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

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.

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

Cancers ◽

10.3390/cancers12061693 ◽

2020 ◽

Vol 12 (6) ◽

pp. 1693

Author(s):

Isabelle Flammang ◽

Moritz Reese ◽

Zixuan Yang ◽

Johannes A. Eble ◽

Sameer A. Dhayat

Keyword(s):

Blood Serum ◽

Pancreatic Ductal Adenocarcinoma ◽

Tumor Tissue ◽

Ductal Adenocarcinoma ◽

Uicc Stage ◽

Mesenchymal Transition ◽

Cell Clones ◽

Peritumoral Tissue ◽

Serum Exosomes

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 < 0.001) and upregulation in blood serum of PDAC UICC (Union for International Cancer Control) stage IV (p = 0.016) and serum exosomes of PDAC UICC stages II to IV (p < 0.001). MiR-192-5p expression in tumor tissue was significantly lower as compared to corresponding peritumoral tissue (PDAC UICC stage II: p < 0.001; PDAC UICC stage III: p = 0.024), 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 0.86; p < 0.0001) and exosomal (AUC of 0.83; p = 0.0004) 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 = 0.029). 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.

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Tumor-derived exosomal long noncoding RNA LINC01133, regulated by Periostin, contributes to pancreatic ductal adenocarcinoma epithelial-mesenchymal transition through the Wnt/β-catenin pathway by silencing AXIN2

Oncogene ◽

10.1038/s41388-021-01762-0 ◽

2021 ◽

Vol 40 (17) ◽

pp. 3164-3179

Author(s):

Yang Liu ◽

Tianchi Tang ◽

Xiaosheng Yang ◽

Peng Qin ◽

Pusen Wang ◽

...

Keyword(s):

Pancreatic Ductal Adenocarcinoma ◽

Noncoding Rna ◽

Pancreatic Tumor ◽

Epithelial Mesenchymal Transition ◽

Noncoding Rnas ◽

Ductal Adenocarcinoma ◽

Overall Survival Rate ◽

Poor Overall Survival ◽

Mesenchymal Transition ◽

Pancreatic Cancer Cells

AbstractPancreatic ductal adenocarcinoma (PDAC) is one of the most fatal malignancies and rapidly progressive diseases. Exosomes and long noncoding RNAs (lncRNAs) are emerging as vital mediators in tumor cells and their microenvironment. However, the detailed roles and mechanisms of exosomal lncRNAs in PDAC progression remain unknown. Here, we aimed to clarify the clinical significance and mechanisms of exosomal lncRNA 01133 (LINC01133) in PDAC. We analyzed the expression of LINC01133 in PDAC and found that exosomal LINC01133 expression was high and positively correlated with higher TNM stage and poor overall survival rate of PDAC patients. Further research demonstrated that Periostin could increase exosome secretion and then enhance LINC01133 expression. In addition, Periostin increased p-EGFR, p-Erk, and c-myc expression, and c-myc could bind to the LINC01133 promoter region. These findings suggested that LINC01133 can be regulated by Periostin via EGFR pathway activity. We also observed that LINC01133 promoted the proliferation, migration, invasion, and epithelial–mesenchymal transition (EMT) of pancreatic cancer cells. We subsequently evaluated the effect of LINC01133 on the Wnt/β-catenin pathway and confirmed that LINC01133 can interact with Enhancer Of Zeste Homolog 2 (EZH2) and then promote H3K27 trimethylation. This can further silence AXIN2 and suppress GSK3 activity, ultimately activating β-catenin. Collectively, these data indicate that exosomal LINC01133 plays an important role in pancreatic tumor progression, and targeting LINC01133 may provide a potential treatment strategy for PDAC.

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High Clinical Value of Liquid Biopsy to Detect Circulating Tumor Cells and Tumor Exosomes in Pancreatic Ductal Adenocarcinoma Patients Eligible for Up-Front Surgery

Cancers ◽

10.3390/cancers11111656 ◽

2019 ◽

Vol 11 (11) ◽

pp. 1656 ◽

Cited By ~ 12

Author(s):

Etienne Buscail ◽

Catherine Alix-Panabières ◽

Pascaline Quincy ◽

Thomas Cauvin ◽

Alexandre Chauvet ◽

...

Keyword(s):

Pancreatic Ductal Adenocarcinoma ◽

Tumor Cells ◽

Circulating Tumor Cells ◽

Liquid Biopsy ◽

Neoadjuvant Treatment ◽

Digital Pcr ◽

Portal Blood ◽

Ductal Adenocarcinoma ◽

Clinical Value ◽

Liquid Biopsies

Purpose: Expediting the diagnosis of pancreatic ductal adenocarcinoma (PDAC) would benefit care management, especially for the start of treatments requiring histological evidence. This study evaluated the combined diagnostic performance of circulating biomarkers obtained by peripheral and portal blood liquid biopsy in patients with resectable PDAC. Experimental design: Liquid biopsies were performed in a prospective translational clinical trial (PANC-CTC #NCT03032913) including 22 patients with resectable PDAC and 28 noncancer controls from February to November 2017. Circulating tumor cells (CTCs) were detected using the CellSearch® method or after RosetteSep® enrichment combined with CRISPR/Cas9-improved KRAS mutant alleles quantification by droplet digital PCR. CD63 bead-coupled Glypican-1 (GPC1)-positive exosomes were quantified by flow cytometry. Results: Liquid biopsies were positive in 7/22 (32%), 13/22 (59%), and 14/22 (64%) patients with CellSearch® or RosetteSep®-based CTC detection or GPC1-positive exosomes, respectively, in peripheral and/or portal blood. Liquid biopsy performance was improved in portal blood only with CellSearch®, reaching 45% of PDAC identification (5/11) versus 10% (2/22) in peripheral blood. Importantly, combining CTC and GPC1-positive-exosome detection displayed 100% of sensitivity and 80% of specificity, with a negative predictive value of 100%. High levels of GPC1+-exosomes and/or CTC presence were significantly correlated with progression-free survival and with overall survival when CTC clusters were found. Conclusion: This study is the first to evaluate combined CTC and exosome detection to diagnose resectable pancreatic cancers. Liquid biopsy combining several biomarkers could provide a rapid, reliable, noninvasive decision-making tool in early, potentially curable pancreatic cancer. Moreover, the prognostic value could select patients eligible for neoadjuvant treatment before surgery. This exploratory study deserves further validation.

