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1. Introduction

The first miRNA (miRNA, miR) was discovered separately by Ambros and Ruvkun in 1993 ^[1][2][1,2]. Nowadays, nearly 2300 miRs have been recognized. Around 50% of miR sequences are accessible in online databases (miRbase; http://www.mirbase.org/; miRBase V22) and multiple software tools allow to predict targets for miRs of choice [3].

MiRNAs are 20-22 nucleotide-long non-coding RNAs (ncRNAs) that play a crucial role in post-transcriptional regulation of gene expression and their biogenesis is well established. In most cases, miRs are synthesized via the canonical pathway. In this mode, miRs are transcribed individually or as a polycistronic transcript by RNA polymerase II (Pol II), less often by RNA polymerase III (Pol III), in a multistep process. The transcription of miRs is initiated by the formation of primary miRNA (pri-miRNA; Figure 1) in the shape of a hairpin ^[4][5][6][4–6]. The microprocessor complex, containing among others, the DiGeorge critical region 8 (DGCR8) and Drosha enzymes, identifies specific motifs within the sequence of pri-miRNA and releases precursor miRNA (pre-miRNA) by cleaving the stem of the hairpin. This process takes place in the nucleus, but once pre-miRNA is formed, Exportin 5 (Exp5) facilitates its transport to the cytoplasm. The complex made of the Dicer enzyme and TRBP (TAR double-stranded RNA binding protein) captures shuttled pre-miRNA. Dicer presents ribonuclease activity and cuts off the loop of the hairpin and cleaves long double-stranded RNA (dsRNA) into shorter ~20 nucleotide fragments. The generated single-stranded mature miRNA originated from the 5′ and 3′ strands are called 5p and 3p, respectively.

Figure 1. A graphical representation of the canonical pathway of miRNA biogenesis in animals. The MIR gene encodes pri-miRNA. Modification of the pri-miRNA hairpin with two free ends takes place in the cell nucleus. The DGCR8 (DiGeorge critical region 8) and Drosha enzymes cut off the free strands from the hairpin giving pre-miRNA. Then, pre-miRNA is transported into the cytoplasm by Exportin 5 (Exp5), where the Dicer and TRBP (TAR double-stranded RNA binding protein) complex removes the hairpin’s loop and cleaves the molecule into the miRNA duplex. One of the duplex strands, along with the RNA-induced silencing complex (RISC), is involved in mRNA targeting. The second one is degraded.

Biogenesis of miRs via the non-canonical pathways has also been described and is generally divided into two groups: Dicer- and Drosha/DGCR8-independent paths. This mode is often linked with pathological conditions, including cancer ^[4][7][4,7].

The miRNA guide strand anchored to the Argonaute 2 (Ago2) protein targets mRNA during the RNA-induced silencing complex (RISC) loading process ^[4][5][4,5]. Mature miR contains a 2-8 nucleotide-long “seed sequence” that binds to target nucleotides in the 3′ untranslated region of cognate mRNAs, however, binding sites have also been reported in the 5′UTR and coding sequence. The rest of the miR sequence can bind with less complementarity and this allows a miRNA to target multiple mRNAs [4].

The formation of miRNA/Ago2 can harm the production of peptides on various levels, such as: induction of mRNA degradation, affecting proper ribosome assembly and finally, degradation of growing peptides during the process of translation. While the degradation of the mRNA sequence is permanent, the repression of translation can be reversed through detaching miRNA [6]. It has been shown that one microRNA can bind to hundreds of nearly-complementary mRNA sequences and also, one mRNA might be a target for several miRs [8]. MiRs may also cooperate with other ncRNAs including long non-coding RNAs (lncRNAs) [9]. It is assumed that miRs control the expression of nearly 60% of protein-coding genes [10].

