**4.2 Post-transcriptional regulation**

Post-transcriptional regulation has emerged as another important mechanism in define the miRNA expression pattern, which mainly involves the processing of the miRNA after transcription. On the post-transcriptional level, the expression of microRNAs can be downregulated due to changes in the activity of key miRNA biogenesis enzymes, such as Dicer and Drosha. Dicer and Drosha generally operate in complexes with double-stranded RBP partner (such as TRBP and DGCR8). Both the levels and activity of all of these proteins are subject to regulate the accumulation of miRNAs. For example, a decrease in TRBP leads to Dicer destabilization and pre-miRNA processing defects [9, 13]. In addition, recent studies have also demonstrated that post-translational changes in the Ago family of protein could cause significant changes in miRNA expression profiles [9, 13].

Another important contributor to miRNA levels is the stability of miRNA, which depends on the stage of development or cell type involved. It has been discovered that some proteins can bind miRNAs and affect their half-life [9, 14]. For example, HuR, a member of the ElaV family of RNA-binding proteins has been shown to suppress the inhibitory effect of miRNAs [14]. On the other hands, it has been shown that overexpression of Argonaute proteins can decelerate miRNA degradation and increase miRNA stability [9, 15].

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*Therapeutic Implication of miRNA in Human Disease DOI: http://dx.doi.org/10.5772/intechopen.82738*

**4.3 Endogenous and xenobiotics regulation**

regulation by corticosterone.

significantly different [24].

**5. Clinical implication of miRNAs**

The presence of physiological and pathological conditions have been demonstrated to regulate miRNA expression. Previous studies have shown that steroid hormones can regulate miRNA expression [16, 17]. Treatment with estradiol or tamoxifen has been shown significant changes of different miRNAs expressions in patients with breast cancer and in various breast cancer cell lines [16, 17]. In addition, corticosterone also can directly regulate miRNAs expressions [18]. Rats given chronic corticosterone showed significant behavioral disorder associated with differential regulation of 26 miRNAs in the rat prefrontal cortex [18]. Off interesting, those altered miRNAs that were modulated by corticosterone have binding sites for glucocorticoid receptor element (GRE), which were either simple, composite or tethering type within the 1-kb upstream of the transcription start site. These finding suggests that binding with GRE is a common regulatory mechanism of miRNA

In addition to endogenous regulation, xenobiotics can affect miRNA expression. Increasing evidence from *in vivo* and *in vitro* experiments have showed that specific carcinogen could differentially alter certain miRNAs expressions [19]. Chronic treatment with benzene in mice had showed significant changes in certain miRNAs expressions [20]. Aflatoxin B1, a genotoxic carcinogen, has been reported that it can affect the profile of miRNA expression in different animal models and cell lines [21, 22]. Therefore, miRNAs can serve as biomarkers of toxicity of carcinogen agents and may be useful for early cancer diagnosis. Furthermore, harmful life styles such as alcohol consumption and tobacco smoking can impair miRNAs expressions [23, 24]. Cigarette smoking can change microRNA profile in many human organs and induces the change of plasma miRNA expression profiles in healthy subjects [25, 26]. It has been reported that 24 miRNAs were up-regulated and 11 miRNAs were down-regulated in plasma from smokers [26]. In addition, the serum miRNA profiles in nonsmokers, smokers, and lung-cancer patients were

MicroRNAs are becoming well recognized as their expression levels are changed in different diseases such as cancer, liver disease, coronary heart ischemic disease, and metabolic disease. Some miRNAs are increased, whereas others are decreased in a specific disease, creating a signature miRNA pattern that could serve as a biomarker or molecular therapeutic target for a particular disease. For example, in the case of cancers, the overexpressed miRNAs are commonly considered as oncogenes. On the other hand, some of the miRNAs are expressed very low levels in certain cancerous cells and usually prevent tumor development. These groups of miRNAs are called as tumor suppressor miRNAs. Let-7 is one of these tumor suppressor miRNAs [27]. The miRNAs have remarkable potential in the clinical arena because they can be detected in the blood, serum, tissues (fresh and formalin-fixed paraffin-embedded), and fine-needle aspirate specimens. Recently, novel in situ hybridization techniques have been described to detect miRNAs in tissues, which enables direct miRNA and histomorphologic correlation [28]. The clinical implications of miRNA use in medicine are present in both diagnostic and therapeutic approaches. In miRNA-based diagnostics, miRNA expression profiling has been evaluated as a reliable diagnostic biomarker for differentiating between normal and tumor specimens [29, 30]. Ali et al. have reported that the expression of *Antisense Therapy*

expression.

**4. Regulation of miRNAs**

**4.1 Transcriptional regulation**

both normoxia and hypoxia [12].

increase miRNA stability [9, 15].

**4.2 Post-transcriptional regulation**

There are multiple levels of regulation of miRNA expression [5]. Those regulatory mechanisms mainly include transcriptional and post-transcriptional mechanisms, as well as effects of endogenous and exogenous compounds on the miRNA

Similar to protein-coding genes, miRNA genes can also be regulated through transcription level. The promoters of miRNA genes are controlled by transcription factors (TFs). Many TFs regulate miRNA gene expression through positive or negative mechanism in a tissue-specific or developmental-specific manner. For instance, MYC inhibits expression of tumor suppressor miRNA-15a, which promote MYC-mediated tumorigenesis [6]. On the other hands, MYC can stimulate expression of miR-9 in neuroblastoma cells, resulting in regulation of E-cadherin and cancer metastasis [7]. It has shown that p53 enhances the expression of miR-34 and miR-107 families, which induce cell cycle arrest and apoptosis [8]. In addition to regulate by TFs, the expression of miRNA can be regulated by methylation of the promoter. Most of the miRNA promoter region has certain CpG islands. For example, promoter hypermethylation of genes such as miR-132, miR-34b/c, miR-218-1/2, and miR33b have been associated with or denote a poor prognosis of various cancers [9, 10]. In addition, the changes in DNMT1 and DNMT3b DNA methyltransferases lead to alter the miRNAs (miR-148a, miR-34b/c, miR-9 and let-7) gene promoter methylation status, resulting in regulation of their gene transcription levels [11]. Furthermore, it has reported that miR-210 is highly induced by hypoxia in various cancer cell lines [12], whose expression is not only regulated by the transcription factors hypoxia-inducible factor-1 (HIF-1), but also regulated by DNA demethylation mechanism in neural progenitor cells under

Post-transcriptional regulation has emerged as another important mechanism

Another important contributor to miRNA levels is the stability of miRNA, which depends on the stage of development or cell type involved. It has been discovered that some proteins can bind miRNAs and affect their half-life [9, 14]. For example, HuR, a member of the ElaV family of RNA-binding proteins has been shown to suppress the inhibitory effect of miRNAs [14]. On the other hands, it has been shown that overexpression of Argonaute proteins can decelerate miRNA degradation and

in define the miRNA expression pattern, which mainly involves the processing of the miRNA after transcription. On the post-transcriptional level, the expression of microRNAs can be downregulated due to changes in the activity of key miRNA biogenesis enzymes, such as Dicer and Drosha. Dicer and Drosha generally operate in complexes with double-stranded RBP partner (such as TRBP and DGCR8). Both the levels and activity of all of these proteins are subject to regulate the accumulation of miRNAs. For example, a decrease in TRBP leads to Dicer destabilization and pre-miRNA processing defects [9, 13]. In addition, recent studies have also demonstrated that post-translational changes in the Ago family of protein could cause significant changes in miRNA expression profiles

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[9, 13].
