Epigenetics is dynamic and heritable modifications to the genome that occur independently of DNA sequence. It requires interactions cohesively with various enzymes and other molecular components. Aberrant epigenetic alterations can lead to inappropriate onset of genetic expressions and promote tumorigenesis. As the epigenetic modifiers are susceptible to extrinsic factors and reversible, they are becoming promising targets in multiple cancer therapies. Recently, various epi-drugs have been developed and implicated in clinical use. The use of epi-drugs alone, or in combination with chemotherapy or immunotherapy, has shown compelling outcomes, including augmentation of anti-tumoral effects, overcoming drug resistance, and activation of host immune response.

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Epigenetic regulation in human cancer: the potential role of epi-drug in cancer therapy

Pancreatic cancer has the worst prognosis among common tumors which is attributed to its aggressive phenotype, diagnosis at advanced, inoperable stages, and resistance to systemic therapy. Non-coding RNAs (ncRNAs) such as microRNAs, long non-coding RNAs, and circular RNAs have been established as important regulators of gene expression and their deregulation has been implicated in multiple diseases and foremost cancer. In the tumor microenvironment, non-coding RNAs can be distributed among cancer cells, stromal cells, and immune cells via small extracellular vesicles (sEVs), thereby facilitating intercellular communication and influencing major cancer hallmarks such as angiogenesis, evasion of the immune system, and metastatic dissemination. Furthermore, sEV-ncRNAs have shown promising potential as liquid biopsies with diagnostic and prognostic significance. In this review, we summarize the role of sEVs as carriers of ncRNAs and underlying molecular mechanisms in pancreatic cancer. Moreover, we review the potential of sEV-ncRNAs as biomarkers and highlight the suitability of sEVs as delivery vehicles for ncRNA-based cancer therapy.

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Small extracellular vesicle non-coding RNAs in pancreatic cancer: molecular mechanisms and clinical implications.

Pancreatic ductal adenocarcinoma (PDAC) is characterized by fast tumor progression and diagnosis at advanced, inoperable stages Previous studies could demonstrate an involvement of miR-192-5p in epigenetic regulation of visceral carcinomas Due to contradictory results, however, the clinical utility of miR-192-5p in PDAC has yet to be determined MiR-192-5p expression was analyzed by RT-qRT-PCR in human PDAC and benign tissue (n = 78), blood serum (n = 81) and serum exosomes (n = 74), as well as in PDAC cell lines (n = 5), chemoresistant cell clones (n = 2), and pancreatic duct cell line H6c7 Analysis of EMT-associated (epithelial-to-mesenchymal transition) proteins was performed by immunohistochemistry and Western blot MiR-192-5p was deregulated in PDAC as compared to healthy controls (HCs), with downregulation in macrodissected tissue (p < 0001) and upregulation in blood serum of PDAC UICC (Union for International Cancer Control) stage IV (p = 0016) and serum exosomes of PDAC UICC stages II to IV (p < 0001) MiR-192-5p expression in tumor tissue was significantly lower as compared to corresponding peritumoral tissue (PDAC UICC stage II: p < 0001; PDAC UICC stage III: p = 0024), while EMT markers ZEB1 and ZEB2 were more frequently expressed in tumor tissue as compared to peritumoral tissue, HCs, and chronic pancreatitis Tissue-derived (AUC of 086; p < 00001) and exosomal (AUC of 083; p = 00004) miR-192-5p could differentiate between PDAC and HCs with good accuracy Furthermore, high expression of miR-192-5p in PDAC tissue of curatively resected PDAC patients correlated with prolonged overall and recurrence-free survival in multivariate analysis In vitro, miR-192-5p was downregulated in gemcitabine-resistant cell clones of AsPC-1 (p = 0029) Transient transfection of MIA PaCa-2 cells with miR-192-5p mimic resulted in downregulation of ZEB2 MiR-192-5p seems to possess a tumor-suppressive role and high potential as a diagnostic and prognostic marker in PDAC

https://www.mdpi.com/2072-6694/12/6/1693/pdf

Tumor-Suppressive miR-192-5p Has Prognostic Value in Pancreatic Ductal Adenocarcinoma.

