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Hypoxia-Induced miR-675-5p Supports β-Catenin Nuclear Localization by Regulating GSK3-β Activity in Colorectal Cancer Cell Lines
- Source :
- International Journal of Molecular Sciences, Volume 21, Issue 11, International Journal of Molecular Sciences, Vol 21, Iss 3832, p 3832 (2020)
- Publication Year :
- 2020
- Publisher :
- MDPI, 2020.
-
Abstract
- The reduction of oxygen partial pressure in growing tumors triggers numerous survival strategies driven by the transcription factor complex HIF1 (Hypoxia Inducible Factor-1). Recent evidence revealed that HIF1 promotes rapid and effective phenotypic changes through the induction of non-coding RNAs, whose contribution has not yet been fully described. Here we investigated the role of the hypoxia-induced, long non-coding RNA H19 (lncH19) and its intragenic miRNA (miR-675-5p) into HIF1-Wnt crosstalk. During hypoxic stimulation, colorectal cancer cell lines up-regulated the levels of both the lncH19 and its intragenic miR-675-5p. Loss of expression experiments revealed that miR-675-5p inhibition, in hypoxic cells, hampered &beta<br />catenin nuclear localization and its transcriptional activity, while lncH19 silencing did not induce the same effects. Interestingly, our data revealed that miRNA inhibition in hypoxic cells restored the activity of Glycogen Synthase Kinase 3&beta<br />(GSK-3&beta<br />) reducing the amount of P-Ser9 kinase, thus unveiling a role of the miR-675-5p in controlling GSK-3&beta<br />activity. Bioinformatics analyses highlighted the serine/threonine-protein phosphatases PPP2CA, responsible for GSK-3&beta<br />activation, among the miR-675-5p targets, thus indicating the molecular mediator through which miR-675-5p may control &beta<br />catenin nuclear localization. In conclusion, here we demonstrated that the inhibition of the hypoxia-induced non-coding RNA miR-675-5p hampered the nuclear localization of &beta<br />catenin by regulating GSK-3&beta<br />activity, thus proposing the miR-675-5p as a new therapeutic target for the treatment of colorectal cancer.
- Subjects :
- 0301 basic medicine
Transcription factor complex
Kaplan-Meier Estimate
lcsh:Chemistry
0302 clinical medicine
GSK-3
poxiahy
lcsh:QH301-705.5
long non-coding H19
Spectroscopy
beta Catenin
Kinase
Chemistry
General Medicine
Cell Hypoxia
Computer Science Applications
Cell biology
Gene Expression Regulation, Neoplastic
030220 oncology & carcinogenesis
Colorectal Neoplasms
Protein Binding
Active Transport, Cell Nucleus
colorectal cancer
miR-675
Transfection
Catalysis
Article
Inorganic Chemistry
03 medical and health sciences
Cell Line, Tumor
microRNA
Gene silencing
Humans
Physical and Theoretical Chemistry
Molecular Biology
Glycogen Synthase Kinase 3 beta
hypoxia
Organic Chemistry
RNA
Computational Biology
β-catenin
HCT116 Cells
MicroRNAs
030104 developmental biology
lcsh:Biology (General)
lcsh:QD1-999
Microscopy, Fluorescence
Catenin
Mutation
Nuclear localization sequence
Subjects
Details
- Language :
- English
- ISSN :
- 14220067
- Volume :
- 21
- Issue :
- 11
- Database :
- OpenAIRE
- Journal :
- International Journal of Molecular Sciences
- Accession number :
- edsair.doi.dedup.....0a4e6a99a708d5542cc88b6e85c47228