Sensitive to the effects of environmental factors miR-638 and common diseases

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Sensitivity to the effects of environmental factors: miR-638 and common diseases

A.N. Kucher

Research Institute of Medical Genetics, Tomsk National Research Medical Center, Russian Academy of Science, Tomsk, Russia.

Research suggests that the etiology of widespread diseases is promoted by various exogenous factors, the effects of which can be demonstrated depending on the genetic features of individuals. Among these genetic factors, diseases that introduce risk to the structural diversity of the genome have been frequently studied. However, recent research on the epigenetic components of multifactorial diseases has also been conducted [1–5]. Changes in the spectrum and level of microRNA, as well as epigenetic modifications (including DNA methylation), are considered important components of a disease's pathologic makeup, including the intermediate effects of unfavorable environmental factors that contribute to disease development [6–9]. In this context, miR‑638 is of interest since it is sensitive to the exposure of different biotic and abiotic agents. The degree of change to miR-638 depends on the affecting agents, the duration of the effect, and the types of cells involved [10–17]. Low levels of miR‑638 were detected in individuals experiencing chronic benzene poisoning, compared with individuals not in contact with the substance (control group) and those who had short-term contact with the substance. Concurrently, individuals experiencing short-term exposure to benzene had higher levels of miR‑638 than had those in the control group [13]. Existing research also registered a considerable increase in miR‑638 among workers exposed to polycyclic aromatic hydrocarbons [11]. An increase in miR‑638 was registered during cell treatment with benzo(a)pyrene (in a dose-dependent manner) [11], whereas bidirectional effects were detected following exposure to inorganic arsenic (evidenced by a reduction in endothelial cells of the umbilical vein and an increase in leukocyte culture в) [15, 18]. It is assumed that this microRNA can be employed as a biomarker for the assessment of unfavorable environmental factors in the work place [15].

A stimulating impact on miR‑638 expression was determined for a number of viruses, including the enterovirus (EV71) [16] and the chikungunya disease virus (CHIKV) [12]. However, Liu et al. [14] demonstrated that the hepatitis C virus inhibited the expression of this microRNA in the cells of human hepatoma. Furthermore, miR‑638 can affect the degree of infection and, in particular, can reduce the transcription of the hepatitis B virus [19, 20]. Additionally, miR‑638 is sensitive to oxidative stress [21] and temperature conditions (its level is reduced at high temperatures) [22]. Naraballobh et al. [22] assigned microRNA (including miR‑638) an important regulatory role in the acute response to modified environmental conditions, which stipulates remodeling in cells and tissues. Because of the specificity in the function of microRNA, miR‑638 controls the expression of many genes at a translational level. Accordingly, changes in the expression of this microRNA (including under the effect of biotic and abiotic environmental factors) can impact a range of metabolic pathways.

miR‑638 is expressed in multiple tissues including brain, kidney, skin, and fat, among others. It is also expressed in more than 800 cell lines (including different types of blood cells) and in more than 500 types of tumor across multiple organs [23, 24]. A high level of miR-628 expression can be explained by the fact that it is involved in the regulation of the cell cycle [25–27].

The MIR638 gene is localized to chromosome 19p13.2. An intron of the DNM2 gene (dynamin 2); polymorphic variants (primarily single nucleotide replacements) are registered in the gene of this microRNA, but they are all low polymorphic [28, 29].

This review presents data on the possible pathologic genetic effects of miR‑638 that are sensitive to environmental factors. For this purpose, 1) an analysis of the functional value of genes that can be regulated by miR‑638 was performed and 2) data sourced from scientific publications on the involvement of miR‑638 in the pathogenesis of different diseases was integrated.

Downstream targets of miR‑638, their involvement in metabolic pathways, and links with diseases

Genes that are regulated by miR-638 were identified using TargetScanHuman (version 7.2; updated March 2018) [30, 31]. In total, miR-638 demonstrated potential binding sites across 1,877 transcripts (a total of 2,136 binding sites). Thus, at a translational level, miR‑638 can control the expression of roughly 2,000 genes.

To determine the extent to which sets of genes are random and have target sites for miR‑638, their excess representation (deviation from random expression) among genes associated with different categories of pathologies/groups of pathology (as per the Disease database) and metabolic pathways (as per the KEGG Pathway Database) was assessed using the analytical internet resource Web­Gestalt [32, 33]. Data were obtained on the basis of the hypergeometric test. The level of statistical significance was determined using allowance, as per the Benjamini–Hochberg method.