Early-stage diagnosis of pancreatic ductal adenocarcinoma (PDAC) is difficult due to non-specific symptoms. Circulating miRNAs in body fluids have been emerging as potential non-invasive biomarkers for diagnosis of many cancers. Thus, this study aimed to assess a panel of miRNAs for their ability to differentiate PDAC from chronic pancreatitis (CP), a benign inflammatory condition of the pancreas. Next-generation sequencing was performed to identify miRNAs present in 60 FFPE tissue samples (27 PDAC, 23 CP and 10 normal pancreatic tissues). Four up-regulated miRNAs (miR-215-5p, miR-122-5p, miR-192-5p, and miR-181a-2-3p) and four down-regulated miRNAs (miR-30b-5p, miR-216b-5p, miR-320b, and miR-214-5p) in PDAC compared to CP were selected based on next-generation sequencing results. The levels of these 8 differentially expressed miRNAs were measured by qRT-PCR in 125 serum samples (50 PDAC, 50 CP, and 25 healthy controls (HC)). The results showed significant upregulation of miR-215-5p, miR-122-5p, and miR-192-5p in PDAC serum samples. In contrast, levels of miR-30b-5p and miR-320b were significantly lower in PDAC as compared to CP and HC. ROC analysis showed that these 5 miRNAs can distinguish PDAC from both CP and HC. Hence, this panel can serve as a non-invasive biomarker for the early detection of PDAC.

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Panel of serum miRNAs as potential non-invasive biomarkers for pancreatic ductal adenocarcinoma.

Circulating tumor cells (CTCs) are considered reliable cancer biomarkers for the liquid biopsy of many types of tumors. The direct detection of CTCs in human blood with normal biosensors, however, remains challenging because of severe biofouling in blood that contains various proteins and a large number of cells. Herein, we report the construction of an antifouling electrochemical biosensor capable of assaying CTCs directly in blood, based on a designed multifunctional peptide and the electrodeposited conducting polymer poly(3,4-ethylenedioxythiophene) (PEDOT). The designed peptide possesses antifouling capability in complex biological media and specific recognition ability to capture breast cancer cells MCF-7. Meanwhile, electrodeposited PEDOT can promote electron transfer at the sensing interface, improve the signal-to-noise ratio for the detection, and thus enhance the sensitivity of the biosensor. The integration of the multifunctional peptide and conducting polymer PEDOT ensures that the developed biosensor is able to perform directly in blood samples without purification or separation. The antifouling electrochemical biosensor for the detection of MCF-7 cells exhibits a wide linear range over 4 orders, with a limit of detection (LOD) of 17 cells mL-1. More interestingly, even when performing in 25% human blood, the biosensor still retains a linear response with an LOD of 22 cells mL-1, without suffering significantly from biofouling in real blood. This work provides a promising strategy for the direct analysis of CTCs in human blood without a complicated pretreatment, and it may find practical application in the liquid biopsy of cancers.

Antifouling Electrochemical Biosensor Based on the Designed Functional Peptide and the Electrodeposited Conducting Polymer for CTC Analysis in Human Blood.

Pancreatic ductal adenocarcinoma (PDAC) is a highly malignant tumor entity, characterized by rapid disease progression, early metastatic dissemination, and late diagnosis at advanced tumor stages. Recently, we explored the clinical impact of several microRNAs (miR) associated with proliferation, epithelial-to-mesenchymal transition (EMT), and chemoresistance in tissue and blood serum specimens of PDAC patients. Here, we evaluated the potential of these miRs as diagnostic and prognostic biomarkers in PDAC in serum exosomes and their respective EpCAM-positive (epithelial cell adhesion molecule) subset. Expression analysis by RT-qRT-PCR (real-time quantitative reverse transcription polymerase chain reaction) revealed an overexpression of miR-200b and miR-200c in serum exosomes of PDAC patients as compared to healthy controls (p < 0.001; p = 0.024) and patients with chronic pancreatitis (p = 0.005; p = 0.19). Receiver operating characteristic (ROC) curve analysis showed that a biomarker panel consisting of miR-200b and miR-200c from total and EpCAM-positive serum exosomes enhanced the diagnostic accuracy of carbohydrate antigen 19-9 (CA.19-9) to 97% (p < 0.0001). Univariate survival analysis revealed a correlation between shorter overall survival (OS) and high expression of miR-200c in total serum exosomes (p = 0.038) and miR-200b in EpCAM-positive serum exosomes (p = 0.032), whereas EpCAM exosomal miR-200b was also indicative of shorter OS in the subgroup of patients treated with curative intent (p = 0.013). Multivariate survival analysis showed that miR-200b derived from EpCAM-positive serum exosomes might serve as an independent prognostic factor in PDAC (p = 0.044). Our findings indicate a potential role of exosomal miR-200 as diagnostic and prognostic liquid biopsy marker in PDAC and call for validation in a larger, multicenter setting.

https://www.mdpi.com/2072-6694/12/1/197/pdf

Moritz Reese

Papers

Potential of Exosomal microRNA-200b as Liquid Biopsy Marker in Pancreatic Ductal Adenocarcinoma.

Small extracellular vesicle non-coding RNAs in pancreatic cancer: molecular mechanisms and clinical implications.

Tumor-Suppressive miR-192-5p Has Prognostic Value in Pancreatic Ductal Adenocarcinoma.