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miR-217-5p induces apoptosis by directly targeting PRKCI, BAG3, ITGAV and MAPK1 in colorectal cancer cells

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Journal of Cell Communication and Signaling Aims and scope

Abstract

Apoptosis is a genetically directed process of programmed cell death. A variety of microRNAs (miRNAs), endogenous single-stranded non-coding RNAs of about 22 nucleotides in length have been shown to be involved in the regulation of the intrinsic or extrinsic apoptotic pathways. There is increasing evidence that the aberrant expression of miRNAs plays a causal role in the development of diseases such as cancer. This makes miRNAs promising candidate molecules as therapeutic targets or agents. MicroRNA (miR)-217-5p has been implicated in carcinogenesis of various cancer entities, including colorectal cancer. Here, we analyzed the pro-apoptotic potential of miR-217-5p in a variety of colorecatal cancer cell lines showing that miR-217-5p mimic transfection led to the induction of apoptosis causing the breakdown of mitochondrial membrane potential, externalization of phosphatidylserine, activation of caspases and fragmentation of DNA. Furthermore, elevated miR-217-5p levels downregulated mRNA and protein expression of atypical protein kinase c iota type I (PRKCI), BAG family molecular chaperone regulator 3 (BAG3), integrin subunit alpha v (ITGAV) and mitogen-activated protein kinase 1 (MAPK1). A direct miR-217-5p mediated regulation to those targets was shown by repressed luciferase activity of reporter constructs containing the miR-217-5p binding sites in the 3′ untranslated region. Taken together, our observations have uncovered the apoptosis-inducing potential of miR-217-5p through its regulation of multiple target genes involved in the ERK-MAPK signaling pathway by regulation of PRKCI, BAG3, ITGAV and MAPK1.

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Abbreviations

AEG-1:

Astrocyte-elevated gene-1

AP-1:

Activating protein-1

BAG3:

BAG family molecular chaperone regulator 3

BIRC3:

Baculoviral IAP repeat containing 2

BRCA1:

BRCA1 DNA repair associated

CCCP:

Carbonyl cyanide m-chlorophenyl hydrazine

CRC:

Colorectal cancer

CTNNB1:

Catenin beta 1

DMSO:

Dimethyl sulfoxide

DT:

Death inducing

EGFR:

Epidermal growth factor receptor

ElK1:

Ets like protein 1

ERK:

Extracellular-signal regulated kinase

FCS:

Fetal calf serum

FITC:

Fluorescein isothiocyanate

GAPDH:

Glyceraldehyde 3-phosphate dehydrogenase

HRP:

Horseradish peroxidase

ITGAV:

Integrin subunit alpha v

MAP K1:

Mitogen-activated protein kinase 1

miR:

MicroRNA

MMP:

Mitochondrial membrane potential

MYC:

Transcriptional activator MYC

NF-kB:

Nuclear factor-kappa B

NT:

Non-targeting

PARP:

Poly (ADP-ribose) polymerase

PBS:

Phosphate-buffered saline

PI:

Propidium iodide

PIK3CA:

Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha

PPIA:

Peptidylprolyl isomerase A

PRKCI:

Protein kinase c iota type I

PS:

Phosphatidylserine

RAC1:

Ras-related C3 botulinum toxin substrate 1

RAF1:

Raf-1 proto-oncogene, serine/threonine kinase

SDS-PAGE:

Sodium dodecyl sulfate polyacrylamide gel electrophoresis

siRNA:

Small interfering RNA

SOX2:

Sex determining region Y-box 2

TGFBR2:

Transforming growth factor beta receptor 2

TMRE:

Tetramethylrhodamine ethyl ester perchlorate

TRAIL:

Tumor necrosis factor related apoptosis inducing ligand

UTR:

Untranslated region

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Acknowledgements

HCT 116 cells were kindly provided by Prof. Dr. Verena Jendrossek, IFZ, University of Duisburg-Essen and HT-29 and SW480 were kindly provided by Prof. Dr. Uwe Knippschild, University Hospital Ulm.

Funding

This study was funded by the Postgraduate Scholarships Act of the Ministry for Science, Research and Arts of the federal state government of Baden-Wuerttemberg, Germany. Further acknowledgements address the International Graduate School in Molecular Medicine of Ulm University, Germany, for scientific encouragement and support to Michael Kleemann.

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  1. Marion Flum and Michael Kleemann contributed equally to this work.

Authors and Affiliations

  1. Institute of Applied Biotechnology, University of Applied Sciences Biberach, Hubertus-Liebrecht-Str. 35, 88400, Biberach, Germany

    Marion Flum, Michael Kleemann, Helga Schneider, Benjamin Weis, René Handrick & Kerstin Otte

  2. Faculty of Medicine, University of Ulm, Albert-Einstein-Allee 11, 89079, Ulm, Germany

    Marion Flum

  3. Boehringer Ingelheim Pharma GmbH & Co KG, Cell Culture Development CMB, Birkendorfer Straße 65, 88397, Biberach, Germany

    Simon Fischer

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  1. Marion Flum
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Correspondence to Michael Kleemann.

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Flum, M., Kleemann, M., Schneider, H. et al. miR-217-5p induces apoptosis by directly targeting PRKCI, BAG3, ITGAV and MAPK1 in colorectal cancer cells. J. Cell Commun. Signal. 12, 451–466 (2018). https://doi.org/10.1007/s12079-017-0410-x

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