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PMID: 25678598 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

MAPK7 Regulates EMT Features and Modulates the Generation of CTCs.

Molecular cancer research : MCR ·Vol. 13 ·No. 5 ·2015-05-00 ·Pages 934-43

Javaid S, Zhang J, Smolen GA, Yu M, Wittner BS, Singh A, Arora KS, Madden MW, Desai R, Zubrowski MJ, Schott BJ, Ting DT, Stott SL, Toner M, Maheswaran S, Shioda T, Ramaswamy S, Haber DA

Abstract

Epithelial-to-mesenchymal transition (EMT) has been implicated in models of tumor cell migration, invasion, and metastasis. In a search for candidate therapeutic targets to reverse this process, nontumorigenic MCF10A breast epithelial cells were infected with an arrayed lentiviral kinome shRNA library and screened for either suppression or enhancement of a 26-gene EMT RNA signature. No individual kinase gene knockdown was sufficient to induce EMT. In contrast, grouped epithelial markers were induced by knockdown of multiple kinases, including mitogen activated protein kinase 7 (MAPK7). In breast cancer cells, suppression of MAPK7 increased E-cadherin (CDH1) expression and inhibited cell migration. In an orthotopic mouse model, MAPK7 suppression reduced the generation of circulating tumor cells and the appearance of lung metastases. Together, these observations raise the possibility that targeting kinases that maintain mesenchymal cell properties in cancer cells, such as MAPK7, may lessen tumor invasiveness. Suppression of MAPK7 induces epithelial markers, reduces generation of circulating tumor cells and appearance of lung metastases.

MeSH Terms
Animals Antigens, CD Breast Neoplasms/blood,enzymology,pathology Cadherins/biosynthesis,genetics Cell Line, Tumor Epithelial-Mesenchymal Transition/genetics Female Gene Knockdown Techniques Humans Mice Mice, Inbred NOD Mitogen-Activated Protein Kinase 7/genetics,metabolism Neoplastic Cells, Circulating/metabolism,pathology RNA, Small Interfering/genetics,metabolism Transcriptome
Chemicals
Antigens, CD CDH1 protein, human Cadherins RNA, Small Interfering MAPK7 protein, human Mitogen-Activated Protein Kinase 7
Authors & Affiliations
18 authors, click to expand affiliations / ORCID
Javaid Sarah
Massachusetts General Hospital Cancer Center and Harvard Medical School, Charlestown, Massachusetts. Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts.
Zhang Jianmin
Massachusetts General Hospital Cancer Center and Harvard Medical School, Charlestown, Massachusetts.
Smolen Gromoslaw A
Massachusetts General Hospital Cancer Center and Harvard Medical School, Charlestown, Massachusetts.
Yu Min
Massachusetts General Hospital Cancer Center and Harvard Medical School, Charlestown, Massachusetts.
Wittner Ben S
Massachusetts General Hospital Cancer Center and Harvard Medical School, Charlestown, Massachusetts. Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts.
Singh Anurag
Massachusetts General Hospital Cancer Center and Harvard Medical School, Charlestown, Massachusetts.
Arora Kshitij S
Massachusetts General Hospital Cancer Center and Harvard Medical School, Charlestown, Massachusetts.
Madden Marissa W
Massachusetts General Hospital Cancer Center and Harvard Medical School, Charlestown, Massachusetts.
Desai Rushil
Massachusetts General Hospital Cancer Center and Harvard Medical School, Charlestown, Massachusetts.
Zubrowski Matthew J
Massachusetts General Hospital Cancer Center and Harvard Medical School, Charlestown, Massachusetts.
Schott Benjamin J
Massachusetts General Hospital Cancer Center and Harvard Medical School, Charlestown, Massachusetts.
Ting David T
Massachusetts General Hospital Cancer Center and Harvard Medical School, Charlestown, Massachusetts. Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts.
Stott Shannon L
Massachusetts General Hospital Cancer Center and Harvard Medical School, Charlestown, Massachusetts. Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts. BioMEMS Resource Center, Massachusetts General Hospital Center for Bioengineering in Medicine, Charlestown, Massachusetts.
Toner Mehmet
BioMEMS Resource Center, Massachusetts General Hospital Center for Bioengineering in Medicine, Charlestown, Massachusetts. Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts.
Maheswaran Shyamala
Massachusetts General Hospital Cancer Center and Harvard Medical School, Charlestown, Massachusetts. Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts.
Shioda Toshi
Massachusetts General Hospital Cancer Center and Harvard Medical School, Charlestown, Massachusetts. Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts.
Ramaswamy Sridhar
Massachusetts General Hospital Cancer Center and Harvard Medical School, Charlestown, Massachusetts. Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts.
Haber Daniel A
Massachusetts General Hospital Cancer Center and Harvard Medical School, Charlestown, Massachusetts. Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts. Howard Hughes Medical Institute, Chevy Chase, Maryland. haber@helix.mgh.harvard.edu.
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Article Info
Journal
Molecular cancer research : MCR
Abbr.
Mol Cancer Res
ISSN
1557-3125
DOI
10.1158/1541-7786.MCR-14-0604
Email
haber@helix.mgh.harvard.edu
Published
2015-05-00
Epub
2015-00-12
Pages
934-43
Language
English
Region
United States
NLM ID
101150042
PMCID
PMC4433453
Subset
IM
Grants
NCI NIH HHS · R01 CA129933 · United States
NIBIB NIH HHS · NIBIB-EB008047 · United States
NCI NIH HHS · K99 CA149169 · United States
NIBIB NIH HHS · U01 EB012493 · United States
NIBIB NIH HHS · R01 EB008047 · United States
NCI NIH HHS · CA-129933 · United States
Howard Hughes Medical Institute · United States
NIBIB NIH HHS · P41 EB002503 · United States
External Links
PubMed source DOI: 10.1158/1541-7786.MCR-14-0604 PMC Full Text View journal details
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