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Welcome to the April, 2013 edition of SciEP newsletter, providing monthly summaries of articles on science & education related topics of interest to scientist and professionals. The mission of our journals is to provide an open access forum for publishing new findings on issues pertinent to scientific and academic field. We also invite you to submit original research papers, review articles, short reports, or case studies are considered for publication in our Multidisciplinary Journals.

American Journal of Public Health Research
DOI: 10.12691/ajphr-1-1-3

The Implementation of a Tele-Homecare System with Service Oriented Architecture and HL7 Message Transmission Standard
Ching-Sung Wang

American Journal of Medical and Biological Research
DOI: 10.12691/ajmbr-1-1-2

The Influence of Ethanol on Pyruvate Kinases Activity in Vivo, in Vitro, in Silico
Lelevich Sergey Vladimirovich, Khrustalev Vladislav Victorovich, Barkovsky Eugene Victorovich, Shedogubova Tatyana Aleksandrovna

American Journal of Medical Sciences and Medicine
DOI: 10.12691/ajmsm-1-1-1

Clinical and Histological Features in Wegener Granulomatosis
Li Cavoli Gioacchino, Passantino Rita, Bono Luisa, Tortorici Calogera, Ferrantelli Angelo, Giammarresi Carlo, Rotolo Ugo

American Journal of Infectious Diseases and Microbiology
DOI: 10.12691/ajidm-1-1-2

The Curse of Lymphatic Filariasis: Would the Continual Use of Diethylcarbamazine Eliminate this Scourge in Papua New Guinea?
Anne Lanham, Lillian Mwanri

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Impact of miRNA Alteration on Cancer Pathogenesis

Emmanuel Atiatorme*, Richard Osafo

Department of Biotechnology, Andhra University, College of Advance Sciences Technology, Visakhapatnam, India

Abstract: MicroRNAs (miRNAs) are a type of non-coding RNA that controls gene expression post-transcriptionally through either translational repression or mRNA degradation. By regulating the translation of oncogenes and tumor suppressor genes, altered miRNA expression is linked to the development and progression of numerous human malignancies. Cleavage and translational modification of target proteins are some possible ways that miRNA affects target gene expression. MiRNAs are increasingly becoming recognized as critical regulators of biological processes such as differentiation, embryonic development, cell cycle, proliferation, apoptosis, stress resistance, fat metabolism, immunological defense, virus-related illnesses, and, most crucially, carcinogenesis. On the other hand, they appear to be key prognostic markers in patients with a variety of cancers, and they could be used as therapeutic tools. The current review focuses on recent findings in this fascinating new field of research, with a particular focus on the role of miRNA alterations in cancer pathogenesis. We explained how miRNA expression is altered in cancer at both the transcriptional and post-transcriptional levels, and how this elucidates some abnormal miRNA expression in cancer as well as some potential treatment controls for carcinogenesis. Our findings revealed that some miRNAs have evolved unique features and roles that control other transcriptional or posttranscriptional silencing pathways, resulting in carcinogenesis. The dynamic aspect of miRNA-based control in complex regulatory networks is highlighted by the evolution of miRNA processing and functional diversity. This review will aid in understanding how miRNA dysregulation affects cancer cell formation, as well as the development of more effective and secure miRNA-based therapies.

Keywords: argonaute, GW182, microRNA, miRNPs, translational repression

Received February 02, 2022; Revised March 04, 2022; Accepted March 11, 2022

Citation: Emmanuel Atiatorme, Richard Osafo, Impact of miRNA Alteration on Cancer Pathogenesis. Journal of Cancer Research and Treatment, 10 (1). 1-11. January 2022. doi:10.12691/jcrt-10-1-1

1. Introduction

Cancer is a broad term that refers to a variety of diseases that can affect various organs in the body. Normal cell behavior is to divide and die in an orderly manner, but cancer cells can continually divide uncontrollably to produce malignant cells, [1,2]. There are approximately 200 types of cancer [3]. Among the various types of cancer, lung, prostate, breast, stomach, liver, pancreatic, and colon cancers are the leading causes of death worldwide, accounting for 10 million deaths as of the year 2020 [4]. According to GLOBOCAN 2020, about 19.1 million new cancer cases arises globally [5]. Cancer formation results from the abnormal cell/tissue growth known as a tumor which has the potential to invade or spread to other parts of the body.

