PMID- 30905815
OWN - NLM
STAT- MEDLINE
DCOM- 20200325
LR  - 20200325
IS  - 1872-7980 (Electronic)
IS  - 0304-3835 (Linking)
VI  - 453
DP  - 2019 Jul 1
TI  - Targeting of TMPRSS4 sensitizes lung cancer cells to chemotherapy by impairing 
      the proliferation machinery.
PG  - 21-33
LID - S0304-3835(19)30169-7 [pii]
LID - 10.1016/j.canlet.2019.03.013 [doi]
AB  - High mortality rates caused by NSCLC show the need for the identification of 
      novel therapeutic targets. In this study we have investigated the biological 
      effects and molecular mechanisms elicited by TMPRSS4 in NSCLC. Overexpression of 
      TMPRSS4 in LKR13 cells increased malignancy, subcutaneous tumor growth and 
      multiorganic metastasis. In conditional knock-down (KD) experiments, abrogation 
      of TMPRSS4 in H358 and H2170 cells altered proliferation, clonogenicity, tumor 
      engraftment and tumor growth. Reduction in S and G2/M phases of the cell cycle, 
      decreased BrdU incorporation and increased apoptosis was also found. 
      Transcriptomic analysis in KD cells revealed downregulation of genes involved in 
      DNA replication, such as MCM6, TYMS and CDKN1A (p21). In patients, expression of 
      a signature of MCM6/TYMS/TMPRSS4 genes was highly associated with poor prognosis. 
      Downregulation of TMPRSS4 significantly increased sensitivity to chemotherapy 
      agents. In experiments using cisplatin, apoptosis and expression of the 
      DNA-damage marker gamma-H2A was higher in cells lacking TMPRSS4. Moreover, in vivo 
      assays demonstrated that tumors with no TMPRSS4 were significantly more sensitive 
      to cisplatin than controls. These results show that TMPRSS4 can be considered as 
      a novel target in NSCLC, whose inhibition increases chemosensitivity.
CI  - Copyright (c) 2019 Elsevier B.V. All rights reserved.
FAU - Exposito, Francisco
AU  - Exposito F
AD  - IDISNA and Program in Solid Tumors, Center for Applied Medical Research (CIMA), 
      University of Navarra, 31008, Pamplona, Navarra, Spain; Department of Pathology, 
      Anatomy and Physiology, School of Medicine, University of Navarra, 31008, 
      Pamplona, Navarra, Spain; CIBERONC, ISC-III, Spain.
FAU - Villalba, Maria
AU  - Villalba M
AD  - IDISNA and Program in Solid Tumors, Center for Applied Medical Research (CIMA), 
      University of Navarra, 31008, Pamplona, Navarra, Spain; Department of Pathology, 
      Anatomy and Physiology, School of Medicine, University of Navarra, 31008, 
      Pamplona, Navarra, Spain; CIBERONC, ISC-III, Spain.
FAU - Redrado, Miriam
AU  - Redrado M
AD  - IDISNA and Program in Solid Tumors, Center for Applied Medical Research (CIMA), 
      University of Navarra, 31008, Pamplona, Navarra, Spain.
FAU - de Aberasturi, Arrate L
AU  - de Aberasturi AL
AD  - IDISNA and Program in Solid Tumors, Center for Applied Medical Research (CIMA), 
      University of Navarra, 31008, Pamplona, Navarra, Spain.
FAU - Cirauqui, Cristina
AU  - Cirauqui C
AD  - IDISNA and Program in Solid Tumors, Center for Applied Medical Research (CIMA), 
      University of Navarra, 31008, Pamplona, Navarra, Spain.
FAU - Redin, Esther
AU  - Redin E
AD  - IDISNA and Program in Solid Tumors, Center for Applied Medical Research (CIMA), 
      University of Navarra, 31008, Pamplona, Navarra, Spain; Department of Pathology, 
      Anatomy and Physiology, School of Medicine, University of Navarra, 31008, 
      Pamplona, Navarra, Spain.
FAU - Guruceaga, Elizabeth
AU  - Guruceaga E
AD  - Bioinformatics Platform. Center for Applied Medical Research (CIMA), University 
      of Navarra, Pamplona, Spain.
FAU - de Andrea, Carlos
AU  - de Andrea C
AD  - Department of Pathology, Anatomy and Physiology, School of Medicine, University 
      of Navarra, 31008, Pamplona, Navarra, Spain.
