MicroRNA - Volume 9, Issue 3, 2020

The adverse developmental effects of exposure to Cigarette Smoke (CS) during pregnancy are documented in this paper. These include low birth weight, congenital anomalies, preterm birth, fetal mortality and morbidity. The current biological thought now recognizes that epigenetics represents a fundamental contributing process in embryogenesis, and that the environment can have a profound effect on shaping the epigenome. It has become increasingly recognized that genes encoding microRNAs (miRNAs) might be potential loci for congenital disabilities. One means by which CS can cause developmental anomalies may be through epigenetic mechanisms involving altered miRNA expression. While several studies have focused on genes affected by CS during embryonic/ fetal development, there is a paucity of knowledge on the involvement of miRNAs in this process. This brief review summarizes the current state of knowledge in this area.

Human Papillomavirus (HPV) is among the most common sexually transmitted infections in both females and males across the world that generally do not cause symptoms and are characterized by high rates of clearance. Persistent infections due at least to twelve well-recognized High-Risk (HR) or oncogenic genotypes, although less frequent, can occur, leading to diseases and malignancies, principally cervical cancer. Three vaccination strategies are currently available for preventing certain HR HPVs-associated diseases, infections due to HPV6 and HPV11 low-risk types, as well as for providing cross-protection against non-vaccine genotypes. Nevertheless, the limited vaccine coverage hampers reducing the burden of HPV-related diseases globally. For HR HPV types, especially HPV16 and HPV18, the E6 and E7 oncoproteins are needed for cancer development. As for other tumors, even in cervical cancer, non-coding microRNAs (miRNAs) are involved in posttranscriptional regulation, resulting in aberrant expression profiles. In this study, we provide a summary of the epidemiological background for HPV occurrence and available immunization programs. In addition, we present an overview of the most relevant evidence of miRNAs deregulation in cervical cancer, underlining that targeting these biomolecules could lead to wide translational perspectives, allowing better diagnosis, prognosis and therapeutics, and with valuable applications in the field of prevention. The literature on this topic is rapidly growing, but advanced investigations are required to achieve more consistent findings on the up-regulated and down-regulated miRNAs in cervical carcinogenesis. Because the expression of miRNAs is heterogeneously reported, it may be valuable to assess factors and risks related to individual susceptibility.

Glutathione (GSH) is the most abundant antioxidant that contributes to regulating the cellular production of Reactive Oxygen Species (ROS) which, maintained at physiological levels, can exert a function of second messengers in living organisms. In fact, it has been demonstrated that moderate amounts of ROS can activate the signaling pathways involved in cell growth and proliferation, while high levels of ROS induce DNA damage leading to cancer development. Therefore, GSH is a crucial player in the maintenance of redox homeostasis and its metabolism has a role in tumor initiation, progression, and therapy resistance. Our recent studies demonstrated that neuroblastoma cells resistant to etoposide, a common chemotherapeutic drug, show a partial monoallelic deletion of the locus coding for miRNA 15a and 16-1 leading to a loss of these miRNAs and the activation of GSH-dependent responses. Therefore, the aim of this review is to highlight the role of specific miRNAs in the modulation of intracellular GSH levels in order to take into consideration the use of modulators of miRNA expression as a useful strategy to better sensitize tumors to current therapies.

MicroRNAs appear as small molecule modifiers, which improve many new findings and mechanical illustrations for critically important biological phenomena and pathologic events. The best-characterized non-coding RNA family consists of about 2600 human microRNAs. Rich evidence has revealed their crucial importance in maintaining normal development, differentiation, growth control, aging, modulation of cell survival or apoptosis, as well as migration and metastasis as microRNAs dysregulation leads to cancer incidence and progression. By far, microRNAs have recently emerged as attractive targets for therapeutic intervention. The rationale for developing microRNA therapeutics is based on the premise that aberrantly expressed microRNAs play a significant role in the emergence of a variety of human diseases ranging from cardiovascular defects to cancer, and that repairing these microRNA deficiencies by either antagonizing or restoring microRNA function may yield a therapeutic benefit. Although microRNA antagonists are conceptually similar to other inhibitory therapies, improving the performance of microRNAs by microRNA replacement or inhibition that is a less well- described attitude. In this assay, we have condensed the last global knowledge and concepts regarding the involvement of microRNAs in cancer emergence, which has been achieved from the previous studies, consisting of the regulation of key cancer-related pathways, such as cell cycle control and the DNA damage response and the disruption of profile expression in human cancer. Here, we have reviewed the special characteristics of microRNA replacement and inhibition therapies and discussed explorations linked with the delivery of microRNA mimics in turmeric cells. Besides, the achievement of biomarkers based on microRNAs in clinics is considered as novel non-invasive biomarkers in diagnostic and prognostic assessments.

Aims: This study aimed at examining the effect of 3-bp pre-miR-3131 insertion/deletion (ins/del) polymorphism on Breast Cancer (BC) risk. Objectives: Totally 403 women including 199 BC patients and 204 women who have no cancer were included in this case-control study. Genotyping of miR-3131 3-bp ins/del polymorphism was performed by mismatch PCR-RFLP method. Methods: The findings expressed that the pre-miR-3131 3-bp ins/del variant was not related to the risk of BC in all genetic tested models. While, the ins/del genotype was related to late onset BC (OR=2.53, 95%CI=1.27-4.84, p=0.008). Results: Pooled results from the meta-analysis indicated to that the pre-miR-3131 ins/del is related to with an increased risk of cancer in heterozygous (OR=1.26, 95%CI=1.06-1.51, p=0.01), dominant (OR=1.33, 95%CI=1.14-1.54, p=0.0002), and allele (OR=1.24, 95%CI=1.06-1.45, p=0.006) genetics models. Conclusion: It is concluded that, our findings did not support a relationship between pre-miR-3131 ins/del polymorphism and the risk of BC. While, this variant was significantly related to late onset BC. Combined results of this study with previous studies indicated that this polymorphism increased the risk of cancer. More studies in a study with larger population with variety of ethnicities are required to verify our findings.