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HMGA1 correlates with advanced tumor grade and decreased survival in pancreatic ductal adenocarcinoma

Modern Pathology ◽

10.1038/modpathol.2009.139 ◽

2009 ◽

Vol 23 (1) ◽

pp. 98-104 ◽

Cited By ~ 56

Author(s):

Alexandra C Hristov ◽

Leslie Cope ◽

Francescopaolo Di Cello ◽

Marcelo Delos Reyes ◽

Mansher Singh ◽

...

Keyword(s):

Pancreatic Ductal Adenocarcinoma ◽

Tumor Grade ◽

Ductal Adenocarcinoma ◽

Advanced Tumor

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Upregulated MicroRNA-483-3p is an Early Event in Pancreatic Ductal Adenocarcinoma (PDAC) and as a Powerful Liquid Biopsy Biomarker in PDAC

OncoTargets and Therapy ◽

10.2147/ott.s288936 ◽

2021 ◽

Vol Volume 14 ◽

pp. 2163-2175

Author(s):

Huilin Shao ◽

Yue Zhang ◽

Jie Yan ◽

Xinchao Ban ◽

Xiaojie Fan ◽

...

Keyword(s):

Pancreatic Ductal Adenocarcinoma ◽

Liquid Biopsy ◽

Ductal Adenocarcinoma ◽

Early Event

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Survival Analysis of Multi-Omics Data Identifies Potential Prognostic Markers of Pancreatic Ductal Adenocarcinoma

Frontiers in Genetics ◽

10.3389/fgene.2019.00624 ◽

2019 ◽

Vol 10 ◽

Cited By ~ 13

Author(s):

Nitish Kumar Mishra ◽

Siddesh Southekal ◽

Chittibabu Guda

Keyword(s):

Survival Analysis ◽

Pancreatic Ductal Adenocarcinoma ◽

Prognostic Markers ◽

Ductal Adenocarcinoma ◽

Omics Data

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Mo1344 DEVELOPMENT OF A NOVEL CIRCULAR RNA-BASED, NONINVASIVE LIQUID BIOPSY ASSAY FOR THE EARLY DETECTION OF PANCREATIC DUCTAL ADENOCARCINOMA

Gastroenterology ◽

10.1016/s0016-5085(20)32821-3 ◽

2020 ◽

Vol 158 (6) ◽

pp. S-857

Author(s):

SOUVIK GHATAK ◽

Satoshi Nishiwada ◽

Eunsung Jun ◽

Fuminori Sonohara ◽

Yasuhiro Kodera ◽

...

Keyword(s):

Early Detection ◽

Pancreatic Ductal Adenocarcinoma ◽

Liquid Biopsy ◽

Circular Rna ◽

Ductal Adenocarcinoma

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BRM270 Inhibits the Proliferation of CD44 Positive Pancreatic Ductal Adenocarcinoma Cells via Downregulation of Sonic Hedgehog Signaling

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2019/8620469 ◽

2019 ◽

Vol 2019 ◽

pp. 1-8 ◽

Cited By ~ 4

Author(s):

Do Luong Huynh ◽

Hyebin Koh ◽

Nisansala Chandimali ◽

Jiao Jiao Zhang ◽

Nameun Kim ◽

...

Keyword(s):

Pancreatic Cancer ◽

Pancreatic Ductal Adenocarcinoma ◽

Sonic Hedgehog ◽

Hedgehog Signaling ◽

Ductal Adenocarcinoma ◽

Cell Phenotype ◽

Sonic Hedgehog Signaling ◽

Mesenchymal Transition ◽

Pancreatic Cancer Cells ◽

Adenocarcinoma Cells

Pancreatic cancer has a poor survival rate as compared to other types of cancer. Surface marker CD44 plays important role in epithelial-mesenchymal transition and cancer stem cell phenotype. Therefore, targeting CD44 positive pancreatic cancer cells might enhance therapies effectiveness. Our previous studies indicated the antitumorigenesis effect of BRM270 in osteosarcoma, lung cancer, and glioblastoma; however there is no evidence on BRM270 impacts on pancreatic cancer growth. In this study, we investigated the effect of BRM270 on the isolated CD44 positive pancreatic ductal adenocarcinoma cells (CD44+PDAC). Results showed that CD44 positive cells undergo apoptosis induced by BRM270. Moreover, BRM270 also inhibits stemness and metastasis traits in CD44+PDAC via Sonic hedgehog signaling pathway and SALL4 expression.In vivostudy indicated that tumor growth derived from CD44+PDAC was suppressed as daily uptake by BRM270 5 mg/kg. These data suggest the alternative approach in antipancreatic tumorigenesis via herbal plants extract and selectively targeting CD44+PDAC cells in tumor.

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