FAU - Vicent, Silvestre
AU  - Vicent S
AD  - IDISNA and Program in Solid Tumors, Center for Applied Medical Research (CIMA), 
      University of Navarra, 31008, Pamplona, Navarra, Spain; Department of Pathology, 
      Anatomy and Physiology, School of Medicine, University of Navarra, 31008, 
      Pamplona, Navarra, Spain; CIBERONC, ISC-III, Spain.
FAU - Ajona, Daniel
AU  - Ajona D
AD  - IDISNA and Program in Solid Tumors, Center for Applied Medical Research (CIMA), 
      University of Navarra, 31008, Pamplona, Navarra, Spain; CIBERONC, ISC-III, Spain; 
      Department of Biochemistry and Genetics, School of Science, University of 
      Navarra, Pamplona, Spain.
FAU - Montuenga, Luis M
AU  - Montuenga LM
AD  - IDISNA and Program in Solid Tumors, Center for Applied Medical Research (CIMA), 
      University of Navarra, 31008, Pamplona, Navarra, Spain; Department of Pathology, 
      Anatomy and Physiology, School of Medicine, University of Navarra, 31008, 
      Pamplona, Navarra, Spain; CIBERONC, ISC-III, Spain.
FAU - Pio, Ruben
AU  - Pio R
AD  - IDISNA and Program in Solid Tumors, Center for Applied Medical Research (CIMA), 
      University of Navarra, 31008, Pamplona, Navarra, Spain; CIBERONC, ISC-III, Spain; 
      Department of Biochemistry and Genetics, School of Science, University of 
      Navarra, Pamplona, Spain.
FAU - Calvo, Alfonso
AU  - Calvo A
AD  - IDISNA and Program in Solid Tumors, Center for Applied Medical Research (CIMA), 
      University of Navarra, 31008, Pamplona, Navarra, Spain; Department of Pathology, 
      Anatomy and Physiology, School of Medicine, University of Navarra, 31008, 
      Pamplona, Navarra, Spain; CIBERONC, ISC-III, Spain. Electronic address: 
      acalvo@unav.es.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20190321
PL  - Ireland
TA  - Cancer Lett
JT  - Cancer letters
JID - 7600053
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Membrane Proteins)
RN  - 04Q9AIZ7NO (Pemetrexed)
RN  - 15H5577CQD (Docetaxel)
RN  - 6PLQ3CP4P3 (Etoposide)
RN  - EC 3.4.21.- (Serine Endopeptidases)
RN  - EC 3.4.21.- (TMPRSS4 protein, human)
RN  - EC 3.4.21.- (Tmprss4 protein, mouse)
RN  - Q20Q21Q62J (Cisplatin)
RN  - U3P01618RT (Fluorouracil)
RN  - YL5FZ2Y5U1 (Methotrexate)
SB  - IM
MH  - Animals
MH  - Antineoplastic Agents/*pharmacology
MH  - Cell Line, Tumor
MH  - Cell Proliferation/drug effects
MH  - Cisplatin/pharmacology
MH  - Docetaxel/pharmacology
MH  - Etoposide/pharmacology
MH  - Fluorouracil/pharmacology
MH  - HEK293 Cells
MH  - Humans
MH  - Lung Neoplasms/*drug therapy/*enzymology/pathology
MH  - Membrane Proteins/*antagonists & inhibitors/genetics/metabolism
MH  - Methotrexate/pharmacology
MH  - Mice
MH  - Molecular Targeted Therapy
MH  - Pemetrexed/pharmacology
MH  - Serine Endopeptidases/genetics/metabolism
OTO - NOTNLM
OT  - Apoptosis
OT  - Chemosensitivity
OT  - Metastasis
OT  - Tumor growth
EDAT- 2019/03/25 06:00
MHDA- 2020/03/26 06:00
CRDT- 2019/03/26 06:00
PHST- 2018/09/26 00:00 [received]
PHST- 2019/03/07 00:00 [revised]
PHST- 2019/03/18 00:00 [accepted]
PHST- 2019/03/25 06:00 [pubmed]
PHST- 2020/03/26 06:00 [medline]
PHST- 2019/03/26 06:00 [entrez]
AID - S0304-3835(19)30169-7 [pii]
AID - 10.1016/j.canlet.2019.03.013 [doi]
PST - ppublish
SO  - Cancer Lett. 2019 Jul 1;453:21-33. doi: 10.1016/j.canlet.2019.03.013. Epub 2019 
      Mar 21.