Background: Arum conophalloides (A. conophalloides) is a wild edible delicate plant, widely used in traditional medicine. Objective: This study aimed to examine the effects of A. conophalloides extracts on biochemical, molecular, and histopathological changes in the rat. Methods: Fifty adult male Sprague-Dawley rats were divided into 5 groups (10 each) as follows: G1 or control, received distilled water; G2 and G3, treated with the aqueous extract at doses of 200 and 400 mg/kg; G4 and G5, treated with the hydroalcoholic extract at doses of 200 and 400 mg/kg. Prior to and at the end of the experiments, the serum levels of biochemistry parameters and the relative expression of miR-122 were assessed. Moreover, the liver and kidney tissues were examined microscopically. Results: Liver and kidney tissues showed normal structure in all groups. There were no significant changes in biochemical indices or the expression of miR-122 in the extract-treated groups at the dose of 200 mg/kg. However, the group that received the aqueous extract at the dose of 400 mg/kg exhibited a significantly lower level of HDL, LDL, ALT, and ALP in comparison to the control. Additionally, miR-122 expression in this group exhibited a 10-fold increase (P=0.009). Conclusion: The serum level of hepatocyte-specific miR-122 will be more helpful in detecting hepatic changes in early stages than ALT and AST activity or histopathological evaluations of liver sections. Our findings highlight the potential hepatotoxicity of A. conophalloides aqueous extract in a rat model.

Background: Hepatitis B is a liver infection disease caused by the Hepatitis B Virus (HBV) that can become chronic and develop into hepatocellular carcinoma. HBV was classified as a double-stranded DNA virus. Currently, there is a report showing that HBV virus-encoded miRNA called HBV-miR-3 controls the replication of HBV. However, the regulation of HBV-miR-3 in host cells remains unclear. Objective: This study aimed to investigate the regulation of HBV-miR-3 in host gene target which is related to chronic HBV infection and HCC process. Methods: In this study, we analyzed the read count of HBV-miR-3 from next-generation sequencing of chronic hepatitis patients in Pegylated interferon alpha-2a (PEG-IFN-α-2a) treatment. To understand the regulation of HBV-miR-3 in host cells, the HBV-miR-3 recognition sites were predicted in host target genes using miRDB. The effect of HBV-miR-3 in host cells was examined using qPCR and 3′ UTR dual luciferase assay. Results: The read count of HBV-miR-3 was found in chronic hepatitis patients before treatment. Moreover, the decrease of HBV-miR-3 was correlated with response group of chronic hepatitis patients after treatment. On the other hand, the abundance of HBV-miR-3 showed no difference in nonresponse group of chronic patients after PEG-IFN-α-2a treatment. To study the role of HBV-miR-3 in patients, four HBV-miR-3 target regions from Protein phosphatase 1A (PPM1A) and DIX domain containing 1 (DIXDC1) were identified in the human genome using miRDB. Interestingly, we found that HBV-miR-3 hybridized with PPM1A mRNA. The mRNA expression from RT-qPCR showed no difference between HepG2 transfected with pSilencer_scramble or pSilencer_HBV-miR-3. However, the reporter assay showed that PPM1A mRNA was suppressed by HBV-miR-3. The protein expression of PPM1A showed a decrease in cells overexpressing HBV-miR-3. Finally, the HBV-miR-3 can promote cell proliferation in cells overexpressing HBV-miR-3. Conclusion: This study is the first report showed the HBV encoded miRNA can regulate host gene expression. HBV-miR-3 silenced PPM1A by inhibiting the translation process of PPM1A. The downregulation of PPM1A promotes cell proliferation related to HCC development.

Aim: Since RAP1B is critical for platelet functions, including hemostasis, this study was conducted to identify RAP1B regulating microRNAs (miRNAs) in ex vivo stored platelets. Background: Previous studies with platelets identified factors affecting RAP1B activity but regulatory miRNAs that affect RAP1B protein expression have not been reported. Objective: To understand the functional significance of miRNA mediated regulation of RAP1B in stored platelets, using microRNA, miR-181a as an example. Methods: A Tagged RNA Affinity approach (MS2-TRAP) was employed to identify miRNAs that bound to the 3' untranslated region (3'UTR) of the RAP1B mRNA in HeLa cells as an assay system. And subsequently, the mRNA 3’UTR:miRNA interactions were verified in platelets through the ectopic expression of miR-181a mimic and appropriate controls. The interaction of such miRNAs with RAP1B mRNA was also validated by qRT-PCR and Western analysis. Results: Sixty-two miRNAs from MS2 assay were then compared with already known 171 platelet abundant miRNAs to identify a common set of miRNAs. This analysis yielded six miRNAs (miR- 30e, miR-155, miR-181a, miR-206, miR-208a and miR-454), which are also predicted to target RAP1B mRNA. From this pool, miR-181a was selected for further study since RAP1B harbors two binding sites for miR-181a in its 3′UTR. Ectopic expression of miR-181a mimic in platelets resulted in lowering the endogenous RAP1B at both mRNA and protein levels. Further, miR-181a ectopic expression reduced the surface expression of the platelet activation marker, P-selectin. Conclusion: MicroRNA-181a can target RAP1B and this interaction has the potential to regulate platelet activation during storage.