MicroRNAs in Pancreatic Ductal Adenocarcinoma: New Approaches For Better Diagnosis And Therapy

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive malignancies with less than an 8% 5-year survival rate, which has remained unchanged over the last 50 years. Early detection is particularly difficult due to the lack of disease-specific symptoms and reliable diagnostic biomarkers. Multimodality treatment including chemotherapy, radiotherapy (used sparingly) and surgery has become the standard of care for patients with PDAC. Carbohydrate antigen 19-9 (CA 19-9) is the most common diagnostic biomarker; however, it is not specific enough for asymptomatic patients. MicroRNAs (miRs/miRNAs) are small non-encoding RNA molecules, which have been related with PDAC progression and metastasis. In particular, miR-21, miR-221, miR-155 and miR-126 have to date been shown to be highly dysregulated in human malignancies including PDAC and are involved in numerous cancer-related mechanisms such as cell growth, differentiation, metastasis, invasion, and cell death. The aim of this thesis was to examine the mode of action of miR-21, miR-221, miR-155 and miR-126 in vitro for improved diagnosis and treatment of PDAC and specifically, investigate the role of the oncogenic miR-21 in cellular proliferation, migration, invasion, apoptosis, cell cycle arrest, senescence, protein content and mitochondrial function by using CRISPR/Cas9 knockouts. The findings provide promising new insights into the metastatic predisposition of PDAC through the evaluation of specific miR signature profiles (in vitro). Such miR signatures could prompt a pioneer precision medicine approach for individual PDAC cases and allow a more effective early diagnosis and control of PDAC, facilitating more effective treatment

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

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

Role of cadmium and nickel on selected microrna expression in pancreatic ductal adenocarcinoma

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy, with a 5-year overall survival of less than 8%. 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. ..

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

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

A meta-analysis excerpt: Is exposure to environmental pollutants associated with pancreatic cancer?

Istraživanje u oblasti karcinoma pankreasa i zagađivača iz životne sredine sve je intenzivnije. Za neke od ovih zagađivača pretpostavlja se da su povezani sa nastankom ili progresijom karcinoma pankreasa. Nijedna meta-analiza o povezanosti navedenog nije sprovedena, dok bi rezultati iste mogli pomoći u tumačenju dostupnih podataka i usmeravanju budućeg istraživanja. ...There is a rise in research on the connection between pancreatic cancer and environmental pollutants. Some of these pollutants are assumed to be associated with the onset or progression of pancreatic cancer. No meta-analyses summarizing the association between these two have been conducted yet, while the results of such an analysis could help interpret current and guide future research. ..