MiRNAs are crucial for maintaining cellular development ^[11][12][11,12], differentiation ^[12][13][14][12–14], the cell cycle ^[15][16][17][15–17], proliferation ^{[18][19][20][21]}[18–21], migration ^[22][23][22,23], and apoptosis ^[24][25][24,25]. Apart from their intracellular location, miRNAs are found in biological fluids, such as plasma, saliva, urine, breast milk and might be transferred from one species to another ^[10][26][10,26]. It has been observed that disruption of the miRNA network profile can be linked to several diseases, including cardiovascular diseases, nervous system disorders, and sepsis. Imbalance in the miRNA pool has also been reported in various tumors, such as brain, breast, lung, and colon cancer. MiRNAs may act as either cancer suppressors or as oncogenic factors (oncomiRs). MiR-17-92, miR-21, miR-106, and miR-191 are involved in the development of cancer. Their increased expression has been observed in lung, breast, and gastric cancer, as well as in glioblastoma (GB). On the other hand, depletion of miR-15a, miR-34a, and/or miR-126 suppresses the progression of lung, prostate, and breast tumors [10]. Often, the role of the defined miRNAs is tissue-specific. For example, miR-24 and miR-221/222 are recognized as oncomiRs in breast cancer and glioblastoma, while they act as suppressors in laryngeal or tongue squamous cell carcinoma. Similarly, a dual role of miRNA was observed for miR-155 and miR-125. Lack of miRNA homeostasis in cancer cells promotes enhanced proliferation, angiogenesis, migration, and invasiveness, while blocking apoptosis [27].

It is considered that miRNA can also play a key role in triggering multidrug resistance (MDR) in cancer cells. MDR is a rising therapeutic problem in the treatment of numerous types of tumors as it significantly decreases the effectiveness of anti-cancer drug therapies. Various mechanisms are involved in MDR, including induction of anti-apoptotic machinery or overexpression/activation of several ATP binding cassette (ABC) transporters [28]. Among the 49 ABC proteins, P-glycoprotein (P-gp/ABCB1), breast cancer resistance protein (BCRP/ABCG2), and multidrug resistance-associated protein 1 (MRP1/ABCC1) are the most studied. It has been shown that their high expression correlates with poor prognosis in cancer patients and that a significant portion of cancer-related deaths might be linked with MDR ^{[29][30][31][32][33]}[29–33]. Therefore, there is a need for (i) better understanding of how expression and activity of MDR proteins is managed in tumor cells, (ii) identification of critical genes/proteins/pathways involved in the MDR phenotype of cancer cells, and (iii) elucidation of the role of miRNA in modulation of the MDR phenomenon. Application of antibody- and nano-based vehicles has resulted in major progress in the development of innovative drug delivery systems over the last years ^[34][35][34,35]. Convergence of these strategies with miRNA’s properties might significantly improve therapeutic procedures and effectively impair the progression of diseases, especially in terms of escaping MDR action. The role of miRNA-7 in carcinogenesis and modulation of MDR-encoding genes has been especially highlighted and studied.

2. MiRNA-7

MiRNA-7 (miR-7, hsa-miRNA-7) was first reported in Drosophila melanogaster, nevertheless, the sequence of the guide strand is strongly conserved across different species, which highlights its importance [36]. In humans, miR-7 originates from three precursors: pri-miR-7-1, pri-miR-7-2, and pri-miR-7-3 (Figure 2). They are encoded by the MIR7-1, MIR7-2, and MIR7-3 genes located on three chromosomes: 9q21, 15q26, and 19q13, respectively [37]. Pri-miR-7-1 and pri-miR-7-3 lie within introns of the heterogeneous nuclear ribonucleoprotein K-encoding gene (HNRNPK) and pituitary specific factor 1 gene (PIT1), respectively. The pri-miR-7-2-encoding gene is placed in the intergenic region of chromosome 15 ^[38][39][38,39]. Originally, miR-7 referred to miR-7-5p, since it seemed to be the only mature miRNA from all three precursors that affects cellular pathways. However, other biologically significant miRNAs, miR-7-1-3p and miRNA-7-2-3p, have also been reported ^{[40][41][42][43][44][45]}[40–45]. There are slight changes within the sequence of nucleotides between the miRNAs.

2.1. MiR-7 Biogenesis and Regulation

Mature miR-7 is the product of the canonically transcribed MIR7-1, MIR7-2, and MIR7-3 genes and regulation of transcription proceeds separately for each locus.

