Irina V. Bure

Gastric cancer (GC) remains the most common malignant tumor of the gastrointestinal tract and one of the leading causes of cancer-related deaths worldwide. Non-coding RNAs (ncRNAs), including microRNAs (miRNAs), are involved in the pathogenesis and progression of GC and, therefore, may be potential diagnostic and prognostic biomarkers. Our work was aimed at investigating the predicted regulation of ARID1A by miR-129-5p and miR-3613-3p and the clinical value of their aberrant expression in GC. The study included tumor and adjacent non-tumor tissues from 110 GC patients, 38 sectional normal gastric tissue samples, as well as 65 plasma samples of GC patients and 49 plasma samples of healthy donors. Expression levels of ARID1A and both miRNAs were quantified by reverse transcription-polymerase chain reaction (RT-PCR). We have identified significant associations of their expression with the clinical and pathological characteristics of GC patients both in tissues and plasma. To validate predicted target pairs miR-129-5p/ARID1A and miR-3613-3p/ARID1A, in vitro experiments on cancer cell lines were conducted. The obtained results suggest a complex role of ARID1A, miR-129-5p and miR-3613-3p in GC and potential regulation of ARID1A expression by both miRNAs.

According to the Cancer Genome Atlas (TCGA), gastric cancers are classified into four molecular subtypes: Epstein–Barr virus-positive (EBV+), tumors with microsatellite instability (MSI), tumors with chromosomal instability (CIN), and genomically stable (GS) tumors. However, the gastric cancer (GC) with chromosomal instability remains insufficiently described and does not have effective markers for molecular and histological verification and diagnosis. The CIN subtype of GC is characterized by chromosomal instability, which is manifested by an increased frequency of aneuploidies and/or structural chromosomal rearrangements in tumor cells. Structural rearrangements in the CIN subtype of GC are not accidental and are commonly detected in chromosomal loci, being abnormal because of specific structural organization. The causes of CIN are still being discussed; however, according to recent data, aberrations in the TP53 gene may cause CIN development or worsen its phenotype. Clinically, patients with the CIN subtype of GC demonstrate poor survival, but receive the maximum benefit from adjuvant chemotherapy. In the review, we consider the molecular mechanisms and possible causes of chromosomal instability in GC, the common rearrangements of chromosomal loci and their impact on the development and clinical course of the disease, as well as the driver genes, their functions, and perspectives on their targeting in the CIN subtype of GC.

Chromatin remodeling is the one of the main epigenetic mechanisms of gene expression regulation both in normal cells and in pathological conditions. In recent years, a growing number of investigations have confirmed that epigenetic regulators are tightly connected and form a comprehensive network of regulatory pathways and feedback loops. Genes encoding protein subunits of chromatin remodeling complexes are often mutated and change their expression in diseases, as well as non-coding RNAs (ncRNAs). Moreover, different mechanisms of their mutual regulation have already been described. Further understanding of these processes may help apply their clinical potential for establishment of the diagnosis, prognosis, and treatment of the diseases. The therapeutic targeting of the chromatin structure has many limitations because of the complexity of its regulation, with the involvement of a large number of genes, proteins, non-coding transcripts, and other intermediary molecules. However, several successful strategies have been proposed to target subunits of chromatin remodeling complexes and genes encoding them, as well as the ncRNAs that regulate the operation of these complexes and direct them to the target gene regions. In our review, we focus on chromatin remodeling complexes and ncRNAs, their mutual regulation, role in cellular processes and potential clinical application.