From the analysis of genes as potential targets for miR‑638, 533 diseases/groups of pathologies and 62 metabolic pathways were detected, which is greater than that expected purely by change (p < 0.05). Table 1 provides examples of such diseases and metabolic pathways, the number of genes attributed to appropriate categories, and the design parameters that characterize an excess of representation for miR‑638 target genes.

Genes that are potentially regulated by miR‑638 are presented as statistically significantly excessive for a wide range of diseases of the central nervous system and cardiovascular system, among oncological diseases, inflammatory and autoimmune pathologies, in the regulation of cell cycles, and in supporting genome stability, and are indicated as being involved in metabolic pathways and disorders, in which functioning can be a reason for these pathologies. The number of metabolic pathways in which the target genes of miR‑638 are represented in excess directly indicates pathological conditions (e.g., oncologic disease, amyotrophic lateral sclerosis, renal cell cancer, and small-cell lung cancer). The causes of the above diseases include smoking, unfavorable environmental exposure (pollutants and mutagens), and viruses, among others. Additionally, miR‑638 is also sensitive to exposure to environmental factors at the methylation level of CpG sites, and its expression at these sites [10–13].

Genes that are studied in the context of cardiovascular disease pathogenesis are potentially regulated by miR‑638. This microRNA regulates the expression of genes that are involved in blood coagulation (F8, F13A1, and F10), the metabolism of fats and carbohydrates (SLC2A9, LDLR, and FADS1), encoding calcium (CACNA1C) and potassium (KCND3, KCNJ5) channels, cardiotrophin 1 (CTF1), methylenetetrahydrofolate reductase (MTHFR), and vascular endothelial growth factor А (VEGFA). Additionally, miR‑638 regulates the expression of oncogenes (RAN, FEV, USP6, PIM1, and RAB36), cell cycle genes (CDKN2B and CCND1), and the BRCA1 gene. Moreover, miR‑638 controls proteins involved in repair processes (RFC3, RFC2, MSH3, and RPA1). Thus, on the basis of this analytical approach, it appears that changes in the level of miR‑638 can result in disorders of different metabolic pathways that are important to the pathogenesis of a wide range of diseases. This proposition is confirmed herein by conducting clinical and experimental studies.

Clinical and experimental confirmation of the involvement of miR‑638 in the pathogenesis of multifactorial diseases

Significant evidence was obtained regarding changes in the expression of miR‑638 in different multifactorial diseases (Table 2). Changes in the expression of miR‑638 in the tumor tissue of different organ systems (e.g., intestinal tract, breast, and lung) are highlighted compared with normal tissue, and in the blood serum of patients with oncopathology, compared with healthy individuals. The majority of studies detected a reduction in the level of this microRNA in tumors and in the blood serum of patients. Contradictory results were obtained only for breast cancer, where two studies detected lower levels of miR‑638 in tumor tissue [34, 35] and one study detected the reverse situation [36], where this can be linked to the clinical features of patients included in the study. Specifically, the level of expression of this microRNA was higher in patients with triple-negative breast cancer compared with that in patients with other forms of breast cancer [34]. It is also known that miR‑638 expression can be affected by certain medications [11, 34].

Where patients had low levels of miR‑638 in tumor tissue and blood serum prior to treatment, this was associated with a more unfavorable clinical presentation (large tumor size, later disease stage, and occurrence of metastases) [25, 26, 35, 40, 42–44], as well as negative survival forecasts (general and remote relapse free) [27, 35, 38, 40, 42, 43]. These situations were observed for tumors in different organ systems (Table 1) except for nasopharyngeal carcinoma, where a reduction in survival was demonstrated for people with higher levels of miR‑638 [38].

One of the mechanisms that regulates the expression of microRNA is the methylation of its gene promoter. Hypermethylation of the host gene of miR‑638 (DNM2) was registered in colorectal cancer tissue [62]. Zhang et al. demonstrated that the CpG island in the area of the miR‑638 promoter in colorectal cancer tissue was hypermethylated. Therefore, a lower level of microRNA expression was observed, and weakening of the methylation level was sufficient for the recovery of miR‑638 expression in tumor cells [27]. When miR‑638 expression increased, inhibition of proliferation was observed, as well as the invasion of cancer cells and termination of the cell cycle in the G1 phase, whereas repression of miR‑638 resulted in contrasting effects [27]. Similar results were obtained in experimental studies by other authors [25, 35, 42, 45–47]. This explains a more favorable forecast for patients who had increased levels of miR‑638 following treatment. For example, patients with non-small lung cancer cells who had undergone chemotherapy with cisplatin demonstrated increased serum miR‑638 and demonstrated longer survival than did patients with a reduced level of this microRNA [37]. The high level of expression of miR‑638 stipulated an elevated sensitivity of tumor cells to cisplatin, which ultimately resulted in a reduction of the tumor cells' viability in response to chemotherapy [63]. The same authors determined that high expression of miR‑638 affected the recovery processes of damaged DNA by means of suppressing the expression of γH2AX [63]. miR‑638 also reduced the ability of DNA recovery in triple-negative breast cancer cells that had been impacted by ultraviolet irradiation and cisplatin [34]. These mixed results indicate the different physiological effects of microRNA (miR‑638 in particular) under different conditions.

