MicroRNA therapeutics: design of single-stranded miR-216b mimics to target KRAS in pancreatic cancer cells

Annalisa Ferino, Giulia Miglietta, Raffaella Picco, Stefan Vogel, Jesper Wengel, Luigi E. Xodo*

*Corresponding author for this work

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Abstract

Datasets reporting microRNA expression profiles in normal and cancer cells show that miR-216b is aberrantly downregulated in pancreatic ductal adenocarcinoma (PDAC). We found that KRAS, whose mutant G12D allele drives the pathogenesis of PDAC, is a target of miR-216b. To suppress oncogenic KRAS in PDAC cells, we designed single-stranded (ss) miR-216b mimics with unlocked nucleic acid (UNA) modifications to enhance their nuclease resistance. We prepared variants of ss-miR-216b mimics with and without a 5ʹ phosphate group. Both variants strongly suppressed oncogenic KRAS in PDAC cells and inhibited colony formation in pancreatic cancer cells. We observed that the designed ss-miR-216b mimics engaged AGO2 to promote the silencing of KRAS. We also tested a new delivery strategy based on the use of palmityl-oleyl-phosphatidylcholine (POPC) liposomes functionalized with ss-miR-216b conjugated with two palmityl chains and a lipid-modified cell penetrating peptide (TAT). These versatile nanoparticles suppressed oncogenic KRAS in PDAC cells.

Original languageEnglish
JournalRNA Biology
Volume15
Issue number10
Pages (from-to)1273-1285
ISSN1547-6286
DOIs
Publication statusPublished - 2018

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MicroRNAs
Pancreatic Neoplasms
Cell-Penetrating Peptides
Nucleic Acids
Down-Regulation
Alleles
Lipids
Neoplasms

Keywords

  • AGO2
  • KRAS
  • miR-216b
  • PDAC cells
  • POPC liposome
  • 3' Untranslated Regions/genetics
  • Nanoparticles/administration & dosage
  • Humans
  • Lipids/chemistry
  • Pancreas/metabolism
  • Liposomes/chemistry
  • Proto-Oncogene Proteins p21(ras)/antagonists & inhibitors
  • MicroRNAs/chemistry
  • Argonaute Proteins/genetics
  • Cell Line, Tumor
  • Cell Proliferation/genetics
  • Gene Expression Regulation, Neoplastic/genetics
  • Carcinoma, Pancreatic Ductal/genetics

Cite this

Ferino, Annalisa ; Miglietta, Giulia ; Picco, Raffaella ; Vogel, Stefan ; Wengel, Jesper ; Xodo, Luigi E. / MicroRNA therapeutics : design of single-stranded miR-216b mimics to target KRAS in pancreatic cancer cells. In: RNA Biology. 2018 ; Vol. 15, No. 10. pp. 1273-1285.
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abstract = "Datasets reporting microRNA expression profiles in normal and cancer cells show that miR-216b is aberrantly downregulated in pancreatic ductal adenocarcinoma (PDAC). We found that KRAS, whose mutant G12D allele drives the pathogenesis of PDAC, is a target of miR-216b. To suppress oncogenic KRAS in PDAC cells, we designed single-stranded (ss) miR-216b mimics with unlocked nucleic acid (UNA) modifications to enhance their nuclease resistance. We prepared variants of ss-miR-216b mimics with and without a 5ʹ phosphate group. Both variants strongly suppressed oncogenic KRAS in PDAC cells and inhibited colony formation in pancreatic cancer cells. We observed that the designed ss-miR-216b mimics engaged AGO2 to promote the silencing of KRAS. We also tested a new delivery strategy based on the use of palmityl-oleyl-phosphatidylcholine (POPC) liposomes functionalized with ss-miR-216b conjugated with two palmityl chains and a lipid-modified cell penetrating peptide (TAT). These versatile nanoparticles suppressed oncogenic KRAS in PDAC cells.",
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MicroRNA therapeutics : design of single-stranded miR-216b mimics to target KRAS in pancreatic cancer cells. / Ferino, Annalisa; Miglietta, Giulia; Picco, Raffaella; Vogel, Stefan; Wengel, Jesper; Xodo, Luigi E.

