PMID- 29728077
OWN - NLM
STAT- MEDLINE
DCOM- 20190114
LR  - 20210510
IS  - 1471-2407 (Electronic)
IS  - 1471-2407 (Linking)
VI  - 18
IP  - 1
DP  - 2018 May 5
TI  - Neuropilin-1 promotes the oncogenic Tenascin-C/integrin beta3 pathway and modulates 
      chemoresistance in breast cancer cells.
PG  - 533
LID - 10.1186/s12885-018-4446-y [doi]
LID - 533
AB  - BACKGROUND: Neuropilin-1 (NRP-1), a non-tyrosine kinase glycoprotein receptor, is 
      associated with poor prognosis breast cancer, however transcriptomic changes 
      triggered by NRP-1 overexpression and its association with chemoresistance in 
      breast cancer have not yet been explored. METHODS: BT-474 NRP-1 variant cells 
      were generated by stable overexpression of NRP-1 in the BT-474 breast cancer cell 
      line. RNA sequencing and qRT-PCR were conducted to identify differentially 
      expressed genes. The role of an upregulated oncogene, Tenascin C (TNC) and its 
      associated pathway was investigated by siRNA-mediated knockdown. Resistant 
      variants of the control and BT-474 NRP-1 cells were generated by sequential 
      treatment with four cycles of Adriamycin/Cyclophosphamide (4xAC) followed by four 
      cycles of Paclitaxel (4xAC + 4xPAC). RESULTS: NRP-1 overexpression increased 
      cellular tumorigenic behavior. RNA sequencing identified upregulation of an 
      oncogene, Tenascin-C (TNC) and downregulation of several tumor suppressors in 
      BT-474 NRP-1 cells. Additionally, protein analysis indicated activation of the 
      TNC-associated integrin beta3 (ITGB3) pathway via focal adhesion kinase (FAK), Akt 
      (Ser473) and nuclear factor kappa B (NF-kB) p65. siRNA-mediated TNC knockdown 
      ablated the migratory capacity of BT-474 NRP-1 cells and inactivated FAK/Akt473 
      signaling. NRP-1 overexpressing cells downregulated breast cancer resistance 
      protein (BCRP/ABCG2). Consequently, sequential treatment with 
      Adriamycin/Cyclophosphamide (AC) cytotoxic drugs to generate resistant cells 
      indicated that BT-474 NRP-1 cells increased sensitivity to treatment by 
      inactivating NRP-1/ITGB3/FAK/Akt/NF-kB p65 signaling compared to wild-type BT-474 
      resistant cells. CONCLUSIONS: We thus report a novel mechanism correlating high 
      baseline NRP-1 with upregulated TNC/ITGB3 signaling, but decreased ABCG2 
      expression, which sensitizes BT-474 NRP-1 cells to Adriamycin/Cyclophosphamide. 
      The study emphasizes on the targetability of the NRP-1/ITGB3 axis and its 
      potential as a predictive biomarker for chemotherapy response.
FAU - Naik, Adviti
AU  - Naik A
AD  - Department of Biology, College of Science, Sultan Qaboos University, P. O. Box 
      36, Muscat, Oman.
FAU - Al-Yahyaee, Aida
AU  - Al-Yahyaee A
AD  - Department of Genetics, College of Medicine, Sultan Qaboos University, P. O. Box 
      35, Muscat, Oman.
FAU - Abdullah, Nada
AU  - Abdullah N
AD  - Department of Biology, College of Science, Sultan Qaboos University, P. O. Box 
      36, Muscat, Oman.
FAU - Sam, Juda-El
AU  - Sam JE
AD  - Department of Life Sciences, Hogeschool van Arnhem en Nijmegen, Kapittelweg 33, 
      6525, Nijmegen, EN, Netherlands.
FAU - Al-Zeheimi, Noura
AU  - Al-Zeheimi N
AD  - Department of Biology, College of Science, Sultan Qaboos University, P. O. Box 
      36, Muscat, Oman.
FAU - Yaish, Mahmoud W
AU  - Yaish MW
AD  - Department of Biology, College of Science, Sultan Qaboos University, P. O. Box 
      36, Muscat, Oman.
FAU - Adham, Sirin A
AU  - Adham SA
AUID- ORCID: 0000-0002-8349-6202
AD  - Department of Biology, College of Science, Sultan Qaboos University, P. O. Box 
      36, Muscat, Oman. sadham@squ.edu.om.
LA  - eng
GR  - 137/The Research Council of OMAN/
PT  - Journal Article
DEP - 20180505
PL  - England
TA  - BMC Cancer
JT  - BMC cancer
JID - 100967800
RN  - 0 (ABCG2 protein, human)
RN  - 0 (ATP Binding Cassette Transporter, Subfamily G, Member 2)
RN  - 0 (ITGB3 protein, human)
RN  - 0 (Integrin beta3)
RN  - 0 (NRP1 protein, human)
RN  - 0 (Neoplasm Proteins)
RN  - 0 (RNA, Small Interfering)
RN  - 0 (TNC protein, human)
RN  - 0 (Tenascin)
RN  - 144713-63-3 (Neuropilin-1)
SB  - IM
MH  - ATP Binding Cassette Transporter, Subfamily G, Member 2/metabolism
MH  - Antineoplastic Combined Chemotherapy Protocols/*pharmacology/therapeutic use
MH  - Breast Neoplasms/drug therapy/*genetics/pathology
MH  - Drug Resistance, Neoplasm/*genetics
MH  - Female
MH  - Gene Expression Profiling
MH  - *Gene Expression Regulation, Neoplastic
MH  - Gene Knockdown Techniques
MH  - Humans
MH  - Integrin beta3/metabolism
MH  - MCF-7 Cells
MH  - Neoplasm Proteins/metabolism
MH  - Neuropilin-1/genetics/*metabolism
MH  - Oncogenes
MH  - RNA, Small Interfering
MH  - Signal Transduction/*genetics
MH  - Tenascin/*metabolism
MH  - Up-Regulation
PMC - PMC5935908
OTO - NOTNLM
OT  - ABCG2
OT  - Adriamycin
OT  - Breast cancer
OT  - Chemoresistance
OT  - Cyclophosphamide
OT  - Integrin beta 3
OT  - NRP-1
OT  - TNC
COIS- ETHICS APPROVAL AND CONSENT TO PARTICIPATE: Not applicable. COMPETING INTERESTS: 
      The authors declare that they have no competing interests. PUBLISHER'S NOTE: 
      Springer Nature remains neutral with regard to jurisdictional claims in published 
      maps and institutional affiliations.
EDAT- 2018/05/08 06:00
MHDA- 2019/01/15 06:00
PMCR- 2018/05/05
CRDT- 2018/05/06 06:00
PHST- 2017/12/19 00:00 [received]
PHST- 2018/04/26 00:00 [accepted]
PHST- 2018/05/06 06:00 [entrez]
PHST- 2018/05/08 06:00 [pubmed]
PHST- 2019/01/15 06:00 [medline]
PHST- 2018/05/05 00:00 [pmc-release]
AID - 10.1186/s12885-018-4446-y [pii]
AID - 4446 [pii]
AID - 10.1186/s12885-018-4446-y [doi]
PST - epublish
SO  - BMC Cancer. 2018 May 5;18(1):533. doi: 10.1186/s12885-018-4446-y.