Figure 2. Biogenesis of miR-7. (A) miR-7 is the result of transcription of the MIR7-1, MIR7-2, and MIR7-3 genes located on chromosomes 9, 15, and 19, respectively. The generated pri-miRs are transformed into pre-miR-7. Exp5 transports them through the nuclear pores to the cytoplasm (B), where pre-miR-7-1, pre-miR-7-2, and pre-miR-7-3 (C) undergo further modifications. The Dicer complex, cleaves double-stranded RNA (dsRNA) into shorter nucleotide duplexes. Sequences marked in pink are involved in the regulation of mRNA expression.

Apart from regulation of expression of genes encoding for proteins engaged in maturation of miRNA, which applies to all miRNAs, the expression of miR-7 is additionally regulated at the transcriptional level via transcription factors binding to their promoters (Table 1) [36].

It has been shown that transcription of MIR7-1 may be activated by c-Myc ^[46] [46] and homeobox D10 (HOXD10) [47], whereas hepatocyte nuclear factor 4 alpha (HNF4α) induces MIR7-2 transcription [48]. Another transcriptional factor capable of enhancing miR-7 expression is forkhead box P3 (FOXP3) [49]. An opposite role in miR-7 regulation was revealed for v-Rel avian reticuloendoheliosis viral oncogene homolog A (RELA), which has a binding site in the promotor region of MIR7-1 and MIR7-2. MiR-7 itself also inhibits RELA in a negative feedback manner, by directly binding to the 3′UTR of the RELA transcript ^[50][51][52][50–52]. Ubiquitin-specific protease 18 (Usp18) is another transcription inhibitor of all MIR7. Usp18 decreases the expression of miR-7 host genes, as well as intergenic pri-miR-7-2 [53].

MiR-7 biogenesis is also regulated at the post-transcriptional level. The product of MIR7-1 (pri-miR-7-1) might undergo regulation by the Hu antigen R (HuR) and the Musashi homolog 2 (MSI2) complex. HuR enhances MSI2 binding to the pri-miR-7 conserved terminal loop. This inhibits maturation of pri-miR-7-1 to pre-miR-7-1 [54]. The QKI-5 and QKI-6 proteins restrain miR-7 biogenesis from the MIR7-1 gene. Both proteins directly bind to the pri-miR-7-1 sequence, preventing its further processing and capturing the transcript within the nucleus [55]. The SF2/ASF splicing factor directly connects to pri-miR-7 and supports Drosha in cleavage and maturation [56].

Lastly, mature miR-7 can be modulated by competitive endogenous RNAs (ceRNAs) such as circular RNAs (circRNAs) [57]. They are highly stable and resistant to exonuclease activity due to their covalently closed loop form [58]. The first documented circRNA attenuating miR-7 was derived from the CDR1 gene antisense strand and it is known as ciRS-7 (CDR1as). CiRS-7 is highly expressed in brain and neuronal tissue and contains over 70 seed-matched binding sites for miR-7. It may abate silencing of miR-7 targeted transcripts in brain, non-small cell lung cancer (NSCLC), esophageal squamous cell carcinoma, papillary thyroid cancer, and colorectal cancer ^{[59][60][61][62][63]}[59–63]. CircSNCA is another circular RNA inhibiting miR-7 in brain and neuronal tissue. The treatment-induced muting of circSNCA alters the miR-7 level and induces apoptosis and autophagy in Parkinson’s disease [64]. Gao et al. (2017, 2019), based on microarray analysis, discovered that expression of circ_0006528 is elevated in doxorubicin (DOX, adriamycin)-resistant breast cancer MCF-7 cells and tumor tissues. It was confirmed that circ_0006528 silencing increases expression of miR-7-5p ^[65][66][65,66]. Additionally, Li et al. (2019) indicated that circ-U2AF1 (circ_0061868) also presents direct binding properties to miR-7-5p. U2AF1 encodes for the U2 small nuclear RNA auxiliary factor 1 protein and plays a significant role in RNA splicing as part of the U2 auxiliary complex. The level of circ-U2AF1 is increased in glioma tissues. It was found that downregulation of circ-U2AF1 results in upregulation of miR-7-5p [67]. Until now, researchers have discovered several novel circRNAs working as a miR-7 sponge, such as circ_0000735 in prostate cancer [68], circ-ITCH in osteosarcoma [69], circ-TFCP2L1 in breast cancer [70], and circ_0015756 in hepatocellular carcinoma (HCC) [71].