Almost every stage of tumor formation and progression is linked to epigenetic changes, according to a large body of evidence [6]. DNA methylation, histones/chromatin structure, nucleosome placement, and noncoding RNAs are all examples of significant epigenetic changes. Chemical exposure to the environment may have altered epigenetic and epigenomic consequences [7]. Chemically induced cancer is driven by epigenetic changes, which could be useful as biomarkers for carcinogen exposure. Although a large body of research has demonstrated the importance of chemical carcinogen-induced epigenetic modifications in cancer development, the specific involvement of miRNAs in chemical-related carcinogenesis remains unknown. However, some researchers are also of the view that cancer is a heterogeneous disease that includes a variety of neoplasm and involves diverse alterations in mRNA and micro-RNA (miRNA) expression profiles [8,9].

MicroRNAs are 22-nucleotide (nt) long RNAs that are encoded by the human genome and influence gene expression in a variety of biological activities. The Argonaute families of proteins, which join with miRNAs to form miRNA-induced silencing complexes (miRISCs), are responsible for miRNA regulatory functions. MiRNAs direct the Argonaute proteins to fully or partially complementary mRNA targets inside these complexes, which are then silenced post-transcriptionally [10].

This RNA can be found in plants, animals, and other eukaryotes, as well as some DNA viruses. RNA polymerase II transcripts with defective self-complementary fold back regions are known as primary miRNA transcripts (pri-miRNAs). The pri-miRNA transcript is first processed in animals by the RNase III domain-containing protein Drosha in collaboration with the RNA binding protein, DiGeorge syndrome Critical Region gene 8 (DGCR8),which binds to the lower stem region of miRNA fold back [11]. A 33-base pair (bp) stems with a terminal loop and two single-stranded flanking regions make up an average animal pri-miRNA [12]. Both the double-stranded stem and flanking sections are required for DGCR8 binding and subsequent Drosha cleavage at 11 bp from the single- and double-stranded RNA junction. Processed miRNA precursors (pre-miRNA) are exported from the nucleus to the cytoplasm and cleaved by the RNase III domain-containing protein Dicer at 22 bp from the Drosha processing site.

In the cytoplasm, the mature miRNA strand is loaded into argonaute(AGO) to form an RNA-induced silencing complex (RICS) with the help of Hsc70/Hsp90 chaperone and ATP, followed by the passenger strand ejection [13]. MiRNAs operate as tight regulators of developmental genes and are engaged in a variety of pathological events by regulating mRNAs at the post-transcriptional level. Over 2000 miRNAs have been discovered to date, and they play critical roles in a variety of biological processes, including differentiation, embryonic development, cell cycle, proliferation, apoptosis, stress resistance, fat metabolism, immune defense, virus-related diseases, and, most importantly, tumorigenesis, through post-transcriptional modulation of targeted mRNAs [14].

MiRNA may act as tumor suppressors or oncogenes, according to new research, and changes in miRNA expression may play a key role in carcinogenesis and cancer progression [15]. MiRNA has been discovered to have a role in carcinogenic pathways including the p53, Bcl2, and k-ras pathways. Interestingly, miRNA appears to be important prognostic markers in patients with a variety of malignancies, and they may be useful in the treatment of cancer [16]. This review focuses on the role of miRNA alteration in cancer pathogenesis. Here, we looked at how miRNA expression is altered in cancer, based on transcriptional and post-transcriptional levels, after a brief elucidation of the mechanism of miRNA regulation and then finally account for some abnormal expression of miRNA in cancer and some possible therapeutic control for carcinogenesis.

2. Mechanism of miRNA regulation

RNA polymerase II transcribes miRNAs as lengthy primary transcripts (pri-miRNA) from several genomic sites [17]. They are found in either separate noncoding RNAs or protein-coding gene introns. Some miRNAs are also grouped in polycistronic transcripts to allow coordinated expression. Several miRNAs are expressed in a tissue-specific and developmental stage-specific manner. The transcriptional control of their host gene promoters may be connected to the expression of intron-encoded miRNAs [18]. SRF (serum response factor), MyoD, and Mef2 have recently been shown to have a role in determining the cardiac tissue-specific expression of miR-1 [19], and Myc in regulating a specific miRNA cluster [20]. Although we only know that miRNA genes are regulated at the transcriptional level, control at the miRNA processing level is still a possibility. Hence the need to investigate its biogenesis and target mRNA cleavage.

