Fibrosis-related miRNAs as serum biomarkers for pancreatic ductal adenocarcinoma.
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ABSTRACT:
SUBMITTER: Suzuki R
PROVIDER: S-EPMC5796986 | biostudies-literature | 2018 Jan
REPOSITORIES: biostudies-literature
Publications
Fibrosis-related miRNAs as serum biomarkers for pancreatic ductal adenocarcinoma.
Suzuki Rei R Asama Hiroyuki H Waragai Yuichi Y Takagi Tadayuki T Hikichi Takuto T Sugimoto Mitsuru M Konno Naoki N Watanabe Ko K Nakamura Jun J Kikuchi Hitomi H Sato Yuki Y Marubashi Shigeru S Masamune Atsushi A Ohira Hiromasa H
Oncotarget 20171217 4
We investigated whether serum microRNAs (miRNAs) could be diagnostic or prognostic markers in pancreatic ductal adenocarcinoma (PDAC). We first identified miRNAs showing altered expression in human pancreatic stellate cells (hPSCs) co-cultured with PDAC cells (Panc-1 and BxPC-3) as compared to hPSCs cultured alone. Among the miRNAs with altered expression, let-7d exhibited reduced expression in an <i>in silico</i> analysis of The Cancer Genome Atlas data. Inhibition of let-7d resulted in enhance ...[more]
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Project description:Background: Sensitive and specific non-invasive biomarkers are urgently needed in order to improve the survival of patients with pancreatic ductal adenocarcinoma (PDAC), which is the fourth leading cause of cancer-related death. We aim to identify serum hub miRNAs as potential diagnostic and prognostic biomarkers for PDAC. Methods: A total of 2578 serum miRNA expression data from 88 PDAC patients and 19 healthy subjects were downloaded from the Gene Expression Omnibus database. Weighted gene co-expression network analysis (WGCNA) was constructed and significant modules were extracted from the network by WGCNA R package. Network modules and hub miRNAs closely related to PDAC were identified. The prognostic value of hub miRNAs was assessed by Kaplan-Meier overall survival analysis. Results: Two modules strongly associated with PDAC were identified by WGCNA, which were labeled as turquoise and brown respectively. Within each module, twenty hub miRNAs were found. At the functional level, turquoise module was mainly associated with tumorigenesis pathways such as P53 and WNT signaling pathway, while the brown module was mostly related to the pathways of cancer such as RNA transport and MAPK signaling pathway. Utilizing overall survival analyses, five "real" miRNAs were able to stratify PDAC patients into low-risk and high-risk groups. Conclusions: The association of specific Hub miRNAs with the development of pancreatic cancer was established by WGCNA analysis. Five miRNAs (mir-16-2-3p, mir-890, mir-3201, mir-602, and mir-877) were identified as potential diagnostic and prognostic biomarkers for PDAC.
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Project description:Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal common cancer because of late diagnosis. Novel biomarkers for PDAC early detection are urgently needed. tRNA-derived small RNAs (tsRNAs) are novel small RNAs might serve as biomarkers for cancer diagnosis and participate in diverse physiological and pathological process. We investigated whether the expression of tsRNAs in serum could be a noninvasive method in the early detection of PDAC. Blood sample of PDAC patients and healthy controls were collected from Ruijin Hospital, Shanghai, China. Tumor and adjacent normal pancreas tissues were collected from 51 patients with PDAC undergoing therapeutic surgery. The testing cohort comprised 6 PDAC patients and 6 healthy controls and the expression of small RNAs in serum was analyzed by small RNA sequence. We verified the diagnostic performance of serum tsRNAs by qPCR in validation cohort including 110 PDAC patients and 100 healthy controls. Expression level of tsRNAs in tissue was also verified in another independent cohort including 51 tumor and 51 adjacent normal pancreas tissues. Unpaired t-test and paired t-test are used for comparing depending on whether the samples are paired. The predictive performance of tsRNAs was evaluated by Kaplan-Meier survival and receiver operating characteristic (ROC) curve. There were 45 tsRNAs expressed at remarkably higher levels, 6 tsRNAs expressed at lower levels in PDAC patients, respectively, compared with healthy volunteers. tsRNA-ValTAC-41, tsRNA-MetCAT-37 and tsRNA-ThrTGT-23 expressed significant highly (P < 0.05) in serum of PDAC patients in validation cohort. tsRNA-ValTAC-41 or tsRNA-MetCAT-37 combined with CA19-9 could increase the AUC of PDAC prediction (AUC = 0.947 and 0.949 respectively), relative to CA19-9 test alone. Besides, patients with higher serum tsRNA-ValTAC-41 level showed shorter overall survival (OS). tsRNA-ValTAC-41 also expressed at remarkably higher level in tumor tissue, and it was obviously associated with tumor staging both in serum and tissue. We provide tsRNAs profiles observed by small RNA sequencing. The diagnostic accuracy of tsRNA-ValTAC-41 and tsRNA-MetCAT-37 in serum of PDAC patients were verified. Further studies for tsRNA-ValTAC-41 are needed to confirm the findings. These tsRNAs may be promising and effective candidates in the development of highly sensitive, noninvasive biomarkers for PDAC diagnosis.