LncRNAs are an alternative group of ncRNAs that play a significant role in regulating the network of gene expression and miRNAs [72]. Recently, altered expression of lncRNAs was linked with miR-7 silencing in multiple tumors. Zheng et al. (2020) confirmed competitive binding properties of cancer susceptibility 21 (CASC21) lncRNA to miR-7-5p, which results in activation of YAP1 in colorectal cancer [73]. Other lncRNAs targeting miR-7-5p in colorectal cancer are lncRNA RP4, terminal differentiation-induced non-coding RNA (TINCR), and Rhophilin Rho GTPase binding protein 1 antisense RNA 1 (RHPN1-AS1 lcRNA) ^[74][75][76][74–76]. Song et al. (2020) confirmed the effect of RHPN1-AS1 lcRNA in HCC [77]. KCNQ1 overlapping transcript 1 (KCNQ1OT1) lncRNA, which interacts with miR-7-5p, is an example of a lncRNA-based MDR modulator in HCC [78].

It has been reported that lncRNA LINC00115, which is upregulated in triple-negative breast cancer and correlates with poor prognosis, acts as a sponge of miR-7-5p [79]. LINC00115 may also regulate miR-7 expression in lung adenocarcinoma [80]. In renal cell carcinoma, maternally expressed gene 3 (MEG3) lncRNA, which is overexpressed in this type of cancer, targets miR-7 [81]. The activity of MEG3 is frequently decreased in various tumors, such as HCC, cervical, and breast cancer. Another lncRNA found in breast cancer is the Hox transcript antisense intergenic RNA (HOTAIR), which suppresses miR-7 indirectly [82].

FOXD2 adjacent opposite strand RNA 1 (FOXD2-AS1) is an oncogenic lncRNA. Thyroid cancer survivors with high expression of FOXD2-AS1 are more prone to relapse. Liu et al. (2019) proved that FOXD2-AS1 has a binding site for miR-7-5p and its downregulation restores a decreased level of miR-7-5p in thyroid carcinoma [83].

Other lncRNAs affecting miR-7-5p include SOX21 antisense RNA 1 (SOX21-AS1) lncRNA in cervical cancer and urothelial cancer associated 1 (UCA1) lncRNA in hypoxia-resistant gastric cancer cells ^[84][85][84,85]. Antisense non-coding RNA in the INK4 locus (ANRIL) is also engaged in tumorigenesis of many tissues. Li et al. (2020) linked the level of miR-7-5p with ANRIL and its role in the progression of T-cell acute lymphoblastic leukemia [86]. LncRNA Cyrano discovered in the brain similarly presents miR-7 sponging capability [87].

Table 1. The list of reported miR-7 regulators in cancer.

­↑, upregulation; ↓, downregulation.

2.2. MiR-7 Expression and Role in Tissues

MiR-7 is particularly critical in tissue of neuroendocrine origin, such as pancreas or brain. It plays an important role in the development and differentiation of those organs [39]. The hypothalamus and pituitary gland are especially enriched in miR-7, in contrast to the cerebellum, cerebral cortex, striatum, or substantia nigra, where its expression is lower. Such an arrangement may be the result of the presence of MIR7-3 in the intron of the PIT1-encoding gene. In the pituitary gland, miR-7 is involved in regulating the secretion of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) via the prostaglandin F2 receptor negative regulator (PTGRF) [39]. Moreover, miR-7 represses the translation of paired box gene 6 (PAX6; important factor in brain and eye organogenesis) by targeting two sites in the 3′UTR [88]. MiR-7 regulates genes involved in repairing neurons [89] and enables synaptic plasticity [90]. Considering the importance of miR-7 in brain tissue, it is not surprising that its downregulation results in the occurrence of pathological conditions like Parkinson’s disease [91] and brain tumors ^{[92][93][94][95]}[92–95]. On the other hand, upregulation of miR-7 is correlated with progression of Alzheimer’s disease [96], schizophrenia [97], and neuroinflammatory processes ^[98][99][98,99].