Figure 1. A schematic diagram of the mechanism of miRNA biogenesis. RNA Polymerase II (Pol II) transcribes the nascent primary miRNA (pri-miRNA). The DROSHA/DGCR8 microprocessor complex in the nucleus cleaves the pri-miRNA, releasing a hairpin-shaped precursor (pre-miRNA). Exportin 5(XPO5) transports pre-miRNA from the nucleus to the cytoplasm .DICER1 cleaves pre-miRNA in the cytoplasm to generate the mature miRNA

2.1. Mechanism of miRNA Biogenesis

Following transcription, two members of the RNase-III family of enzymes, Drosha and Dicer, work together to process the pri-miRNAs.These proteins are aided in their tasks by their companion double-stranded RNA-binding domain (dsRBD) containing proteins: DGCR8 with Drosha, R2D2 with Drosophila Dicer-2 [17], and Transactivation Response element RNA –Binding protein (TRBP) with human Dicer-1. [21]. The nuclear Drosha excises a 70-nt precursor called the pre-miRNA from the pri-miRNA, which can be folded into a stem-loop structure with multiple bulges and mismatches. Exportin-5 transports pre-miRNA to the cytoplasm in a Ran-GTP-dependent manner [Figure 1]. Dicer cleaves the pre-miRNA in the cytoplasm to produce a 22-bp duplex intermediate [22]. Only one strand of the duplex accumulates as mature miRNA, following the thermodynamic asymmetry rule. According to the asymmetry rule, the mature miRNA's 5'end is located near the end of the duplex, which has lower thermodynamic energy [23].

After that, the mature miRNA is assembled into effecter complexes known as miRNPs (miRNA-containing ribonucleoprotein particles), which are very similar to the RISC. The size of functional RISCs and miRNPs varies, ranging from the “minimum” RISC of 160 kDa to the holo-RISC that fractionates at the 80S. The identification of several protein components has resulted from the biochemical characterization of these various complexes [22]. The function of these proteins in the RNAi and miRNA pathways remains unknown. The highly conserved Argonaute (Ago) protein is the only protein constantly present in the RISC and miRNP complex [24]. A single-stranded short RNA linked with an Ago protein is thought to be present in the minimum effector complex.

The miRNA leads the complex to its target by base-pairing with the target mRNA, once it has been formed. MiRNAs bind to a single, usually completely complementary location in the target mRNA's coding or 3'-untranslated regions (UTRs) mostly in the case of plants. Most animal miRNAs, on the other hand, bind to numerous partially complementary locations in the 3'UTRs. Target sequences inserted into coding or 5' UTR sequences are likewise functional [25]. Complementarity is often limited to the nucleotides 2-8 in the miRNA's 5'end. These nucleotides make up the ''seed” sequence [Figure 2], meaning that they initiate miRNA-target mRNA binding [23]. The extent of base-pairing to the miRNA determines the destiny of the target mRNA. If a miRNA has complete or near-perfect complementarity with the target mRNA, it will drive the destruction of that mRNA [26]. The presence of several, partially complementary sites in the target mRNA, on the other hand, will guide the suppression of protein accumulation without having a significant impact on mRNA levels [18].

2.2. Cleavage of mRNA in the RISC/miRNP Complex

When the accurate base-paired to their target mRNA, both siRNAs, and miRNAs cause a single phosphodiester link in the target mRNA to be cleaved. This cleavage is caused by the RISC's “Slicer” activity, which is located between the residues coupled to siRNA nucleotides 10 and 11 (counting from the siRNA 5’ end).

Figure 2. Mechanisms of miRNA biological functions: The mature miRNA molecule, the argonaute2 (AGO2) protein, and accessory proteins formed the miRNA-induced silencing complex (RISC), in which the miRNA strand locates the 3'UTRs end of targeted mRNA to regulate the stability and translation efficiency via an antisense mechanism, resulting in their degradation or translational repression

Argonautes are highly conserved 100-kDa proteins found in Archaeal and eubacteria, and they comprise the core of the RISC. They have the PAZ and PIWI signature domains [24]. The Argonaute PAZ domain has an oligonucleotide-binding fold that anchors the single-stranded 3'end of small RNAs [27]. Most importantly, the PIWI domain of two Archaeal proteins was shown to have a fold similar to that of RNase H [28], an enzyme that cleaves RNA. This immediately suggested that the mRNA-cleaving ‘‘Slicer” activity could be found in the Ago protein. Co-crystal structures of an archaeal Ago protein with siRNA mimics revealed that the PIWI domain has a conserved binding pocket for the 5' phosphate of short RNAs [29]. These findings point to a scenario in which the short RNA is jammed between the Ago protein's PAZ and PIWI domains, bringing the target mRNA scissile bond close to the catalytic core. Although all human Ago proteins bind both miRNAs and siRNAs, mRNA cleavage is only supported by Ago2-containing complexes [30,31].

