Journal of Cell Communication and Signaling

, Volume 12, Issue 2, pp 451–466 | Cite as

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

  • Marion Flum
  • Michael Kleemann
  • Helga Schneider
  • Benjamin Weis
  • Simon Fischer
  • René Handrick
  • Kerstin Otte
Research Article

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.

Keywords

Apoptosis Cell death Colorectal cancer miR-217-5p Target analysis 

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

Notes

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.

Compliance with ethical standards

Conflicts of interest

The authors declare no conflict of interest.

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Copyright information

© The International CCN Society 2017

Authors and Affiliations

  • Marion Flum
    • 1
    • 2
  • Michael Kleemann
    • 1
  • Helga Schneider
    • 1
  • Benjamin Weis
    • 1
  • Simon Fischer
    • 3
  • René Handrick
    • 1
  • Kerstin Otte
    • 1
  1. 1.Institute of Applied BiotechnologyUniversity of Applied Sciences BiberachBiberachGermany
  2. 2.Faculty of MedicineUniversity of UlmUlmGermany
  3. 3.Boehringer Ingelheim Pharma GmbH & Co KG, Cell Culture Development CMBBiberachGermany

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