In the human pancreas, the highest expression of miR-7 occurs between 13 and 18 weeks of gestation. It is correlated with a hormone secretion boost [100]. In the adult pancreas, the islets are characterized by the greatest expression of miR-7 [101], where it regulates proliferation via targeting regenerating islet-derived (Reg) proteins [102]. Moreover, miR-7 is actively engaged in regulation of insulin secretion and its decreased level is correlated with the development of diabetes ^[103][104][103,104]. Lower expression is also observed in pancreatic cancer and might serve as a putative biomarker of disease progression ^[105][106][105,106].

An altered pattern of miR-7 expression and its influence on tumor progression is observed in other types of cancer like breast cancer ^[51][107][51,107], lung cancer [108], melanoma [109], colorectal cancer [110], and hepatocellular carcinoma [111]. Association of miRNA with the formation of multiple tumors may result from a wide range of activity and involvement in primary cellular pathways. MiR-7 regulates proliferation and protects organs against excessive growth. Downregulation of miRNA in tumors leads to uncontrolled proliferation.

Osteosarcoma patients with low levels of miR-7 have poor prognosis [112]. Additionally, cell lines originating from osteosarcoma exhibit enhanced proliferation in comparison to normal osteoblastic cells [112]. Xia et al. (2018) observed that in pancreatic cancer, miRNA-7 causes intensified proliferation through targeting of MAP3K9, hence suppressing NF-κB and MEK/ERK pathways [106]. In pancreatic cancer, increased proliferation is also a consequence of disruption of the EGFR/STAT3 signaling pathway.

Another type of cancer with disruption in the miR-7 status and poor patient outcome is colorectal cancer (CRC). A depletion of miR-7 in CRC also triggers the EGFR pathway ^[113][114][113,114]. Moreover, miR-7 inhibits Krüppel-like factor 4 (KLF4), which acts as an oncogene transcription factor [115]. Another target in CRC is X-ray repair cross complementing 2 (XRCC2), a DNA-repair protein [110]. MiRNA-7 increases proliferation, migration, and angiogenesis through its targets, while decreasing apoptosis in CRC ^{[110][114][115]}[110,114,115]. In addition, miR-7 blocks metastasis via thyroid receptor interactor protein 6 (TRIP6) [116].

In gastric cancer, miR-7 reduces proliferation and increases apoptosis. However, Lin et al. (2020) linked this function with suppression of Raf-1 [117]. Shi et al. (2014) noticed that expression of both, miR-7 and proteasome activator subunit 3 (REGγ; PSME3), is interfered. REGγ is a direct target for miR-7 and its silencing reduces proliferation and triggers apoptosis [118]. Meanwhile, Wang et al. (2019) investigated the influence of sponging of miR-7 on acceleration of proliferation and migration in triple-negative breast cancer. They associated these findings with serine/threonine-protein kinase PAK 1, which is a direct target for miRNA [70]. Furthermore, miR-7 directly binds to focal adhesion kinase (FAK) triggering downstream effects. In accordance with this, cells showed reduced migration and invasiveness [119]. On the other hand, Yin et al. (2019) found that in glioblastoma, the special AT-rich binding protein 1 (SATB1) is frequently overexpressed. They linked SATB1 with cell migration and invasiveness through its direct impairment by miR-7-5p. The level of miR-7 is also reduced in glioblastoma microvasculature [120]. Restoring its amount prevents extensive proliferation of vascular endothelial cells by targeting Raf-1 [121]. MiR-7 suppresses angiogenesis even in murine xenograft glioblastoma [122]. In melanoma, proliferation and metastasis is inhibited by restoring miR-7 through RELA/NF-κB [109]. In contrast, in non-small cell lung cancer, miR-7 inhibits growth and metastasis via the NOVA alternative splicing regulator 2 (NOVA2) [108] and Bcl-2, a critical regulator of apoptosis [123].

The majority of reports indicate a suppressor role of miR-7 in neoplastic diseases. Restoring the level of miRNA-7 suppresses proliferation and invasiveness and induces apoptosis, reducing malignancy of tumor cells. Since miR-7 is involved in regulation of expression of multiple genes, disrupting its endogenous levels leads to changes in essential signaling pathways. This observation indicates that miR-7 might be a key player in the development of MDR in cancer cells. 

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