Indeed, the mutation study of Ago2 validated the catalytic involvement of three DDH amino acids in the PIWI domain, which are related to the catalytic DDE amino acids of RNase H. [30]. The discovery that bacterially produced Ago2 protein can direct mRNA cleavage when complexes with a single-stranded siRNA have proved unequivocally that Ago2 is the only protein required for this action in humans [32]. In the 3'UTR of the Hoxb8 mRNA, the mammalian miR196 has a near-perfect complementary sequence that causes direct mRNA cleavage and degradation of the target mRNA [33]. All other mammalian miRNAs are thought to base-pair to their targets at partially complementary locations, inhibiting protein accumulation.

2.2.1. Decapping and Degradation of Targeted mRNA

It's worth noting that miRNAs currently appear to influence gene silence via different mechanisms such as endonucleolytic cleavage and cleavage independent mRNA degradation. The prototypical miRNAs, lin-4 and let-7, were found to lower target mRNA levels in recent research of Caenorhabditis elegans [34]. RISC components, AGO1/2, miRNAs, and targeted mRNAs have all been found to be localized within cytoplasmic processing bodies (P-bodies), sometimes known as GW-bodies [Figure 3] which is derived from GW182, a major subunit of these structures [35]. The decapping complex DCP1/ DCP2 and the 5'-3' exonuclease XRN1 genes are involved in mRNA turnover, and P-bodies concentrate them. The RNA-binding proteins GW182 and DCP 1/DCP2 are needed for miRNA-mediated gene silence [36], implying that P-body components play an important role in the miRNA pathway and miRNA-mediated decapping and degradation of targeted mRNAs.

Figure 3. Mechanisms of miRNA decapping, and destruction of target mRNA: Long primary miRNAs (pri-miRNAs) are transcribed and cleaved at hairpin-stems by the Drosha/DGCR8 microprocessor complex, resulting in pre-miRNAs in the nucleus. Pre-miRNAs are cleaved into miRNA duplexes by Dicer/TRBP after nuclear export, and the guide strand of the duplexes is integrated into RISC. Because Dicer/TRBP is linked to Ago2, a critical component of RISC, these two stages may be linked. MiRNAs are expected to influence around 30% of the genes in the human genome through a variety of processes, with oncogenes and tumor suppressor genes among their targets. Within P-bodies, miRNAs can cause deadenylation, decapping, and destruction of target mRNAs, as well as suppressing translation at the initiation and elongation phases (GW-bodies). [Figure credit: Reference [35]]

The Argonaute proteins interact physically with GW182, whose silencing delocalizes resident P-body proteins and inhibits miRNA-mediated silencing [37]. Ref [38] recently proposed that the miRNA machinery components Dicer and Ago are vital for mRNA decay directed by an Adenylate/uridylate–rich elements (AU-rich element) in 3'UTR (ARE) and the human miR-16, which is complementary to ARE is also required for such ARE-RNA decay, implying a functional link between mRNA decay and miRNA machinery. As a result of the accumulation of miRNA and target mRNA complexes in P-bodies, it's possible that miRNA-mediated gene silencing involves sequestration, decapping, and destruction of target mRNA. Furthermore, miR-125 b and let-7 have been demonstrated to speed up the removal of poly (A) tails as a first step in the rapid degradation of mRNAs containing poorly complementary regions [39].

Deadenylation of target mRNAs, resulting in the disruption of the closed mRNA structure and exposing of the cap-E IF4E complex (Figure 3), is one proposed scenario for miRNA-mediated mRNA accumulation in P-bodies. This interacts with a P-body component, the EIF4E-transporter (EIF4E- T), and then causing the target mRNAs to be sequestered [40]. Because of nearly perfect base pairing, miRNAs cause cleavage and subsequent destruction of target mRNAs in plants. Furthermore, miR-196-directed cleavage of mouse HOXB8 mRNA has been demonstrated using the conserved almost perfect base pairing. As a result, it appears that numerous pathways are involved in miRNA-directed gene silencing.

3. MicroRNA Regulation Control at Transcriptional Level

MiRNA expression changes in cancer can be caused by genetic alterations in miRNA genomic loci. In B-cell chronic lymphocytic leukemia (CLL), for example, the chromosomal locus of the miR-15/miR-16 cluster is frequently removed [41,42]. In myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), miR-146a is reduced as a result of chromosome 5q deletion [43]. MiRNA expression is controlled at the transcriptional level, which is mediated by transcription factors and the epigenetic control of DNA methylation, in addition to it microprocessors effect.

