Differentiation of mammary tumors and reduction in metastasis upon Malat1 lncRNA loss

Genes and Development - Tập 30 Số 1 - Trang 34-51 - 2016
Gayatri Arun1, Sarah D. Diermeier1, Martin Akerman1, Kung-Chi Chang1,2, John E. Wilkinson3, Stephen Hearn1, Youngsoo Kim4, A. Robert MacLeod4, Adrian R. Krainer1,2, Larry Norton5, Edi Brogi5, Mikala Egeblad1, David L. Spector1,2
11Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA
22Molecular and Cellular Biology Program, Stony Brook University, Stony Brook, New York 11790, USA
33Department of Pathology, University of Michigan, Ann Arbor, Michigan 48109, USA
44Ionis Pharmaceuticals, Inc., Carlsbad, California 92010, USA
55Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA

Tóm tắt

Genome-wide analyses have identified thousands of long noncoding RNAs (lncRNAs). Malat1 (metastasis-associated lung adenocarcinoma transcript 1) is among the most abundant lncRNAs whose expression is altered in numerous cancers. Here we report that genetic loss or systemic knockdown of Malat1 using antisense oligonucleotides (ASOs) in the MMTV (mouse mammary tumor virus)-PyMT mouse mammary carcinoma model results in slower tumor growth accompanied by significant differentiation into cystic tumors and a reduction in metastasis. Furthermore, Malat1 loss results in a reduction of branching morphogenesis in MMTV-PyMT- and Her2/neu-amplified tumor organoids, increased cell adhesion, and loss of migration. At the molecular level, Malat1 knockdown results in alterations in gene expression and changes in splicing patterns of genes involved in differentiation and protumorigenic signaling pathways. Together, these data demonstrate for the first time a functional role of Malat1 in regulating critical processes in mammary cancer pathogenesis. Thus, Malat1 represents an exciting therapeutic target, and Malat1 ASOs represent a potential therapy for inhibiting breast cancer progression.

Từ khóa


Tài liệu tham khảo

10.1086/381039

10.1200/JCO.2013.54.1870

10.1038/nsmb.2207

10.1093/bioinformatics/btu638

10.1073/pnas.97.7.3444

10.1074/jbc.M112.411033

10.1038/nrg3662

10.1016/j.ceb.2013.08.005

10.1038/emboj.2010.199

10.1016/j.cell.2014.12.021

10.1038/ncb2965

1999, DD3: a new prostate-specific Gene, highly overexpressed in prostate cancer, Cancer Res, 59, 5975

10.1016/j.cell.2008.04.043

10.1016/j.cell.2013.11.029

10.1002/embr.201337642

10.1016/j.molcel.2009.01.026

1986, Presence of α-lactalbumin, epidermal growth factor, epithelial membrane antigen, and gross cystic disease fluid protein (15,000 daltons) in breast cyst fluid, Cancer Res, 46, 3728

10.1016/j.gene.2006.09.028

10.1101/gr.132159.111

2012, Landscape of transcription in human cells, Nature, 48, 101

10.1093/bioinformatics/bts635

10.4161/rna.21089

10.1038/nature11143

10.1038/nature11247

10.1016/j.cell.2014.08.018

2013, RNA sequencing of cancer reveals novel splicing alterations, Scientific Rep, 3, 1689, 10.1038/srep01689

2013, Isolation of mouse mammary organoids for long-term time-lapse imaging, Cold Spring Harb Protoc, 2013, 130

10.1016/j.devcel.2008.03.003

10.1186/1471-2164-10-163

10.1038/nsmb.2315

10.1038/nature08975

10.1158/0008-5472.CAN-12-2850

10.1128/MCB.12.3.954

2004, Dynamic in vivo imaging and cell tracking using a histone fluorescent protein fusion in mice, BMC Biotechnol, 24, 33

10.1101/gr.135350.111

10.1016/j.molcel.2010.05.004

10.1186/gb-2007-8-5-r76

10.1089/nat.2013.0443

10.1186/1471-2164-8-39

10.1038/sj.onc.1206928

10.1242/dev.091793

10.1093/nar/gkr089

10.1186/bcr3138

10.1016/j.ccr.2008.01.011

10.1158/0008-5472.CAN-08-0436

10.1016/S0002-9440(10)63568-7

10.1038/sj.onc.1209846

10.1101/gad.11.2.179

10.1186/s13059-014-0550-8

10.1093/bioinformatics/btt285

10.1186/1471-2105-10-161

10.1046/j.1365-2443.2001.00482.x

10.1038/ncb2717

10.1161/CIRCRESAHA.114.303265

10.1371/journal.pone.0034949

10.1261/rna.033217.112

10.1242/jcs.040394

10.1101/gad.1484207

10.1158/2159-8290.CD-ITI11-02

10.1038/nbt.1914

10.1038/ng.2771

10.1083/jcb.201207087

10.1146/annurev-biochem-051410-092902

10.1093/bioinformatics/btp616

10.1016/j.gde.2013.11.012

10.1126/science.1234852

10.1038/modpathol.2010.33

10.1038/nrc1187

10.1101/cshperspect.a000646

10.1083/jcb.115.5.1383

10.1074/jbc.270.37.21639

10.1073/pnas.0506580102

10.1016/j.febslet.2010.10.008

10.1038/9304

10.1038/nn.2778

10.1016/j.molcel.2010.08.011

2014, PVT1 dependence in cancer with MYC copy-number increase, Nature, 512, 82, 10.1038/nature13311

10.1158/0008-5472.CAN-08-1769

10.4161/org.5.2.8321

10.1016/j.molcel.2014.07.012

10.1016/j.cell.2008.10.012

10.1101/gad.1800909

10.1093/bioinformatics/btr508

10.1111/j.1349-7006.2006.00147.x

10.1016/j.cell.2011.08.054

10.1038/emboj.2013.175

10.1016/j.cell.2008.09.045

10.1016/j.celrep.2012.06.003

Thông tin
Thông tin xuất bản

Genes and Development

Tập 30 Số 1

34-51

Thông tin tác giả