Definition

miR-7 is an ancient miRNA involved in the fine-tuning of several signaling pathways, acting mainly as tumor suppressor. Through downregulation of PI3K and MAPK pathways, its dominant role is the suppression of proliferation and survival, stimulation of apoptosis and inhibition of migration. Besides these functions, it has numerous additional roles in the differentiation process of several cell types, protection from stress and chromatin remodulation. In the brain, one of the most investigated tissues, its downregulation is linked to glioblastoma cell proliferation. miR-7 deregulation is found also in other tumor types, such as liver, lung and pancreas. In some types of lung and oral carcinoma, it can act as oncomir. However, the miR-7 roles in cell fate determination and maintenance of cell homeostasis are still to be fully discovered, as well as the possibilities of its use as a specific biotherapeutic.

1. Introduction

MicroRNAs are short non-coding RNAs (ncRNA) involved in the regulation of specific mRNA translation. Through this process, they regulate numerous cellular functions, participate in signaling circuits and fine-tune cellular differentiation.

miRNAs (miRs) have a complex pathway of biogenesis and regulation of their function. While mature miRNAs are short single-stranded noncoding RNAs of 20–23 nt, they start as pri-miRNAs, several hundred base pairs long with a complex formation pathway. These primary miRNAs are first processed by a microprocessor containing Drosha, an enzyme that cleaves the stem of a hairpin structure formed by future miR sequence and producing pre-miRNA. After nuclear export, further processing is completed by the Dicer enzyme in the cytoplasm, which removes the loop region and produces a miRNA duplex. Only one strand of the duplex is chosen to become the mature miRNA, loaded on the RNA-induced silencing complex (RISC) containing the Argonaute protein. RISC complex with specific miR targets complementary mRNAs and fully complementary mRNA are degraded. Since mature miRNAs of higher eukaryotic cells most often are not fully complementary to their target mRNA, they could cause a translation inhibition [1].

Usually, one mRNA can be targeted by several miRNAs on its 3’UTR. It is supposed that the target site spacing can influence cooperative repression. Although a great number of genes can be influenced by a single miR, in general, miRs act according to the cellular program in a specific cell type and therefore target only a subset of transcripts [2].

One of the first known, and also most investigated miRNAs is miR-7. The seed sequence GGAAGA is evolutionarily conserved and is found in Nematodes, Insects as well as Vertebrates [3]. In Mammals miR-7 dominantly acts as a tumor suppressor and regulates several basic cellular processes, which include proliferation, differentiation, apoptosis, migration and expression of stem cell features. Most discoveries are in regard to its role in the brain and sensory cell differentiation in man and Drosophila, respectively. miRs-7 may stabilize different regulatory networks depending on the conditions of environmental fluctuation during development such as participating in Notch and Epidermal growth factor receptor (EGFR) coherent and incoherent feedforward loops during photoreceptor determination in Drosophila [4].

miR-7 is encoded in three different sites in the human genome. MIR7-1 sequence is present inside the last intron of the heterogeneous nuclear ribonucleoprotein K (hnRNPK) gene, on chromosome 9 (9q21.32) and is considered to be the dominant gene responsible for miR-7 expression. MIR7-2 sequence is present in the intergenic region on chromosome 15, and MIR7-3 in the intron of pituitary gland specific factor 1 gene (PGSF1) or MIR-7 host gene on chromosome 19 [5].

2. Regulation of MiR-7 Expression

miRNA genes' transcription is regulated by their promoters and their products are members of signaling circuits of different cellular processes. miRs are also regulated at several steps during processing into their active form by means of binding to different proteins [6]. miRs can bind different long non-coding RNAs and circular RNAs either to be degraded or to be “preserved” for later function.

As a tumor suppressor, miR-7 expression is often downregulated in different cancer cells (i.e., in brain, lung and colon cancer cells [7-9]). It is also involved in signaling circuits directing differentiation in different tissues and it is regulated by specific transcription factors [10-13]. The miR-7 promoter was found to be silenced by DNA methylation in cancer stem cells [14]. In breast carcinoma, its expression is estrogen-dependent [15]. miR-7 was found to be engaged in a signaling loop with EGFR through Usp18 (Ubp43), a ubiquitin-specific peptidase, whose downregulation raises miR-7 levels [16]. It is also regulated by hepatocyte growth factor (HGF) in breast cells [17]. miR-7 was found to belong to a p53-dependent non-coding RNA network [18,19], as well as the Myc signaling circuit [20].

Different proteins can regulate pri-miR degradation [1]. There are also several proteins, which influence miR-7 maturation, such as protein quaking isoforms (QKI), Musashi homolog 2 (MSI2) and Hu antigen R (HuR) [21,22]. Hansen et al. described the existence of circular RNAs, which contain multiple target sites complementary to a specific miR and consequently influence its activities by binding toit. They can function as miR “sponges” that keep them out of function. The first such molecule was detected in neurons, the cerebellar degeneration-related protein 1 Cdr1 antisense RNA which has many binding sites for miR7 and Hansen et al. named it  as ciRS-7. It contains miR-7 sequences transcribed in the antisense orientation from the CDR1 gene, forming circular RNA (circRNA) Cdr1as with more than 70 binding sites for miR-7 and one perfectly complementary site for miR-671 [23-25]. It seems that Cdr1as binds miR-7s and serves as their reservoir, and their release is regulated with miR-671, which causes cleavage of Cdr1as and liberation of miR-7s to exert their activities. Furthermore, miR-7 was found to be a member of a regulatory network consisting of four ncRNAs: one long ncRNA, one circular and two microRNAs, in the mouse cerebellum [26]. Cyrano is a long ncRNA, which pairs with miR-7 and triggers its destruction. At the same time, this long ncRNA enables upregulation of circular Cdr1as, otherwise downregulated by miR-7. miR-671 was found to be involved in Cdr1as destruction. There are several other circular RNAs, beside ciRS, which downregulate miR-7 activities, and numerous long noncoding RNAs which bind to miR-7 [27-33] as well as other types of RNA:  3′UTR Ube3a-1 mRNA [34] and Small Nucleolar RNA Host Gene 15 (SNHG15) regulating Klf4 through miR-7 [35].