3.1. MicroRNA Dysregulation by Transcription Factors.

Several investigations have shown that aberrant pri-miRNA production in cancer is caused by changes in transcriptional activators or repressors. The transcription factor p53, for example, regulates the expression of the miR-34 family genes (miR-34a, miR-34b, and miR-34c), indicating the importance of p53 activity in predicting miR-34 expression in human malignancies. P53 is activated and regulates miR-34 production in response to DNA damage and oncogenic stress, which affects cell cycle arrest, apoptosis, and senescence (Table 1). Upregulated p53 also activates miR-145 transcriptionally, inducing apoptosis [44]. On the other hand, oncogenic RAS signaling also promotes carcinogenesis and suppresses the miR-143/145 cluster. The RAS-responsive element-binding protein 1 (RREB1) causes the miR-143/145cluster to be transcriptionally repressed, and miR-143/145 decreases RREB1 production, producing a tumor-promoting feedback loop of RAS signaling [45]. Other transcription factors that regulate miR-145 in human malignancies include CCAAT-enhancer-binding protein Beta (C-EBP), Transcription Factor 4 (TCF4), and Forkhead transcription factors, FOXO1 and FOXO3 [46]. In acute myeloid leukemia (AML) patients, the transcriptional co-factor meningioma1 (MN1) gene is substantially expressed, and its overexpression is inversely linked with miR-20a and miR-18b transcripts.

Table 1. MiRNA Transcriptional Dysregulation in Cancer

MYC-activated miR-17/92 promotes cancer progression by regulating the expressions of E2F Transcription Factor 1, connective tissue growth factor (CTGF), thrombospondin1 (THBS1), and phosphatase and tensin homolog (PTEN) in different malignancies [44]. In lymphoma, on the other hand, MYC decreases the expression of oncosuppressor miRs like miR-26, miR-29, miR-30, and let-7 family members [65]. In hypoxia, the hypoxia-inducible factor-alpha (HIF1) transcription factor promotes the expression of miR-210 and miR-155 [51,66]. Furthermore, transcription of the miR-200 family gene is repressed by the zinc-finger E-box-binding homeobox (ZEB) transcription factors ZEB1 and ZEB2, which are known as important activators for promoting the epithelial-mesenchymal transition (EMT). In nasopharyngeal cancer, miR-200c has also been identified as a transcriptional target of MYC [67]. By binding to the defined miR-21promoter, activation protein1 (AP1), Ets family transcription factor PU.1, nuclear factor I (NFI), and signal transducer and activator of transcription 3 (STAT3), miR-21 transcription is activated [68]. As a result, cancer therapy strategies that target or activate specific transcription factors responsible for the abundance of oncomiRs or oncosuppressor miRs could be investigated.

Nuclear receptors (NRs) are ligand-activated transcription factors that regulate gene expression by binding to target genes' regulatory regions or DNA sequences. Since it was discovered that the NR superfamily contains 48 human members, including the hormone receptors estrogen receptor (ER), progesterone receptor (PR), androgen receptor (AR), glucocorticoid receptor (GR), and mineralocorticoid receptor (MR) [44], several studies have demonstrated that NRs, particularly ER and AR, not only indirectly change miRNA abundance through diverse signaling pathways but also directly change miRNA abundance. In breast cancer, ER binds to the miR-221/222 gene's promoter region and recruits the nuclear receptor co-receptor/silencing mediator for the retinoid thyroid hormone receptor (NCoR/SMRT) complex to limit miR-221/222 expression. ER also suppresses miR-515 transcription, resulting in higher levels of the carcinogenic sphingosine kinase1 (SK1) [58]. AR, like ER, can control the transcriptional output of miRNA loci. For example, oncomiRs, miR-125b, miR-21, miR-221/222, miR-27a, and miR-32, as well as oncosuppressor miRs, miR-135a, and miR-141 [61] have all been found to be directly controlled by AR during prostate cancer growth. Using chromatin immunoprecipitation (ChIP) analysis, researchers were able to show that AR is recruited to the promoter regions of these miRNAs. Other NRs, in addition to ER and AR, can control miRNA expression in cancer. PR, for example, can control the expression of numerous miRNAs in human malignancies, including miR-141, miR-23, miR-320, and let-7 [63]. In leukemia cell lines, glucocorticoids have been found to upregulate miR-15, miR-16, and miR-223 by activating both GR and MR [59]. Therefore, a better knowledge of the molecular basis of NR's control of miRNA expression could lead to new cancer treatment options.

In all, we could deduce that transcription factors can dysregulate miRNAs and genetic or epigenetic changes that result in transcription factor dysregulation can cause miRNA dysregulation, which contributes to malignant transformation.MiRNA expression profiles that identify malignant tissues from normal tissues have been identified by reference [69]. They discovered that several miRNA genes were dysregulated in multiple tumor types, implying that these miRNAs could be downstream targets of pathways that are frequently dysregulated in cancer.

