miR-342-5p as a Potential Regulator of HER2 Breast Cancer Cell Growth.
Biomarkers, Tumor
/ genetics
Breast Neoplasms
/ genetics
Cell Line, Tumor
Cell Proliferation
/ genetics
Cell Transformation, Neoplastic
/ genetics
Cytochrome-B(5) Reductase
/ genetics
Female
Gene Expression Regulation, Neoplastic
/ genetics
Guanine Nucleotide Exchange Factors
/ genetics
Humans
MicroRNAs
/ genetics
Receptor, ErbB-2
/ metabolism
CYB5R3
HER2 signaling
MAPK
RAPGEF6
miR-342-5p
non-coding.
Journal
MicroRNA (Shariqah, United Arab Emirates)
ISSN: 2211-5374
Titre abrégé: Microrna
Pays: United Arab Emirates
ID NLM: 101631045
Informations de publication
Date de publication:
2019
2019
Historique:
received:
13
06
2018
revised:
20
07
2018
accepted:
03
12
2018
pubmed:
7
12
2018
medline:
24
4
2019
entrez:
7
12
2018
Statut:
ppublish
Résumé
HER2 positive Breast Cancers (BC) have aggressive behavior and poor prognosis. Previously, we have identified miR-342-5p as an upstream regulator of HER2 signaling, as well as inhibitor of HER2 positive BC cell line growth. Here, we aimed to further investigate the molecular mechanisms behind miR-342-5pinduced HER2 pathway deregulation. Two HER2 amplified breast cancer cell lines were transiently transfected with miR-342-5p mimic or negative control, and gene expression was analyzed by Agilent microarrays. Three clinical datasets with BC patients were used to identify correlations between candidate genes and miR-342- 5p, and associations with survival. Pathway analyses of all deregulated genes revealed a significant suppression of the HER2 downstream pathways ERK/MAPK and SAPK/JNK, whereas the miR-342-5p predicted target genes were enriched for pathways associated with cell motility.Biological functions linked to mitochondrial stability were ranked among the top toxicological functions in both gene lists. Among the most deregulated genes, Cytochrome B5 Reductase 3 (CYB5R3) and Rap Guanine Nucleotide Exchange Factor 6 (RAPGEF6) significantly anticorrelated and correlated, respectively, with miR-342-5p in all three clinical BC datasets. Low CYB5R3 levels and high RAPGEF6 levels were significantly associated with survival, although this was not directly associated with HER2 expression. Our data suggest that miR-342-5p overexpression in HER2 positive BC cell lines elicits broad effects on HER2 downstream signaling, cell motility and mitochondrial stability. Together these effects may render cells less proliferative and more sensitive to cellular stress.
Sections du résumé
BACKGROUND
HER2 positive Breast Cancers (BC) have aggressive behavior and poor prognosis. Previously, we have identified miR-342-5p as an upstream regulator of HER2 signaling, as well as inhibitor of HER2 positive BC cell line growth.
OBJECTIVE
Here, we aimed to further investigate the molecular mechanisms behind miR-342-5pinduced HER2 pathway deregulation.
METHOD
Two HER2 amplified breast cancer cell lines were transiently transfected with miR-342-5p mimic or negative control, and gene expression was analyzed by Agilent microarrays. Three clinical datasets with BC patients were used to identify correlations between candidate genes and miR-342- 5p, and associations with survival.
RESULTS
Pathway analyses of all deregulated genes revealed a significant suppression of the HER2 downstream pathways ERK/MAPK and SAPK/JNK, whereas the miR-342-5p predicted target genes were enriched for pathways associated with cell motility.Biological functions linked to mitochondrial stability were ranked among the top toxicological functions in both gene lists. Among the most deregulated genes, Cytochrome B5 Reductase 3 (CYB5R3) and Rap Guanine Nucleotide Exchange Factor 6 (RAPGEF6) significantly anticorrelated and correlated, respectively, with miR-342-5p in all three clinical BC datasets. Low CYB5R3 levels and high RAPGEF6 levels were significantly associated with survival, although this was not directly associated with HER2 expression.
CONCLUSION
Our data suggest that miR-342-5p overexpression in HER2 positive BC cell lines elicits broad effects on HER2 downstream signaling, cell motility and mitochondrial stability. Together these effects may render cells less proliferative and more sensitive to cellular stress.
Identifiants
pubmed: 30520388
pii: MIRNA-EPUB-95080
doi: 10.2174/2211536608666181206124922
doi:
Substances chimiques
Biomarkers, Tumor
0
Guanine Nucleotide Exchange Factors
0
MIRN342 microRNA, human
0
MicroRNAs
0
RAPGEF6 protein, human
0
CYB5R3 protein, human
EC 1.6.2.2
Cytochrome-B(5) Reductase
EC 1.6.2.2
Receptor, ErbB-2
EC 2.7.10.1
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
155-165Informations de copyright
Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.