Role of microRNAs in response to cadmium chloride in pancreatic ductal adenocarcinoma

Maria Mortoglou,Aleksandra Buha Djordjevic,Vladimir Djordjevic,Katherine Mani,David Wallace,Lauren York,Elizabeth Valle,Hunter Collins,Pinar Uysal-Onganer

doi:10.1007/s00204-021-03196-9

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is one of the most fatal and aggressive malignancies with a 5-year survival rate less than 9%. Early detection is particularly difficult due to the lack of symptoms even in advanced stages. microRNAs (miRs/miRNAs) are small (~ 18–24 nucleotides), endogenous, non-coding RNAs, which are involved in the pathogenesis of several malignancies including PDAC. Alterations of miR expressions can lead to apoptosis, angiogenesis, and metastasis. The role of environmental pollutants such as cadmium (Cd) in PDAC has been suggested but not fully understood. This study underlines the role of miRs (miR-221, miR-155, miR-126) in response to cadmium chloride (CdCl2) in vitro. Lethal concentration (LC50) values for CdCl2 resulted in a toxicity series of AsPC-1 > HPNE > BxPC-3 > Panc-1 = Panc-10.5. Following the treatment with CdCl2, miR-221 and miR-155 were significantly overexpressed, whereas miR-126 was downregulated. An increase in epithelial–mesenchymal transition (EMT) via the dysregulation of mesenchymal markers such as Wnt-11, E-cadherin, Snail, and Zeb1 was also observed. Hence, this study has provided evidence to suggest that the environmental pollutant Cd can have a significant role in the development of PDAC, suggesting a significant correlation between miRs and Cd exposure during PDAC progression. Further studies are needed to investigate the precise role of miRs in PDAC progression as well as the role of Cd and other environmental pollutants.

Highlights

Pancreatic ductal adenocarcinoma (PDAC) is the deadliest and most prevalent pancreatic cancer (PCa) type, which accounts for 90% of PCa cases (Von Hoff et al 2009; Hidalgo et al 2015)
The current study found that miR-221 and miR155 were upregulated in metastatic PDAC cell lines treated with CdCl2, while miR-126 was downregulated
Wnt-11, Snail and Zeb1 were considerably upregulated following C dCl2 exposure, while E-cadherin expression level was decreased in PDAC cell lines treated with CdCl2 compared to non-treated cells

Summary

Introduction

PDAC is the deadliest and most prevalent pancreatic cancer (PCa) type, which accounts for 90% of PCa cases (Von Hoff et al 2009; Hidalgo et al 2015). PDAC can be characterized as a “silent killer” and presents the worst prognosis between all cancer types due to the widespread metastasis that patients appear at the time of diagnosis, which is usually in late stages of malignancy (Bortesi et al 2011). Interest in the role of Cd as a toxic metal ubiquitously present in the environment has risen during the last decades, especially with the reference to its possible role in various human diseases, especially carcinomas (Anđelković et al 2021; Buha et al 2018, 2019, 2020). Its possible role in PDAC has been recently reviewed by Buha et al (2017)

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