In: RNA Biology, Vol. 15, No. 10, 2018, p. 1273-1285.

Research output: Contribution to journalJournal articleResearchpeer-review

TY - JOUR

T1 - MicroRNA therapeutics

T2 - design of single-stranded miR-216b mimics to target KRAS in pancreatic cancer cells

AU - Ferino, Annalisa

AU - Miglietta, Giulia

AU - Picco, Raffaella

AU - Vogel, Stefan

AU - Wengel, Jesper

AU - Xodo, Luigi E.

PY - 2018

Y1 - 2018

N2 - Datasets reporting microRNA expression profiles in normal and cancer cells show that miR-216b is aberrantly downregulated in pancreatic ductal adenocarcinoma (PDAC). We found that KRAS, whose mutant G12D allele drives the pathogenesis of PDAC, is a target of miR-216b. To suppress oncogenic KRAS in PDAC cells, we designed single-stranded (ss) miR-216b mimics with unlocked nucleic acid (UNA) modifications to enhance their nuclease resistance. We prepared variants of ss-miR-216b mimics with and without a 5ʹ phosphate group. Both variants strongly suppressed oncogenic KRAS in PDAC cells and inhibited colony formation in pancreatic cancer cells. We observed that the designed ss-miR-216b mimics engaged AGO2 to promote the silencing of KRAS. We also tested a new delivery strategy based on the use of palmityl-oleyl-phosphatidylcholine (POPC) liposomes functionalized with ss-miR-216b conjugated with two palmityl chains and a lipid-modified cell penetrating peptide (TAT). These versatile nanoparticles suppressed oncogenic KRAS in PDAC cells.

AB - Datasets reporting microRNA expression profiles in normal and cancer cells show that miR-216b is aberrantly downregulated in pancreatic ductal adenocarcinoma (PDAC). We found that KRAS, whose mutant G12D allele drives the pathogenesis of PDAC, is a target of miR-216b. To suppress oncogenic KRAS in PDAC cells, we designed single-stranded (ss) miR-216b mimics with unlocked nucleic acid (UNA) modifications to enhance their nuclease resistance. We prepared variants of ss-miR-216b mimics with and without a 5ʹ phosphate group. Both variants strongly suppressed oncogenic KRAS in PDAC cells and inhibited colony formation in pancreatic cancer cells. We observed that the designed ss-miR-216b mimics engaged AGO2 to promote the silencing of KRAS. We also tested a new delivery strategy based on the use of palmityl-oleyl-phosphatidylcholine (POPC) liposomes functionalized with ss-miR-216b conjugated with two palmityl chains and a lipid-modified cell penetrating peptide (TAT). These versatile nanoparticles suppressed oncogenic KRAS in PDAC cells.

KW - AGO2

KW - KRAS

KW - miR-216b

KW - PDAC cells

KW - POPC liposome

KW - 3' Untranslated Regions/genetics

KW - Nanoparticles/administration & dosage

KW - Humans

KW - Lipids/chemistry

KW - Pancreas/metabolism

KW - Liposomes/chemistry

KW - Proto-Oncogene Proteins p21(ras)/antagonists & inhibitors

KW - MicroRNAs/chemistry

KW - Argonaute Proteins/genetics

KW - Cell Line, Tumor

KW - Cell Proliferation/genetics

KW - Gene Expression Regulation, Neoplastic/genetics

KW - Carcinoma, Pancreatic Ductal/genetics

U2 - 10.1080/15476286.2018.1526536

DO - 10.1080/15476286.2018.1526536

M3 - Journal article

C2 - 30306823

AN - SCOPUS:85054827631

VL - 15

SP - 1273

EP - 1285

JO - R N A Biology

JF - R N A Biology

SN - 1547-6286

IS - 10

ER -