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

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.

Exosomal microRNAs synergistically trigger stromal fibroblasts in breast cancer

“…In particular, its upregulation has been associated with tumor growth, metastasis, and drug resistance in different types of cancer. 72 , 73 , 74 In breast cancer, exosomal miR-1246 has been used as diagnostic biomarker because of its high expression specificity.…”

Exosomal MicroRNA signature acts as an efficient biomarker for non-invasive diagnosis of gallbladder carcinoma

“…It has been reported that in the diagnosis of GBC, the sensitivity of CEA is only 11.5% and that of CA199 is 71.7% ( Wang et al., 2014 ). In another study, the AUCs of CEA and CA199 were 0.770 (sensitivity = 60%, specificity = 83.3%) and 0.729 (sensitivity = 58%, specificity = 92.6%), respectively ( Ueta et al., 2021 ). Notably, the efficacy of this five exosomal miRNAs-set in GBC diagnosis was better than that of the traditional biomarkers CA199 and CEA when the data from this study and previous studies were compared ( Ueta et al., 2021 ; Wang et al., 2014 ).…”

Meta-analysis of the diagnostic performance of serum carbohydrate antigen 19-9 for the detection of gallbladder cancer

“…There were 20 studies written in Chinese and 7 in English. All were conducted in Asian countries, with 1 in Japan, 28 1 in India, 15 and the rest in China. The overall number of enrolled subjects was 4300, consisting of 1516 patients with GBC and 2784 non-GBC controls (286 healthy individuals and 2498 patients with related benign diseases).…”

“…Regarding study design, only the study of Bind et al 15 was designed prospectively. The majority of studies were single-centered, while six studies 10,16,23,28,29,40 adopted data from at least two centers for analysis. Table 1 shows detailed information on the main characteristics.…”