Extracellular vesicle-shuttled miRNAs as a diagnostic and prognostic biomarker and their potential roles in gallbladder cancer patients

Eijiro Ueta,Koichiro Tsutsumi,Hiroyuki Okada,Hidenori Shiraha,Shigeru Horiguchi,Kazuyuki Matsumoto,Hiroshi Matsushita,Masakuni Fujii,Hironari Kato

doi:10.1038/s41598-021-91804-0

Eijiro Ueta, Koichiro Tsutsumi + Show 7 more

Open Access

https://doi.org/10.1038/s41598-021-91804-0

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Journal: Scientific Reports	Publication Date: Jun 10, 2021
Citations: 26	License type: open-access

Affiliation: Okayama University, Okayama University Hospital

Abstract

Circulating microRNAs (miRNAs) in serum extracellular vesicles (EVs) are a promising biomarker in cancer. We aimed to elucidate the serum EVs miRNA biomarkers to identify patients with gallbladder cancer (GBC) and to clarify their potential roles. One hundred nineteen serum EVs from GBC and non-GBC individuals were isolated by pure-EVs-yieldable size-exclusion chromatography, and then were analyzed using a comprehensive miRNAs array and RT-qPCR-based validation. The functional roles of the identified miRNAs were also investigated using GBC cell lines. Serum EVs miR-1246 and miR-451a were significantly upregulated and downregulated, respectively in GBC patients (P = 0.005 and P = 0.001), in line with their expression levels in cancer tissue according to an in silico analysis. The combination of CEA and CA19-9 with miR-1246 showed the highest diagnostic power (AUC, 0.816; Sensitivity, 72.0%; Specificity, 90.8%), and miR-1246 was an independent prognostic marker of GBC (Hazard ratio, 3.05; P = 0.017) according to a Cox proportional hazards model. In vitro, miR-1246 promoted cell proliferation and invasion, while miR-451a inhibited cell proliferation and induced apoptosis with the targeting of MIF, PSMB8 and CDKN2D. Taken together, miR-1246 in serum EVs has potential application as a diagnostic and prognostic marker and miR-451a may be a novel therapeutic target in GBC.

Highlights

Gallbladder cancer (GBC) is among the most common cancers of the biliary system, and has an aggressive pathophysiology[1]
We found that miR-1246 and miR-451a in serum extracellular vesicles (EVs) were significantly upregulated and downregulated in gallbladder cancer (GBC) patients, respectively, in comparison to benign GB patients and healthy controls, using a comprehensive miRNAs assay and RT-qPCR
The overexpression of miR-451a inhibited cell proliferation and induced apoptosis with targeting of MIF, PSMB8 and CDKN2D, suggesting that miR-451a could be a novel therapeutic target in GBC. This is the first report demonstrating the clinical application of miR-1246 in serum EVs as a diagnostic biomarker and an independent prognostic biomarker, and the potential of miR-451a replacement therapy for GBC

Summary

Introduction

Gallbladder cancer (GBC) is among the most common cancers of the biliary system, and has an aggressive pathophysiology[1]. A risk of pancreatitis and cystic duct perforation, and induces patient discomfort Fourth, tumor markers such as carbohydrate antigen 19-9 (CA19-9) and carcinoembryonic antigen (CEA) levels are affected by cholangitis and obstructive jaundice, and show insufficient diagnostic a bility[9].a novel target that facilitates a high-precision early diagnosis and intensive treatment, besides curative resection, of GBC is needed. MicroRNAs (miRNAs) are small noncoding RNA molecules, containing approximately 22 nucleotides They regulate the expression of specific target genes by binding to the 3′-untranslated regions of mRNAs, and either suppressing translation or facilitating mRNA degradation. These epigenetic mechanisms are associated with various diseases, and the miRNA alterations play critical roles in the initiation and progression of cancer. The specific miRNA profiles of GBC remain to be clarified

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