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Inhibition of miR301 enhances Akt-mediated cell proliferation by accumulation of PTEN in nucleus and its effects on cell-cycle regulatory proteins
Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
Department of Human Anatomy, School of Medicine in Katowice, Medical University of Silesia, Katowice, Poland.
Institute of Automatic Control, Silesian University of Technology, Gliwice, Poland.
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2016 (English)In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 7, no 15, 20953-20965 p.Article in journal (Refereed) Published
Abstract [en]

Micro-RNAs (miRs) represent an innovative class of genes that act as regulators of gene expression. Recently, the aberrant expression of several miRs has been associated with different types of cancers. In this study, we show that miR301 inhibition influences PI3K-Akt pathway activity. Akt overexpression in MCF7 and MDAMB468 cells caused downregulation of miR301 expression. This effect was confirmed by co-transfection of miR301-modulators in the presence of Akt. Cells overexpressing miR301-inhibitor and Akt, exhibited increased migration and proliferation. Experimental results also confirmed PI3K, PTEN and FoxF2 as regulatory targets for miR301. Furthermore, Akt expression in conjunction with miR301-inhibitor increased nuclear accumulation of PTEN, thus preventing it from downregulating the PI3K-signalling. In summary, our data emphasize the importance of miR301 inhibition on PI3K-Akt pathway-mediated cellular functions. Hence, it opens new avenues for the development of new anti-cancer agents preferentially targeting PI3K-Akt pathway.

Place, publisher, year, edition, pages
Impact Journals, LLC , 2016. Vol. 7, no 15, 20953-20965 p.
Keyword [en]
AKT; PI3K; PTEN; mTOR; miR301
National Category
Cell and Molecular Biology Cell Biology Cancer and Oncology Biochemistry and Molecular Biology
URN: urn:nbn:se:liu:diva-127476DOI: 10.18632/oncotarget.7996ISI: 000375804000140PubMedID: 26967567OAI: diva2:923957

Funding agencies: Cancerfonden [2013/391]; GeCONiI [POIG.02.03.01-24-099/13]

Available from: 2016-04-27 Created: 2016-04-27 Last updated: 2016-06-13Bibliographically approved
In thesis
1. PKB/Akt kinase localization and role in stemness maintenance in cancer
Open this publication in new window or tab >>PKB/Akt kinase localization and role in stemness maintenance in cancer
2016 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Cancer incidence rates have increased over the last decade. Currently available therapies are only moderately effective in targeting cancer cells. Established cancer treatment protocols fail to eliminate populations of cancer stem cells (CSCs), which develop resistance against the chemotherapeutic drugs and lead to cancer recurrence. Therefore, understanding the mechanisms by which CSCs resist drugs and identifying molecular markers are both necessary to further improve prognosis and to develop new treatment strategies. Increased protein kinase B/Akt1 gene expression and/or activity have been found increased in majority of cancer types. Akt1 is a key player in PI3K-AktmTOR pathway that is vital for cell survival, proliferation, migration, invasion, metastasis, angiogenesis and apoptosis. In this study, we investigated a series of novel markers to improve the characterization of CSCs, with particular focus the roles of Akt in CSC maintenance and the regulatory role of micro-RNA (miR) in cancer cells. While utilizing in breast cancer cells as models, we found that luminescent conjugated oligothiophenes (LCOs), p-HTMI and p-HTAA have the potential to differentially stain various subpopulations of cancer cells, presumably also CSCs among breast cancer cells. However, further studies are needed to confirm these results. Additionally, when we investigated the effect of Akt intracellular compartmentalization on CSC development, the results revealed that nuclear Akt enhances CSC proliferation (ALDH +/High CD44+/High/CD24-/Low) and clonogenicity, which was counter examined and confirmed by using the Aktspecific inibitor triciribine. Furthermore, while investigating the impact of Akt on miR regulation in cancer cells, we found that Akt overexpression decreased.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2016. 60 p.
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1515
National Category
Cancer and Oncology
urn:nbn:se:liu:diva-127477 (URN)10.3384/diss.diva-127477 (DOI)978-91-7685-806-6 (Print) (ISBN)
Public defence
2016-06-01, Belladonna, Campus US, Linköping, 09:00 (English)
Available from: 2016-04-27 Created: 2016-04-27 Last updated: 2016-04-27Bibliographically approved

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