ivan Department of Microbiology and Immunology Indiana University School of Medicine Indianapolis IN 46202 USA. Department of Medicine Indiana University School of Medicine Indianapolis IN 46202 USA. "Victor Babes" National Institute of Pathology Bucharest Romania. Institute of Cellular Biology and Pathology "Nicolae Simionescu" Bucharest Romania. Laboratory of Molecular and Cellular Neurobiology Department of Cellular Computational and Integrative Biology-CIBIO University of Trento Trento Italy. Laboratory of Translational Genomics Department of Cellular Computational and Integrative Biology-CIBIO University of Trento Trento Italy. Yale Cancer Center Yale University School of Medicine New Haven CT 06520 USA. The Oncology Institute "Prof Dr. Ion Chiricuta" Cluj-Napoca Romania. Metabolite Profiling Facility Bindley Bioscience Center Purdue University West Lafayette IN 47907 USA. Department of Genetics Department of Systems Pharmacology and Translational Therapeutics Institute of Translational Medicine and Therapeutics Perelman School of Medicine University of Pennsylvania Philadelphia PA 19104 USA. Department of Cellular and Integrative Physiology Indiana University School of Medicine Indianapolis IN USA. Departments of Radiation Oncology and Environmental Health Sciences Center for RNA Biomedicine University of Michigan Ann Arbor MI 48109 USA. Department of Surgery Indiana University School of Medicine Indianapolis IN 46202 USA. Department of Pathology and Laboratory Medicine Indiana University School of Medicine Indianapolis IN 46202 USA. Melvin and Bren Simon Cancer Center Indiana University Indianapolis IN USA. Department of Obstetrics and Gynecology Indiana University School of Medicine Indianapolis IN 46202 USA. Department of Pharmacology and Toxicology Department of Pediatrics Wells Center for Pediatric Research Indiana University School of Medicine Indianapolis IN 46202 USA. Indiana University Center for Genomics and Bioinformatics

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

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Dendritic Cell-derived Extracellular Vesicles mediate Mesenchymal Stem/Stromal Cell recruitment

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SCIENTIFIC REPORTS 2017年第1期7卷 1667-1667页

作者： Silva, Andreia M. Almeida, Maria I. Teixeira, Jose H. Maia, Andre F. Calin, George A. Barbosa, Mario A. Santos, Susana G. i3S - Instituto de Investigação e Inovação em Saúde Porto Portugal. INEB - Instituto de Engenharia Biomédica Universidade do Porto Porto Portugal. Instituto de Ciências Biomédicas Abel Salazar Universidade do Porto Porto Portugal. IBMC - Instituto de Biologia Molecular e Celular Universidade do Porto Porto Portugal. Department of Experimental Therapeutics The University of Texas MD Anderson Cancer Center Houston Texas USA. Center for RNA Interference and Non-Coding RNAs The University of Texas MD Anderson Cancer Center Houston Texas USA. i3S - Instituto de Investigação e Inovação em Saúde Porto Portugal. susana.santos@ineb.up.pt. INEB - Instituto de Engenharia Biomédica Universidade do Porto Porto Portugal. susana.santos@ineb.up.pt.

Orchestration of bone repair processes requires crosstalk between different cell populations, including immune cells and mesenchymal stem/stromal cells (MSC). Extracellular vesicles (EV) as mediators of these interactions remain vastly unexplored. Here, we aimed to determine the mechanism of MSC recruitment by Dendritic Cells (DC), hypothesising that it would be mediated by EV. Primary human DC-secreted EV (DC-EV), isolated by ultracentrifugation, were characterized for their size, morphology and protein markers, indicating an enrichment in exosomes. DC-EV were readily internalized by human bone marrow-derived MSC, without impacting significantly their proliferation or influencing their osteogenic/chondrogenic differentiation. Importantly, DC-EV significantly and dose-dependently promoted MSC recruitment across a transwell system and enhanced MSC migration in a microfluidic chemotaxis assay. DC-EV content was analysed by chemokine array, indicating the presence of chemotactic mediators. Osteopontin and matrix metalloproteinase-9 were confirmed inside EV. In summary, DC-EV are naturally loaded with chemoattractants and can contribute to cell recruitment, thus inspiring the development of new tissue regeneration strategies.