3.2. Epigenetic Control of DNA Methylation on miRNA Expression in Cancer

Many tumors have altered patterns of epigenetic alterations, particularly the methylation of CpG islands in the promoter regions of tumor suppressor genes. Such changes are frequently accompanied by abnormal histone modification patterns. As a result, tumor suppressor gene silence in cancer can be triggered not only by deletions and mutations but also by epigenetic alterations [70]. Evidence for an epigenetic link between DNA methylation alteration and miRNA expression in cancer has been increasing in recent years. The methylation of cytosine in the DNA 62 dinucleotide CpG is the most researched epigenetic alteration in cancer cells. CpG islands are non-methylated in normal cells and are transcribed in the presence of the right transcription factors. They are primarily situated in the 5′ region (which includes the promoter, 5′ UTR, and exon 1) of many genes. Tumor suppressors are silenced by methylation of their CpG islands, which leads to malignant transformation [71]. As previously stated, genetic alterations such as deletion, gene amplification, and mutation, as well as transcription factors, can affect miRNA expression. Furthermore, epigenetic modifications, such as methylation of the CpG islands of miRNA promoters, might influence miRNA expression. MiR-127 is repressed by promoter methylation in bladder tumors, according to Saito et al., and its expression can be restored by hypomethylating drugs such as azacitidine [72]. BCL6, an oncogene implicated in the formation of diffuse large B cell lymphoma, is the target of this miRNA, as a result suppressing miR-127 may result in cancer formation. Additional miRNAs that are repressed by methylation in various malignancies and can be reactivated by hypomethylating drugs have been described by other researchers.

Table 2. Epigenetic Alteration Effect on miRNA Expression

In leukemia, lymphoma, breast, colon, and liver malignancies, hypermethylation of the miR-124-1 promoter region is observed, and epigenetic suppression of the miR-124-1loci leads to the activation of its target, CDK6 [73,74]. Endometrial and gastric tumors had methylation of the miR-129-2 promoter region, as well as overexpression of one of its targets, SRY-Box transcription factor4 (SOX4). MiR-200 is frequently inactivated by CpG methylation (Table 2) in bladder, breast, and non-small cell lung malignancies [70]. These findings imply that DNA demethylation can trigger the expression of miRNAs, which may operate as tumor suppressors. We recently discovered that the DNA demethylase TET (ten-eleven translocation) family members (TET1, TET2, and TET3) can expose the epigenetically suppressed miR-200, whereas miR-22 antagonizes miR-200 by directly targeting TETs, promoting breast cancer spreading process and EMT [75]. Among the miR-34 family, the miR-34a and miR-34b/c loci are situated on distinct chromosomes, although both miR-34a and miR-34b/c are hypermethylated in solid malignancies and hematological tumors [76,77]. The role of global methylation in miRNA silencing in CLL has been thoroughly investigated utilizing a genome-wide methylation array and a targeted methylation assay [78,79]. Histone modification, in addition to DNA methylation, influences modulating miRNA expression by chromatin remodeling and collaborating DNA methylation modification. Therefore, a deeper understanding of how various epigenetic components interact with and regulate miRNA expression and output in the pathogenesis of cancer is required.

3.3. Pri-miRNA Processing and Editing Control in Cancer

DROSHA, a class 2 ribonuclease III enzyme, and its cofactor DGCR8 create the “microprocessor,” a heterotrimeric complex that processes the stem-loop secondary structure of the nascent pri-miRNA transcript flanked by single-stranded RNA segments. The microprocessor detects the terminal loop area and the basal junction between the stem and the basal ssRNA segment and then cleaved the dsRNA at 11 bp from the basal junction and released the hairpin-shaped pre-miRNA. The buildup of miscleaved pri-miRNA, as well as the overall generation of pre-miRNA, can be affected by abnormal pri-miRNA processing. Dysregulation of the microprocessor or microprocessor-associated proteins involved in pri-miRNA processing, in addition to genetic mutations of the miRNA sequence, can lead to the overall changes of miRNA expression in cancer.

