Nickel’s Role in Pancreatic Ductal Adenocarcinoma: Potential Involvement of microRNAs

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancer types with a limited overall survival rate due to the asymptomatic progression of symptoms in metastatic stages of the malignancy and the lack of an early reliable diagnostic biomarker. MicroRNAs (miRs/miRNAs) are small (~18–24 nucleotides), endogenous, non-coding RNAs, which are closely linked to the development of numerous malignancies comprising PDAC. Recent studies have described the role of environmental pollutants such as nickel (Ni) in PDAC, but the mechanisms of Ni-mediated toxicity in cancer are still not completely understood. Specifically, Ni has been found to alter the expression and function of miRs in several malignancies, leading to changes in target gene expression. In this study, we found that levels of Ni were significantly higher in cancerous tissue, thus implicating Ni in pancreatic carcinogenesis. Hence, in vitro studies followed by using both normal and pancreatic tumor cell lines and increasing Ni concentration increased lethality. Comparing LC50 values, Ni-acetate groups demonstrated lower values needed than in NiCl2 groups, suggesting greater Ni-acetate. Panc-10.05 cell line appeared the most sensitive to Ni compounds. Exposure to Ni-acetate resulted in an increased phospho-AKT, and decreased FOXO1 expression in Panc-10.05 cells, while NiCl2 also increased PTEN expression in Panc-10.05 cells. Specifically, following NiCl2 exposure to PDAC cells, the expression levels of miR-221 and miR-155 were significantly upregulated, while the expression levels of miR-126 were significantly decreased. Hence, our study has suggested pilot insights to indicate that the environmental pollutant Ni plays an important role in the progression of PDAC by promoting an association between miRs and Ni exposure during PDAC pathogenesis.

Environmental Exposure to Metals, Parameters of Oxidative Stress in Blood and Prostate Cancer: Results from Two Cohorts

“…The carcinogenic effects of metal(loid)s have been related to the modification of tumor suppressor gene expression, the activation of redox-sensitive transcription factors and signaling pathways of proteins involved in cell growth, apoptosis, cell cycle regulation, DNA repair, and differentiation [ 28 , 29 , 30 , 31 , 32 ]. Although precise mechanisms of metal-induced toxicity and carcinogenicity are not well understood, oxidative stress has been recognized to have a substantial role in the activation of inflammatory mediators and other cellular processes involved in the initiation and progression of cancer [ 33 ].…”

Nickel as a potential disruptor of thyroid function: benchmark modelling of human data

“…Criteria such as gender, age or cancer stage were not considered as criteria for excluding subjects from the study. The results of this study indicated higher Ni concentration in cancerous tissue was in comparison with the healthy one ( 6 ). Similar to many other toxic metals, Ni is considered to have the potential to cause endocrine disruption in humans.…”

The effects of endocrine-disrupting chemicals (EDCs) on the epigenome-A short overview

“…89 To support research on causality, studies examining content of toxic substances in tissues have been conducted recently, focusing on EDCs such as cadmium or epigenetic mechanisms such as DNA methylation or those modulated by miRNAs. [90][91][92] Before epigenetic data is used in risk assessment, another key point to consider is that epigenetic mechanisms can overlap and intertwine and that the totality of epigenetic-related effects could differ from the sum of individual modifications should be considered. 88,93 Although the present knowledge on epigenetics and EDCs is limited, thus preventing its use in risk assessment at the moment, recent advancements have paved the way for future experimental studies that could result in information needed to apply this knowledge in realworld risk assessment.…”