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Project description:Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancer types, partly because it is frequently identified at an advanced stage, when surgery is no longer feasible. Therefore, early detection using minimally invasive methods such as blood tests may improve outcomes. However, studies to discover molecular signatures for the early detection of PDAC using blood tests have only been marginally successful. In the current study, a quantitative glycoproteomic approach via data-independent acquisition mass spectrometry was utilized to detect glycoproteins in 29 patient-matched PDAC tissues and sera. A total of 892 N-linked glycopeptides originating from 141 glycoproteins had PDAC-associated changes beyond normal variation. We further evaluated the specificity of these serum-detectable glycoproteins by comparing their abundance in 53 independent PDAC patient sera and 65 cancer-free controls. The PDAC tissue-associated glycoproteins we have identified represent an inventory of serum-detectable PDAC-associated glycoproteins as candidate biomarkers that can be potentially used for the detection of PDAC using blood tests.
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Project description:Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy. Here we show that shotgun and targeted protein sequencing can be used to identify potential prognostic biomarkers in formalin-fixed paraffin-embedded specimens from 9 patients with PDAC with "short" survival (<12 months) and 10 patients with "long" survival (>45 months) undergoing surgical resection. A total of 24 and 147 proteins were significantly upregulated [fold change ≥2 or ≤0.5 and P<0.05; or different detection frequencies (≥5 samples)] in patients with "short" survival (including GLUT1) and "long" survival (including C9orf64, FAM96A, CDH1 and CDH17), respectively. STRING analysis of these proteins indicated a tight protein-protein interaction network centered on TP53. Ingenuity pathway analysis linked proteins representing "activated stroma factors" and "basal tumor factors" to poor prognosis of PDAC. It also highlighted TCF1 and CTNNB1 as possible upstream regulators. Further parallel reaction monitoring verified that seven proteins were upregulated in patients with "short" survival (MMP9, CLIC3, MMP8, PRTN3, P4HA2, THBS1 and FN1), while 18 proteins were upregulated in patients with "long" survival, including EPCAM, LGALS4, VIL1, CLCA1 and TPPP3. Thus, we verified 25 protein biomarker candidates for PDAC prognosis at the tissue level. Furthermore, an activated stroma status and protein-protein interactions with TP53 might be linked to poor prognosis of PDAC.
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Project description:BackgroundFrequent disease relapse and a lack of effective therapies result in a very poor outcome in pancreatic ductal adenocarcinoma (PDAC) patients. Thus, identification of prognostic biomarkers and possible therapeutic targets is essential. Besides their function in cell-cell adhesion, desmogleins may play a role in tumour progression and invasion that has not been investigated in PDAC to date. This study evaluated desmoglein expression as a biomarker in PDAC.MethodsUsing immunohistochemistry, we examined desmoglein 1 (DSG1), desmoglein 2 (DSG2) and desmoglein 3 (DSG3) expression in the tumour tissue of 165 resected PDAC cases. Expression levels were correlated to the patients' clinicopathological parameters and postoperative survival times. We confirmed these results in two independent gene expression data sets.ResultsA total of 36% of the tumours showed high DSG3 expression that correlated significantly with shorter patient survival (P=0.011) and poor tumour differentiation (P<0.001), whereas no such association was detected for DSG1 or DSG2. In RNA-Seq data and in microarray expression data, high DSG3 expression correlated significantly with poor survival (P=0.000356 and P=0.00499).ConclusionsWe identify DSG3 as a negative prognostic biomarker in resected PDAC, as high DSG3 expression is associated with poor overall survival and poor tumour-specific survival. These findings suggest DSG3 and its downstream signalling pathways as possible therapeutic targets in DSG3-expressing PDAC.
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