Improving Gemcitabine Sensitivity in Pancreatic Cancer Cells by Restoring miRNA-217 Levels.

Concetta Panebianco,Tiziana Pia Latiano,Fulvia Terracciano,Francesco Perri,Annacandida Villani,Nadia Trivieri,Adele Potenza,Elena Binda,Valerio Pazienza

doi:10.3390/biom11050639

Abstract

Chemoresistance is a major problem in the therapeutic management of pancreatic cancer, concurring to poor clinical outcome. A number of mechanisms have been proposed to explain resistance to gemcitabine, a standard of care for this malignancy, among which is included aberrant miRNA expression. In the current study, we investigated the role of miR-217, which is strongly down-regulated in cancerous, compared to normal, pancreatic tissues or cells, in sensitizing human pancreatic cancer cell lines to this drug. The low expression of miR-217 in pancreatic cancer patients was confirmed in two gene expression datasets (GSE41372 and GSE60980), and the prognostic value of two target genes (ANLN and TRPS1), was estimated on clinical data from the Tumor Cancer Genome Atlas (TCGA). Transfecting miR-217 mimic in pancreatic cancer cells reduced viability, enhanced apoptosis, and affected cell cycle by promoting a S phase arrest in gemcitabine-treated cells. Moreover, in drug-exposed cells subjected to miR-217 forced expression, a down-regulation for several genes involved in cancer drug resistance was observed, many of which are cell cycle regulators, such as CCND1, CCNE1, CDK2, CDKN1A, CDKN1B, while others, such as ARNT, BRCA1, BRCA2, ELK1, EGFR, ERBB4, and RARA are involved in proliferation and cell cycle progression. Our results support the notion that miR-217 enhances pancreatic cancer sensitivity to gemcitabine, mainly impairing cell cycle progression.

Highlights

The seventh most common cause of death for cancer worldwide and third in developed countries, pancreatic ductal adenocarcinoma (PDAC) is usually a fatal disease [1], with a 5 year survival rate of around 9% from the time of diagnosis [2]
We focused our attention on miR-217, which was shown to be down-regulated in PDAC tissues and cell lines compared to their noncancerous counterpart [24,25,26,27,28,29,30] and to function as a tumor suppressor miRNA in PDAC [25,26,29,30]
Down-regulated whereas CXCL14, ANLN, and TPRS1 up-regulated in pancreatic cancer (Figure 1C)

Summary

Introduction

The seventh most common cause of death for cancer worldwide and third in developed countries, pancreatic ductal adenocarcinoma (PDAC) is usually a fatal disease [1], with a 5 year survival rate of around 9% from the time of diagnosis [2]. Of PDAC carriers [3], while for the remaining patients gemcitabine-based chemotherapy represents the mainstay treatment [4]. Gemcitabine is activated through three steps of phosphorylation, the first of which, mediated by the Biomolecules 2021, 11, 639. Biomolecules 2021, 11, 639 enzyme deoxycytidine kinase (dCK), is the rate-limiting one. The main mechanism of action of gemcitabine is to discontinue the DNA synthesis: once incorporated, it inhibits chain elongation. The diphosphorylated form of gemcitabine inhibits the enzyme ribonucleotide reductase subunit M1 or M2 (RRM1/RRM2), reducing the cellular pool of deoxyribonucleotides and making gemcitabine more likely to be incorporated into DNA

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