RNA editing is a key post-transcriptional method for changing particular nucleotides at the RNA level. The RNA modification enzymes adenosine deaminases acting on RNA (ADARs) convert adenosine (A) to inosine (I) in double-stranded RNAs (dsRNAs). ADAR can modify the secondary structure of the dsRNA in the stem region of the pri-miRNA, preventing it from being processed by the DROSHA/DGCR8 microprocessor complex and leading to its degradation by endonuclease V [85]. MiRNA editing is dysregulated in human malignancies, according to recent research, and miRNA-related editing promotes or inhibits tumor formation and progression. Similarly, the level of miRNA editing differs between patients and cancer types (hyper-edited or hypoedited pri-miRNAs). The tissue specificity of ADARs and their over/underexpression in distinct tumor contexts could explain the various patterns of pri-miRNA editing seen in cancer. Despite this, the pathophysiological significance of pri-miRNA editing events in cancer is largely unknown.

3.4. Defective Pre-miRNA Processing and exporting in Cancer

A complex of XPO5 and RAN-GTP,a cofactor of XPO5, transports pre-miRNA synthesized by the microprocessor in the nucleus into the cytoplasm. It is then processed to produce tiny RNA duplexes with a length of 22 nucleotides. DICER1 identifies the 2 nt 3'overhang of pre-miRNA, which is 22 nt away from the cleavage site [86]. To boost the stability of the DICER1-RNA complex and improve the fidelity of miRNA processing, DICER1 binds with the dsRNA-binding protein TARBP2. Importantly, abnormal miRNA expression in cancer is caused by genetic changes and dysregulation of critical components in the pre-miRNA processing stage. Inactivated XPO5 mutations have been found in the sporadic colon, gastric, and endometrial cancers with microsatellite instability [87], causing a deficiency in pre-miRNA export and resulting in pre-miRNA buildup in the nucleus. XPO5 genetic mutations have also been linked to an increased risk of breast cancer [88]. Additionally, by phosphorylating XPO5 at Thr345, Ser416, and Ser497, the extracellular-signal-regulated kinase/mitogen-activated protein kinase (MAPK/ERK) pathway can inhibit pre-miRNA export [89]. In patients with hepatocellular carcinoma, phosphorylation of XPO5 corresponds with a wider downregulation of miRNAs and poor prognosis, giving functional and clinical evidence of XPO5 dysregulation for improper miRNA processing and carcinogenesis. The upstream signaling regulators for pre-miRNA export via XPO5 or Ran-GTP, however, are yet to be properly explored.

3.5. DICER1, TARBP2, and Argonaute Control in miRNA Expression

In human cancer cell lines and mice models of cancer, global suppression of miRNA synthesis by depletion of DICER1 increases cell proliferation and tumorigenesis [90], implying that DICER1 plays an oncogenic role in carcinogenesis. Many forms of malignancies, including pleuropulmonary blastoma, rhabdomyosarcoma, non-epithelial ovarian cancer, and liver tumor, have recurrent somatic and germline DICER1 mutations that alter protein levels and/or function, resulting in improper pre-miRNA processing [91,92]. In cancer, mutations in the RNase III domain of DICER1 significantly lower the expression of 5p miRNAs (miRNAs generated from the 5' side of the pre-miRNA) [93]. The dysregulation of pre-miRNA processing is also mediated by DICER1-associated regulatory mechanisms. TAp63 reduces tumorigenesis and metastasis by binding directly to DICER [94], implying that both genetic mutation and functional inactivation of DICER1 control global miRNA expression in cancer. In spontaneous and hereditary carcinomas with microsatellite instability, frameshift mutations in TARBP2 are detected, which correlates with lower levels of DICER1 and mature miRNAs [87,95].

In 15% of adenoid cystic carcinomas, TARBP2 is also eliminated [96]. TARBP2, on the other hand, is overexpressed in cutaneous melanoma, adrenocortical carcinoma, and metastatic breast and prostate cancers [97], suggesting that it has a distinct role in many cancer types.

The Argonaute’s only member with intrinsic endonuclease activity, Argonaute 2 (AGO2), is implicated in the accumulation of mature miRNAs [98,99]. AGO2 has been discovered to be overexpressed in a variety of human malignancies, including breast, stomach, and head and neck cancers [100,101]. It is a major regulator of miRNA function and maturation. OncomiRs may be aided in repressing their targets if AGO2 is overexpressed even though AGO2's activities in several forms of cancer have been questioned, its dysregulation has been linked to carcinogenesis in recent years.

