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miR-421 Serum China 90 90 D Wu et al. 2015 [50]
miR-451 Plasma Japan 56 30 D Konishi et al. 2012 [46]
China 200 200 D Zhu et al. 2014 [55]
miR-486-5p Plasma Japan 56 30 D Konishi et al. 2012 [46]
China 200 200 D Zhu et al. 2014 [55]
miR-664 Serum China 118 (with 20 (without P, M Song et al. 2017 [84]
chemotherapy) chemotherapy)
D: diagnostic value; P: prognostic value; M: monitoring value

array-based approach on pre- and postoperative samples . The area under the curve (AUC) values for
[46]
these markers were high, at 0.96 and 0.92, respectively for the diagnosis of gastric cancer . Additionally,
[46]
genome-wide miRNA expression profiles followed by RT-qPCR assays revealed that circulating miR-378
[47]
had an AUC of 0.861 with 87.5% sensitivity and 70.73% specificity . As shown in Table 1, many circulating
miRNAs have been previously identified (by our group and others) as promising blood biomarker candidates
for the detection of gastric cancer: miR-16, miR-17-5p, miR-18a, miR-19b, miR-20a, miR-21, miR-23b, miR-
25, miR-92a, miR-92b, miR-93, miR-100, miR-106, miR-106a, miR-106b, miR-107, miR181c, miR-185, miR-
191, miR-192, miR-199a-3p, miR-200c, miR-210, miR-221, miR-222, miR-223, miR-331, miR-370, miR-378,
miR-421, miR-451, miR-486-5p, and miR-664, all of which are up-regulated in plasma/serum. These are
promising diagnostic biomarkers [32,40,46-55,57,58,69-89] .

LOW LEVEL OF CIRCULATING MICRORNAS IN PLASMA/SERUM IN GASTRIC CANCER
Kosaka et al. [29,59,60] recently suggested that healthy cells secrete some tumor-suppressor miRNAs as a way of
slowing aberrant cell growth. We have previously found that blood-borne tumor-suppressor miRNAs, such as let-
7a and miR-375 [35,45] were significantly downregulated in comparison to those of normal volunteers. Circulating
[32]
miRNAs are released from both normal and cancer tissues, and the majority of these tumor-suppressor miRNAs
are thought to arise from normal tissues. We therefore hypothesize that the progression of cancer causes healthy
cells to become depleted of some tumor-suppressor miRNAs. That hypothesis is supported by our previously
data that shows that a decrease in the plasma level of the tumor-suppressor miR-375 in esophageal cancer
[34]
patients and this is correlated with reduced survival. We have also proposed that tumor progression and
[61]
the resultant poor prognostic outcomes are correlated with the downregulation of tumor-suppressor miRNAs
in the bloodstream [34,35] . As shown in Table 2, various circulating tumor-suppressor miRNAs have previously
been identified as promising blood biomarker candidates for the detection and diagnosis of gastric cancer. These
include miR-15a, miR-17, miR-26a, miR-31, miR-92a, miR-93, miR-106b, miR-122, miR-181b, miR-195-5p, miR-
203, miR-204, miR-206, miR-218, miR-375, miR-503, miR-940, and let-7a, which are downregulated in plasma/
serum with a great degree of diagnostic ability [32,52,56,62,75,79,84,90-100] .

CIRCULATING MICRORNAS RELATED TO MALIGNANT POTENTIAL, TUMOR RECURRENCE,
AND PROGNOSIS BIOMARKERS IN PLASMA/SERUM IN GASTRIC CANCER
Wang et al. have reported that high levels of plasma miR-17-5p and miR-20a were significantly correlated
[70]
with poor overall survival in gastric cancer patients. Valladares-Ayerbes et al. have also reported that
[49]
higher expression levels of miR-200c in blood are associated with poor overall survival. We demonstrated
that the postoperative cause-specific survival was significantly poorer in gastric cancer patients with high
plasma miR-21 levels than in those with low levels . Moreover, the incidence of vascular invasion was
[54]
also slightly higher in gastric cancer patients with high miR-21 levels, and multivariate analysis revealed
that the presence of high miR-21 plasma levels was an independent prognostic factor . Therefore, various
[54]
up-regulated circulating miRNAs have previously been identified as blood-based prognostic biomarkers for
gastric cancer: miR-17-5p, miR-20a, miR-21, miR-23b, miR-25, miR-93, miR-106, miR-106b, miR-200c, miR-
222, and miR-664 [Table 1] [49,53,54,70,74,81,82,84,88] .