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Authors Tang XF, Cao Y, Peng DB, Zhao GS, Zeng Y, Gao ZR, Lv YF, Guo QN
Received 27 August 2018
Accepted for publication 19 November 2018
Published 8 January 2019 Volume 2019:11 Pages 547—559
DOI https://doi.org/10.2147/CMAR.S185495
Checked for plagiarism Yes
Review by Single-blind
Peer reviewers approved by Dr Justinn Cochran
Peer reviewer comments 2
Editor who approved publication: Dr Kenan Onel
Background: Notch
signaling abnormalities are associated with the development of various tumors,
including hematopoietic and epithelium-derived tumors. However, the role of
Notch signaling in tumors originating from mesenchymal cells is unclear. The
effect of Notch3 expression on the prognosis of osteosarcoma and its role and
mechanism in osteosarcoma cells have never been reported.
Materials and methods: In this
study, we performed a clinicopathological analysis of 70 cases of osteosarcoma,
with primary focus on survival. Osteosarcoma cell lines MTH and U2OS were used.
After knockdown of Notch3 by lentiviral transfection and siRNA, the cell cycle,
cell viability, and wound healing capacity were assessed. Subsequently, the
Transwell assay was performed, and the expression levels of hairy and enhancer
of split-1 (Hes1) and matrix metalloproteinase 7 (MMP7) were detected by RT-PCR
and Western blot assay. The expression of MMP7 was also detected after
knockdown of Hes1. Animal experiments were performed by injecting the cell
lines MTH of Notch3 knockdown into mice tail veins and comparing the
development of lung metastasis with the control group.
Results: Comparison of
survival curves showed that Notch3 expression significantly impacts patient
survival. Additionally, multivariate analysis revealed that Notch3 is an
independent prognostic factor for osteosarcoma. In in vivo experiments,
osteosarcoma-associated pulmonary metastasis in nude mice was reduced after
Notch3 silencing. The expression of downstream effector molecule, Hes1, and that
of the invasion and metastasis-associated proteolytic enzyme, MMP7, were
reduced, and MMP7 was further decreased by Hes1 knockdown in in vitro
experiments.
Conclusion: Notch3 is
a prognostic factor for osteosarcoma and might regulate its invasion and metastasis
through the downstream target gene Hes1 and effector MMP7.
Keywords: osteosarcoma,
prognosis, metastasis, Notch3, Hes1, MMP7