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Page 2 of 10 Komatsu et al. J Cancer Metastasis Treat 2018;4:36 I http://dx.doi.org/10.20517/2394-4722.2017.58

[1]
gastric cancer continues to constitute a global health problem as a prevalent form of cancer . Gastric cancer
patients at advanced stages of the disease have a very poor prognosis . Despite these continued difficulties,
[2]
no biomarker molecule has been employed for the early diagnosis of gastric cancer in clinical settings, and
researchers have validated only a scant number of molecules as therapeutic targets . Therefore, for gastric
[3-7]
cancer, identifying novel molecular targets and clinical biomarkers remain vital clinical challenges.

Recently, the concept of a “liquid biopsy” has become widely accepted in the clinical setting. Liquid biopsy
is a less approaches for obtaining genetic and epigenetic aberrations that are closely associated with cancer
[8]
initiation and progression . Moreover, liquid approaches allows for repeated sampling and this makes it
possible to evaluate the longitudinal evolution of a tumor and its heterogeneous characteristics, which single
sampling may fail to capture [9-13] . Understanding circulating tumor cells and cell-free nucleic acids in cancer
patients may bring new insights into prognostic and predictive value of liquid biopsy. In this article, we
review recent research on the circulating miRNAs of gastric cancers, and discuss future perspectives on
next-generation clinical biomarkers and treatment targets in gastric cancer.

THE MOLECULAR FEATURES AND BIOLOGICAL SIGNIFICANCE OF MICRORNAS
Small noncoding RNAs known as microRNAs (miRNAs) regulate how specific protein-coding genes
are translated. After miRNAs were discovered in 1993 , researchers have correlated changes in miRNA
[14]
expression with diseases progression in multiple forms of cancer [15-18] . Numerous recent studies have detailed
how miRNAs can be detected in plasma/serum while keeping their impressive stability [16,19-22] . Plasma/serum
miRNAs resist endogenous ribonuclease activity through binding with plasma proteins such as Argonaute
2 and high-density lipoprotein (HDL) [23,24] or being surrounded by different secretory vesicles, including
plasma/serum exosomes and apoptotic bodies [19,25-27] . Thus, miRNAs in peripheral blood are not digested
by RNase or damaged by other conditions such as low or high pH, extended storage, boiling, and multiple
freeze-thaw cycles. In addition, numerous extracellular miRNAs are made present by active secretion in
addition to cell lysis [10,28,29] ; such miRNAs are able to play a role as intercellular transmitters [22,28,30,31] . As
one possible mechanism, the extracellular miRNAs involved in exosome vesicles has been reported to be
released through ceramide-dependent secretory systems and function in recipient cells .
[29]

CIRCULATING MICRORNAS ARE A PROMISING SOURCE OF DIAGNOSTIC AND PROGNOSITC
INFORMATION IN SOLID TUMORS
[19]
Mitchell et al. first reported that circulating miRNAs had potential utility as new biomarkers in patients
with solid cancers. As noninvasive and reproducible biomarkers in cancer patients, circulating miRNAs have
since attracted the attention of researchers. As indicated by the usefulness of cell-free DNA and circulating
tumor cells, the concept of “liquid biopsy” through circulating miRNAs may also provide ideal individualized
therapeutic strategies for cancer patients and contribute to the development of precision medicine. Indeed,
previous studies, including our own, have identified various blood-based miRNA biomarker candidates,
which are useful for cancer detection, monitoring tumor dynamics, and predicting malignant potential,
prognosis, and chemoresistance in cancer patients [32-45] .

HIGH LEVELS OF CIRCULATING MICRORNAS IN PLASMA/SERUM IN GASTRIC CANCER
Various studies have identified circulating miRNAs for use in the diagnosis and prognosis of gastric cancer
patients [Table 1]. In 2010, we reported the usefulness of circulating miRNAs and demonstrated their
feasibility as biomarkers in the plasma of patients with gastric cancer. We selected four miRNAs (miR-17-5p,
21, 106a, and 106b) that has been previously reported as upregulated in gastric cancer tissues, analyzed their
[32]
levels in plasma using RT-qPCR, and confirmed their utility as diagnostic biomarkers . We then identified
plasma miR-451 and miR-486 as novel cancer screening markers using the Toray® 3D-Gene microRNA