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The microRNA expression signature of pancreatic ductal adenocarcinoma by RNA sequencing: anti-tumour functions of the microRNA-216 cluster.

ABSTRACT: We analysed the RNA sequence-based microRNA (miRNA) signature of pancreatic ductal adenocarcinoma (PDAC). Aberrantly expressed miRNAs were successfully identified in this signature. Using the PDAC signature, we focused on 4 clustered miRNAs, miR-216a-5p, miR-216a-3p, miR-216b-5p and miR-216b-3p on human chromosome 2p16.1. All members of the miR-216 cluster were significantly reduced in PDAC specimens. Ectopic expression of these miRNAs suppressed cancer cell aggressiveness, suggesting miR-216 cluster as anti-tumour miRNAs in PDAC cells. The impact of miR-216b-3p (passenger strand of pre-miR-216b) on cancer cells is still ambiguous. Forkhead box Q1 (FOXQ1) was directly regulated by miR-216b-3p and overexpression of FOXQ1 was confirmed in clinical specimens. High expression of FOXQ1 predicted a shorter survival of patients with PDAC by Kaplan-Meier analysis. Loss-of-function assays showed that cancer cell migration and invasion activities were significantly reduced by siFOXQ1 transfectants. We investigated pathways downstream from FOXQ1 by using genome-wide gene expression analysis. Identification of the miR-216-3p/FOXQ1-mediated network in PDAC should enhance understanding of PDAC aggressiveness at the molecular level.

SUBMITTER: Yonemori K

PROVIDER: S-EPMC5642539 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

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The microRNA expression signature of pancreatic ductal adenocarcinoma by RNA sequencing: anti-tumour functions of the microRNA-216 cluster.

Yonemori Keiichi K Seki Naohiko N Idichi Tetsuya T Kurahara Hiroshi H Osako Yusaku Y Koshizuka Keiichi K Arai Takayuki T Okato Atsushi A Kita Yoshiaki Y Arigami Takaaki T Mataki Yuko Y Kijima Yuko Y Maemura Kosei K Natsugoe Shoji S

Oncotarget 20170726 41

We analysed the RNA sequence-based microRNA (miRNA) signature of pancreatic ductal adenocarcinoma (PDAC). Aberrantly expressed miRNAs were successfully identified in this signature. Using the PDAC signature, we focused on 4 clustered miRNAs, miR-216a-5p, miR-216a-3p, miR-216b-5p and miR-216b-3p on human chromosome 2p16.1. All members of the miR-216 cluster were significantly reduced in PDAC specimens. Ectopic expression of these miRNAs suppressed cancer cell ag ...[more]

PMID: 29050264

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Project description:Background & aimsPancreatic ductal adenocarcinomas (PDACs) frequently metastasize to the lymph nodes; strategies are needed to identify patients at highest risk for lymph node metastases. We performed genome-wide expression profile analyses of PDAC specimens, collected during surgery or endoscopic ultrasound-guided fine-need aspiration (EUS-FNA), to identify a microRNA (miRNA) signature associated with metastasis to lymph nodes.MethodsFor biomarker discovery, we analyzed miRNA expression profiles of primary pancreatic tumors from 3 public data sets (The Cancer Genome Atlas, GSE24279, and GSE32688). We then analyzed 157 PDAC specimens (83 from patients with lymph node metastases and 74 without) from Japan, collected from 2001 through 2017, for the training cohort and 107 PDAC specimens (63 from patients with lymph node metastases and 44 without) from a different medical center in Japan, from 2002 through 2016, for the validation cohort. We also analyzed samples collected by EUS-FNA before surgery from 47 patients (22 patients with lymph node metastases and 25 without; 17 for the training cohort and 30 from the validation cohort) and 62 specimens before any treatment from patients who received neoadjuvant chemotherapy (9 patients with lymph node metastasis and 53 without) for additional validation. Multivariate logistic regression analyses were used to evaluate the statistical differences in miRNA expression between patients with vs without metastases.ResultsWe identified an miRNA expression pattern associated with diagnosis of PDAC metastasis to lymph nodes. Using logistic regression analysis, we optimized and trained a 6-miRNA risk prediction model for the training cohort; this model discriminated patients with vs without lymph node metastases with an area under the curve (AUC) of 0.84 (95% confidence interval [CI], 0.77-0.89). In the validation cohort, the model identified patients with vs without lymph node metastases with an AUC of 0.73 (95% CI, 0.64-0.81). In EUS-FNA biopsy samples, the model identified patients with vs without lymph node metastases with an AUC of 0.78 (95% CI, 0.63-0.89). The miRNA expression pattern was an independent predictor of PDAC metastasis to lymph nodes in the validation cohort (odds ratio, 17.05; 95% CI, 2.43-119.57) and in the EUS-FNA cohort (95% CI, 0.65-0.87).ConclusionsUsing data and tumor samples from 3 independent cohorts, we identified an miRNA signature that identifies patients at risk for PDAC metastasis to lymph nodes. The signature has similar levels of accuracy in the analysis of resected tumor specimens and EUS-FNA biopsy specimens. This model might be used to select treatment and management strategies for patients with PDAC.

Project description:BackgroundPancreatic ductal adenocarcinoma (PDAC) is considered as one of the most aggressive cancers lacking efficient early detection biomarkers. Circulating miRNAs are now being considered to have potency to be used as diagnostic and prognostic biomarkers in different diseases as well as cancers. In case of cancer, a fraction of the circulating miRNAs is actually derived from the tumour tissue. This fraction would function as stable biomarker for the disease and also would contribute to the understanding of the disease development. There are not many studies exploring this aspect in pancreatic cancer and even there is not much overlap of results between existing studies.MethodsIn order to address that gap, we performed a miRNA microarray analysis to identify differentially expressed circulating miRNAs between PDAC patients and normal healthy individuals and also found two more similar datasets to perform a meta-analysis using a total of 182 PDAC patients and 170 normal, identifying a set of miRNAs significantly altered in patient serum. Next, we found five datasets studying miRNA expression profile in tumour tissues of PDAC patients as compared to normal pancreas and performed a second meta-analysis using data from a total of 183 pancreatic tumour and 47 normal pancreas to detect significantly deregulated miRNAs in pancreatic carcinoma. Comparison of these two lists and subsequent search for their target genes which were also deregulated in PDAC in inverse direction to miRNAs was done followed by investigation of their role in disease development.ResultsWe identified 21 miRNAs altered in both pancreatic tumour tissue and serum. While deciphering the functions of their target genes, we characterized key miR-Gene interactions perturbing the biological pathways. We identified important cancer related pathways, pancreas specific pathways, AGE-RAGE signaling, prolactin signaling and insulin resistance signaling pathways among the most affected ones. We also reported the possible involvement of crucial transcription factors in the process.ConclusionsOur study identified a unique meta-signature of 21 miRNAs capable of explaining pancreatic carcinogenesis and possibly holding the potential to act as biomarker for the disease detection which could be explored further.

Dataset Information

The microRNA expression signature of pancreatic ductal adenocarcinoma by RNA sequencing: anti-tumour functions of the microRNA-216 cluster.

Publications

The microRNA expression signature of pancreatic ductal adenocarcinoma by RNA sequencing: anti-tumour functions of the <i>microRNA-216</i> cluster.

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