The fact that in the majority of cases, a lower level of miR‑638 was registered in tumor cells compared with normal cells, allows microRNA to be considered as a tumor suppressor (e.g., for Ewing's sarcoma, cervical cancer, breast cancer, and stomach cancer) [25, 27, 35, 44–46] and as an independent prognostic factor for different oncological diseases (regardless of the disease stage (tumor, nodus, and metastasis) and occurrence of metastases) [27]. However, single studies will be noted herein in which miR‑638 served as an oncogene contributing to cell proliferation, migration, and invasion (for esophageal squamous cell cancer and breast cancer) [36]. According to the analysis of enrichment (Table 1), changes in the expression in oncological diseases are significantly correlated with data related to an excess of genes regulated by miR‑638, among genes associated with pathologies and metabolic pathways.

Low expression of miR‑638 in blood serum or infected tissue has been registered for other diseases such as atherosclerosis of the carotid artery, Behcet's disease, hypertonia, and nephrotic syndrome (Table 2). Interestingly, patients with cardiovascular disease, as in the case of those with oncological disease, demonstrated lower levels of miR‑638. Furthermore, much lower levels of this microRNA were typical for patients with severe clinical presentation [48]. One study determined that the level of this microRNA was lower in smokers compared with that in non-smokers, which correlates with data regarding an increase in the level of methylation of the CpG sites of this miR‑638 for smokers [10]. It is known that miR‑638 is highly expressed in smooth muscle cells of human aorta and is involved in the regulation of proliferation and migration in these cells [64]. This microRNA also affects the proliferation and migration of smooth muscle cells in the respiratory tract (hyper-expression inhibits proliferation and migration), which indicates the potential of miR‑638 in asthma pathogenesis [17].

For the above-noted diseases, miR‑638 is considered a diagnostic marker, as well as a therapeutic target. The level of miR‑638 in blood serum is proposed for use as an invasive biomarker for the vulnerability of patches and the probability of ischemic stroke, particularly among individuals at risk of cardiovascular complications [48]. It has been stated that changing the level of miR‑638 in vascular smooth muscle cells may be useful in the treatment of proliferative vascular diseases [64]. miR‑638 can also serve as a new therapeutic target for the prevention of hyperplasia of smooth muscle cells in the respiratory tract in asthma [17].

A reduction in the expression of miR‑638 was not observed for all pathologies. A number of diseases demonstrated an increase in the level of this microRNA in the blood serum of patients or in infected tissue (Table 2). This situation was detected for esophageal squamous cell cancer, polycystic ovary syndrome, and celiac disease. For example, an increase in the expression of miR‑638 was registered in the blood serum of patients with sporadic amyotrophic lateral sclerosis [53]. However, contradictory results have been obtained for this disease in different studies [53]. Development of this disease can be promoted by a wide range of environmental factors (e.g., heavy metals, pesticides, smoking, and viral infections) [65]. Accordingly, mixed results from different studies regarding changes in the expression of miR‑638 in the case of amyotrophic lateral sclerosis can be explained in a number of ways. On the one hand, sporadic amyotrophic lateral sclerosis can differ on the basis of etiological factors. On the other hand, the focus of changes to the level of this microRNA can differ in response to exogenous stimulants. Specifically, it was demonstrated that infectious agents can result in an increase in the expression of miR‑638 [12, 16, 17]. This means that the same pathological phenotype can result from different pathophysiological pathways, which can be explained by the presence of different genetic components (genes and their structural and functional features), even in the presence of the common intermediate between environmental factors and genes (e.g., microRNA).

During comparison of miR‑638 expression in the samples of infected tissues, a number of cases indicated mixed results, which can be explained by tissue-specific differences. Lu et al. [55] determined bidirectional changes in the level of miR‑638 in different areas of the kidney among patients with lupus nephritis (i.e., low levels in glomeruli and higher levels in tubulointerstitial tissue) compared with control samples (Table 2). However, two additional studies detected an increase in the level of this microRNA in patients with lupus nephritis (in kidney biopsies and in peripheral blood mononuclear cells) [56, 57].

