MicroRNA-Regulated Signaling Pathways: Potential Biomarkers for Pancreatic Ductal Adenocarcinoma

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is the most aggressive and invasive type of pancreatic cancer (PCa) and is expected to be the second most common cause of cancer-associated deaths. The high mortality rate is due to the asymptomatic progression of the clinical features until the advanced stages of the disease and the limited effectiveness of the current therapeutics. Aberrant expression of several microRNAs (miRs/miRNAs) has been related to PDAC progression and thus they could be potential early diagnostic, prognostic, and/or therapeutic predictors for PDAC. miRs are small (18 to 24 nucleotides long) non-coding RNAs, which regulate the expression of key genes by targeting their 3′-untranslated mRNA region. Increased evidence has also suggested that the chemoresistance of PDAC cells is associated with metabolic alterations. Metabolic stress and the dysfunctionality of systems to compensate for the altered metabolic status of PDAC cells is the foundation for cellular damage. Current data have implicated multiple systems as hallmarks of PDAC development, such as glutamine redox imbalance, oxidative stress, and mitochondrial dysfunction. Hence, both the aberrant expression of miRs and dysregulation in metabolism can have unfavorable effects in several biological processes, such as apoptosis, cell proliferation, growth, survival, stress response, angiogenesis, chemoresistance, invasion, and migration. Therefore, due to these dismal statistics, it is crucial to develop beneficial therapeutic strategies based on an improved understanding of the biology of both miRs and metabolic mediators. This review focuses on miR-mediated pathways and therapeutic resistance mechanisms in PDAC and evaluates the impact of metabolic alterations in the progression of PDAC.

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

“…miR-221 is one of the most oncogenic miRs in PDAC alongside miR-21 (Bloomston et al 2007 ; Uysal-Onganer et al 2021 ; Yang et al 2016 ; Zhang et al 2008 ), while the overexpression of miR-221 has been correlated to a number of malignancies, such as hepatocellular carcinoma, prostate adenocarcinoma, and colorectal carcinoma (Liu et al 2014 ; Tao et al 2014 ; Yau et al 2014 ; Zheng et al 2014 ). Enhanced expression levels of miR-221 are closely associated with platelet-derived growth factor (PDGF)-mediated epidermal–mesenchymal transition phenotype, migration, metastasis, and uncontrolled proliferation of PDAC cells through the inhibition of both mitogen-activated protein kinase (MAPK) and transformation of growth factor β (TGF-β) signalling pathways (Masamune et al 2013 ; Su et al 2013 ; Mortoglou et al 2021a , b ). EMT can be characterized as a key component of the metastatic cascade, which includes the repression of E-cadherin and the activation of genes related to motility and invasion (Kalluri and Weinberg 2009 ).…”

“…Furthermore, upregulation in the expression of miR-155 has been also found in PDAC tissue samples (Papaconstantinou et al 2013 ). Elevated levels in the expression of miR-155 can result in poor survival in PDAC patients due to the development of fibrogenesis, through TGF-β (Greither et al 2010 ; Mortoglou et al 2021a , b ) , while overexpression of this miR has been also associated with an increased progression from pancreatic intraepithelial neoplasia 2 (PanIN-2) to PanIN-3 (Ryan et al 2014 ). On the other hand, miR-126 is a tumour suppressor miR, which has been linked to PDAC progression, through the post-transcriptional upregulation of KRAS (Jiao et al 2012 ) and HER2 (Garajová et al 2014 ).…”

“…On the other hand, miR-126 is a tumour suppressor miR, which has been linked to PDAC progression, through the post-transcriptional upregulation of KRAS (Jiao et al 2012 ) and HER2 (Garajová et al 2014 ). HER2 overexpression is observed in more than 30% of PDAC cases (Komoto et al 2009 ; Mortoglou et al 2021a , b ).…”

“…In metastatic process, EMT is responsible for the loss of epithelial cell polarity and cell–cell adhesion (Brabletz et al 2018 ; Ye et al 2017 ), while studies have shown that miRs are linked to the moderation of EMT, stem cell-like differentiation, invasiveness, migration, and proliferation (Piasecka et al 2018 ; Mortoglou et al 2021a , b ). Specifically, EMT is involved in increased tumorigenesis, invasiveness, and metastatic predisposition of several solid tumours including prostate, lung, liver, pancreatic, and breast cancers (Hugo et al 2007 ; Lee et al 2006 ; Ribatti et al 2020 ).…”

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

“…The most common genetic alterations, that are correlated with PDAC prognosis are genetic aberrations in proto-oncogenes including Kirsten rat sarcoma viral homolog ( K-RAS ) and tumour suppressor genes, such as cyclin-dependent kinase inhibitor 2A ( CDKN2A ), tumour protein 53 ( TP53 ) and SMAD family number 4 ( SMAD4 ) [ 5 , 6 , 7 , 8 ]. Recent studies have suggested modifiable risk factors for PDAC such as chronic pancreatitis, diabetes mellitus, and environmental exposures comprising the inhalation of cigarette smoke and exposure to toxic metals, including arsenic, nickel (Ni), and cadmium (Cd) [ 9 , 10 , 11 , 12 ].…”