4. Therapeutic Potentials of miRNA in Carcinogenesis

MiRNAs have been proposed as a potential therapeutic strategy since they are known to influence important cellular processes by simultaneously manipulating several targets [102]. Oncogenic miRNAs are found to be overexpressed in a variety of human malignancies. As a result, inhibiting or down regulating these miRNAs could restore a gene's normal function. Antisense anti-miR oligonucleotides (AMOs), locked nucleic acid (LNA) anti-miRNAs, miRNA sponges, antagomirs, and miRNA masks are some of the tactics used to block miRNAs. The use of “miRNA mimics” is another viable alternate technique for restoring a gene's normal function. Furthermore, SMIRs (small molecule inhibitors of miRNAs) can decrease miRNA synthesis or actively impede miRNA target engagement. Another technique involves agitating the mechanism of transport and blocking extracellular miRNAs in exosomes. A small molecule called GW4869 has been discovered to be a neutral sphingomyelinase inhibitor that can also block miRNA and exosome secretion [103]. It is reasonable to conclude that miRNA-based treatments have considerable promise for the treatment of cancer since they are extremely selective and ideal targets for targeted therapy.

In another sense, current research suggests that miRNAs could be effective therapeutic targets for a variety of disorders, including cancer. That is, in human cells, antisense 2'O-methyloligoribonucleotides, for example may specifically inactivate matching miRNAs [31]. Induction or direct introduction of miR-221 and miR-222 may inhibit the proliferation of erythroleukemia cells expressing the KIT protein [104], whereas efficient and specific silencing of endogenous miRNAs such as miR-21, which can be achieved with the help of an antisense oligonucleotide specific to a loop sequence of pre-miRNA, may be useful in the treatment of glioblastomas [105]. We discovered that inhibiting miR-175p and miR -20a with antisense oligonucleotides can cause death in lung cancer cells overexpressing the miR-17-92 cluster, indicating that a fraction of lung malignancies may be addicted to these microRNAs. “Reference [106]” recently demonstrated that intravenous delivery of a chemically modified cholesterol-conjugated single-strand RNA corresponding to a mature miRNA dubbed an 'antagomir,' could significantly reduce miRNA expression in most organs except the CNS. Upregulation of genes with 3'-UTR miR-122 recognition motifs resulted in a drop in plasma cholesterol levels after administration of an antagomir mentioned above for miR -122, an abundant liver-specific miRNA. These findings suggest that miRNA silencing could be used to treat cancer and other types of disorders in the future. Functional screening for miRNAs involved in cell growth or death using a library of miRNA inhibitors could pave the way for the development of new miRNA-based treatments. Overexpression of tumor suppressor miRNAs, such as the let-7 family, could also be an effective method for controlling tumor growth [107].

5. Conclusion

MiRNAs regulate the expression of target mRNAs in a variety of ways and are influenced by a variety of events. In other words, some miRNAs, if not all, may have reversible interactions with their targets. Furthermore, there are submissions that miRNAs may govern other non-coding RNAs at the post-transcriptional level, including their primary transcripts, implying that miRNA regulatory cascades aren't confined to protein-coding transcripts. The abnormal expression of miRNAs in cancer and the oncogenic or tumor-suppressor activities of miRNAs have been demonstrated in numerous research. Similarly, the regulatory mechanisms that control miRNA expression are linked to cancer diagnosis, prognosis, and treatment, as well as cancer pathogenesis. In malignancies, different key players and their partners engaged in the many sequential step process for generating miRNA show unregulated activity and abundance, some of which are known to be influenced by cancer-associated signaling regulators.

Nevertheless, this current knowledge was behind a comprehensive understanding of how miRNA alteration specifically affects cancer pathogenesis, emphasizing the systemic approach to the multi-layered regulation governing miRNA expression in cancers. We have gone through the many steps that go into making miRNAs, as well as the potential regulatory mechanisms that control miRNA expression in malignancies. Dysregulation of miRNA biogenesis inevitably alters a cell's mRNA profile, which has an impact on miRNA expression and function. MiRNAs with imperfect base pairing to their targets are known to inhibit rather than promote simple degradation of their targets. A significant body of data suggests that miRNAs have a role in a wide range of biological processes involving negative post-transcriptional gene regulation.

Because miRNAs have several targets, their role in carcinogenesis could be owing to their control of a few, or even one, or many, of these targets. Identifying all of the targets of the miRNAs involved in cancer and determining their contribution to malignant transformation must be a future task. Identification of all miRNAs that are dysregulated through pathways that are consistently dysregulated in various types of human malignancies would be another issue. Instead of focusing on specific mutations in protein-coding oncogenes or tumor suppressor genes, which may be difficult to treat, we may focus on their downstream miRNA targets. If these miRNA targets are important for the expression of the malignant phenotype, and cancer cells rely on their dysregulation for proliferation and survival, we can expect tumor regression when miRNAs or anti-miRNAs are used. We have seen a transition in the last few years from traditional chemotherapy to targeted therapies, and miRNAs and anti-miRNAs may be a significant tool for such a new era.

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