Changes in the expression of miR‑638 in the case of pathologies will affect changes in the expression of a number of proteins. For example, changes in the expression of miR‑638 in Ewing's sarcoma caused changes to the expression of the VEGFA protein [46]. In addition, in the case of osteosarcoma, changes in the expression of the proto-oncogene PIM1 were observed [45]. In hepatocellular carcinoma and stomach cancer, changes were observed in the transcription factor SOX2 [22, 43]. In the case of colorectal carcinoma, changes occurred in the protein levels of the TSPAN1 gene [27]. In the case of stomach cancer, chromosome protein MECP2 bound with methylated DNA [26]; in the case of breast cancer, with metalloproteinase BRCA1 [34]; and in the case of pulmonary emphysema, chromosome protein MECP2 bound with TOMM40 [50]. This microRNA also affected the expression of CCND1 (G1/S­specific cyclin­D1) and transcriptional activator NR4A3 (NOR1), which are required for cell proliferation, migration [17], and activation of the Wnt/β­catenin signaling pathway [44], disturbances to which can result in the formation of different pathologies including oncological diseases, metabolic and neurodegenerative disorders, and cardiovascular and endocrine system diseases. Individuals with hypertonia demonstrated a reduction in the level of miR‑638 in kidney tissue, and an increase in the expression of NR4A3 and RENBP when compared with individuals with normal arterial pressure [60]. According to TargetScanHuman, all genes coding the above-mentioned proteins had targets for miR‑638. However, the range of genes regulated by miR‑638 may be more widespread than forecasted by bio-informational methods [50, 60].

The sensitivity of microRNA to environmental effects and the control of the expression of protein-coding genes may depend on the genetic features of the individual. Genetic options (SNP) in the target areas of microRNA can change the expression of appropriate microRNA genes. The distribution of allelic variants as per rs799917 of the BRCA1 gene and rs334348 of the TGFR1 gene showed significant differences among populations with different risks of developing breast cancer. Specificity in the regulatory potential of miR‑638 and miR‑628­5p was detected, which interacted with the mRNA binding sites of the genes, BRCA1 and TGFR1, depending on the genotypic features of the tumor cells of the specified polymorphic variants [66]. Genetic variants in microRNA genes (particularly in the areas of target binding) can impact the expression of target genes. Gene MIR638 includes a large number of polymorphic variants (SNP, insertions, and deletions, though low polymorphisms are typical) [29], which can also modify the regulatory potential of this microRNA.

Genetic components are involved in the regulation of DNA methylation. For example, one study demonstrated that smoking affected methylation in some areas of DNA in the blood leucocytes of native Hawaiians, but this was not the case in Europeans, Japanese, or Americans [67]. In this instance, DNA methylation in fat tissue depended on the SNP associated with smoking [68], among other factors. It was shown that DNA methylation was affected by exogenous and endogenous factors (in particular, smoking and obesity), as well as adaptive genetic factors [69]. This indicates the importance of the genetic features of the examined individuals during analysis of different epigenetic aspects (e.g., DNA methylation and the regulatory potential of microRNA).

The data presented in this review allow miR‑638 to be considered as a marker that is sensitive to environmental effects in a wide range of diseases of a multifactorial nature. First, overlap was observed between diseases/groups of pathologies and metabolic pathways for which the potential target genes of microRNA were present in abundance (Table 1) and for the list of diseases where a change in the level of microRNA was detected in the infected tissue or blood serum of patients during clinical studies (Table 2). Second, data were accumulated to demonstrate that biotic and abiotic factors in the environment (including those serving as risk factors for multifactorial diseases) can affect the level of expression of miR‑638. One of the mechanisms by which the level of expression of this microRNA can be changed is the methylation of CpG sites. Third, a number of cases showed that the level of miR‑638 can affect mRNA and protein expression. The information provided in this review expands our perceptions on the pathogenesis of different multifactorial diseases and can help to determine new examination strategies for gene–environment interactions.

Table 1

Examples of disease categories (as per database Disease) and metabolic pathways (as per the KEGG Pathway Database) for which genes that are potentially regulated by miR­638 were determined.

Table 2

Level of expression of miR­638 in different pathological conditions

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About the authors

Aksana N. Kucher

Author for correspondence.
Email: aksana.kucher@medgenetics.ru
ORCID iD: 0000-0003-3824-3641
SPIN-code: 5251-2055
Scopus Author ID: 7004507293
ResearcherId: A-7789-2014
http://www.medgenetics.ru/science/lpg1/personallpg/201590/

Leading Researcher of the Laboratory of Population Genetics, Doctor of Biological Sciences, Professor

References

Supplementary files