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Deep rna-Seq analysis reveals unexpected features of human prostate basal epithelial cells

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Genomics Data 2016年 7卷 318-320页

作者： Dingxiao Zhang Daechan Park Yue Lu Jianjun Shen Vishwanath R. Iyer Dean G. Tang Department of Epigenetics and Molecular Carcinogenesis University of Texas MD Anderson Cancer Center Smithville TX 78957 United States Institute for Cellular and Molecular Biology Center for Systems and Synthetic Biology and Section of Molecular Genetics and Microbiology University of Texas at Austin Austin TX 78712-0159 United States Centers for Cancer Epigenetics Stem Cell and Developmental Biology RNA Interference and Non-Coding RNAs and Molecular Carcinogenesis University of Texas MD Anderson Cancer Center Houston TX United States

Prostate cancer is the second leading cause of cancer-related deaths among American men [ 1 ]. The prostate gland mainly contains basal and luminal cells, which are constructed as a pseudostratified epithelium. Annotation of prostate epithelial transcriptomes provides a foundation for discoveries that can impact disease understanding and treatment. Here, for the first time, we describe a whole-genome transcriptome analysis of human benign prostatic basal and luminal populations by using deep rna sequencing (GSE67070) [2]. Combined with comprehensive molecular and biological characterizations, we show that the differential gene expression profiles account for their distinct functional phenotypes. Strikingly, in contrast to luminal cells, basal cells preferentially express gene categories associated with stem cells, neural and neuronal development, and rna processing. Of clinical relevance, the treatment failed castration-resistant and anaplastic prostate cancers molecularly resemble a basal-like phenotype. We also identified genes associated with patient clinical outcome. Therefore, we provide a gene expression resource for understanding human prostate epithelial lineages, and link the cell-type specific gene signatures to subtypes of prostate cancer development.

关键词： Prostate epithelial cells Basal cells Luminal cells rna-seq

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Tissue Transglutaminase Activates Cancer-Associated Fibroblasts and Contributes to Gemcitabine Resistance in Pancreatic Cancer

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NEOPLASIA 2016年第11期18卷 689-698页

作者： Lee, Jiyoon Yakubov, Bakhtiyor Ivan, Cristina Jones, David R. Caperell-Grant, Andrea Fishel, Melissa Cardenas, Horacio Matei, Daniela Indiana Univ Sch Med Dept Otolaryngol Head & Neck Surg Indianapolis IN 46202 USA Indiana Univ Sch Med Dept Med Indianapolis IN 46202 USA Univ Texas MD Anderson Canc Ctr Dept Expt Therapeut Houston TX 77030 USA Univ Texas MD Anderson Canc Ctr Ctr RNA Interference & Non Coding RNAs Houston TX 77030 USA Indiana Univ Sch Med Dept Pediat Indianapolis IN 46202 USA Indiana Univ Melvin & Bren Simon Canc Ctr Indianapolis IN 46204 USA Northwestern Univ Dept Obstet & Gynecol Feinberg Sch Med 303 E Super StLurie 4-107 Chicago IL 60611 USA Robert H Lurie Canc Ctr Chicago IL USA Jesse Brown VA Med Ctr Chicago IL USA

Resistance to chemotherapy is a hallmark of pancreatic ductal adenocarcinoma (PDA) and has been partly attributed to the dense desmoplastic stroma, which forms a protective niche for cancer cells. Tissue transglutaminase (TG2), a Ca2+-dependent enzyme, is secreted by PDA cells and cross-links proteins in the tumor microenvironment (TME) through acyl-transfer between glutamine and lysine residues, promoting PDA growth. The objective of the current study was to determine whether secreted TG2 by PDA cells alters the response of pancreatic tumors to gemcitabine. Orthotopic pancreatic xenografts and co-culture of PDA and stromal cells were employed to determine the mechanisms by which TG2 alters tumor-stroma interactions and response to gemcitabine. Analysis of the pancreatic The Cancer Genome Atlas (TCGA) database demonstrated that increased TG2 expression levels correlate with worse overall survival (hazard ratio = 1.37). Stable TG2 knockdown in PDA cells led to decreased size of pancreatic xenografts and increased sensitivity to gemcitabine in vivo. However, TG2 downregulation did not increase cytotoxicity of gemcitabine in vitro. Additionally, multivessel density and gemcitabine uptake in pancreatic tumor tissue, as measured by mass spectrometry (MS-HPLC), were not significantly different in tumors expressing TG2 versus tumors in which TG2 was knocked down. Fibroblasts, stimulated by TG2 secreted by PDA cells, secrete laminin A1, which protects cancer cells from gemcitabine-induced cytotoxicity. In all, our results demonstrate that TG2 secreted in the pancreatic TME orchestrates the cross talk between cancer cells and stroma, impacting tumor growth and response to chemotherapy. Our study supports TG2 inhibition to increase the antitumor effects of gemcitabine in PDA.

关键词： PANCREATIC cancer treatment TRANSGLUTAMINASES DRUG resistance CHEMOTHERAPY (Cancer) ANTINEOPLASTIC agents FIBROBLASTS

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