3. MiR-7 and Chromatin Regulation

miR-7 was found to regulate a number of genes involved in chromatin modulation. It can downregulate histone methyl-transferase gene, SETDB1 in different types of cancer cells [36], as well as TET2 and SMARCD1 [37, 38].

4. MiR-7 in signaling pathways

miR-7 regulation is tightly connected with differentiation processes in the pancreas, brain and some other organs (Fig.1.) [10, 39]. It can also influence global cellular expression through the regulation of master transcription factors, such as KLF4, and thus impact the fate of human embryonic stem cells [40]. miR-7 downregulation is linked to the cell proliferation in many tumors, such as glioblastoma, gastric and lung cancer, as its target genes are EGFR and PI3K and pathways inhibited MAPK, PI3K/Akt, and  NF-κB [7,8,41,42,43]. Some of the miR-7 target genes are involved in cell migration, such as PAK and FAK [7,42,44], and others are involved in apoptosis and protection from stress, such as BCL-2, XIAP and PARP [45,46,47]. miR-7 also interferes with several pathways involved in differentiation, such as Hedgehog, wnt and Hox [48, 49, 50]. It targets numerous mRNAs depending on the intracellular milieu. Its role could be to buffer cellular processes under stress conditions and to coordinate cell proliferation with other functions.

Figure 1. Effects of miR-7 on carcinogenesis in different types of tissues. blue: tumor suppressor’s activities; red: activities as oncomirs.

References

1. Treiber, ; Treiber, N.; Meister, G. Regulation of microRNA biogenesis and its crosstalk with other cellular pathways. Nat. Rev. Mol. Cell Biol. 2019, 20, 5–20.
2. Oliveira, C.; Bovolenta, L.A.; Alves, L.; Figueiredo, L.; Ribeiro, A.O.; Campos, V.F.; Lemke, N.; Pinhal, D. Understanding the Modus Operandi of MicroRNA Regulatory Clusters. Cells 2019, 8, 1103.
3. Zhao, ; Zhou, Y.; Guo, M.; Yue, D.; Chen, C.; Liang, G.; Xu, L. MicroRNA-7: Expression and function in brain physiological and pathological processes. Cell Biosci. 2020, 10, 1–12.
4. Li, ; Cassidy, J.J.; Reinke, C.A.; Fischboeck, S.; Carthew, R.W. A MicroRNA Imparts Robustness against Environmental Fluctuation during Development. Cell 2009, 137, 273–282.
5. Horsham, L.; Ganda, C.; Kalinowski, F.C.; Brown, R.A.; Epis, M.R.; Leedman, P.J. MicroRNA-7: A miRNA with expanding roles in development and disease. Int. J. Biochem. Cell Biol. 2015, 69, 215–224.
6. Choudhury, R.; Alves, F.D.L.; De Andrés-Aguayo, L.; Graf, T.; Cáceres, J.F.; Rappsilber, J.; Michlewski, G. Tissue-specific control of brain-enriched miR-7 biogenesis. Genes Dev. 2013, 27, 24–38.
7. Saydam, ; Senol, O.; Würdinger, T.; Mizrak, A.; Ozdener, G.B.; Stemmer-Rachamimov, A.O.; Yi, M.; Stephens, R.M.; Krichevsky, A.M.; Saydam, N.; et al. miRNA-7 Attenuation in Schwannoma Tumors Stimulates Growth by Upregulating Three Oncogenic Signaling Pathways. Cancer Res. 2011, 71, 852–861.
8. Zhao, ; Wang, K.; Liao, Z.; Li, Y.; Yang, H.; Chen, C.; Zhou, Y.; Tao, Y.; Guo, M.; Ren, T.; et al. Promoter mutation of tumor suppressor microRNA-7 is associated with poor prognosis of lung cancer. Mol. Clin. Oncol. 2015, 3, 1329–1336.
9. Zhang, ; Li, X.; Wu, C.W.; Dong, Y.; Cai, M.; Mok, M.T.S.; Wang, H.; Chen, J.; Ng, S.S.M.; Chen, M.; et al. microRNA-7 is a novel inhibitor of YY1 contributing to colorectal tumorigenesis. Oncogene 2012, 32, 5078–5088.
10. Kredo-Russo, ; Mandelbaum, A.D.; Ness, A.; Alon, I.; Lennox, K.A.; Behlke, M.A.; Hornstein, E. Pancreas-enriched miRNA refines endocrine cell differentiation. Development 2012, 139, 3021–3031.
11. Midgley, ; Morris, G.; Phillips, A.O.; Steadman, R. 17β-estradiol ameliorates age-associated loss of fibroblast function by attenuating IFN-γ/STAT1-dependent miR-7 upregulation. Aging Cell 2016, 15, 531–541.
12. Marzioni, ; Agostinelli, L.; Candelaresi, C.; Saccomanno, S.; De Minicis, S.; Maroni, L.; Mingarelli, E.; Rychlicki, C.; Trozzi, L.; Banales, J.M.; et al. Activation of the developmental pathway neurogenin-3/microRNA-7a regulates cholangiocyte proliferation in response to injury. Hepatology 2014, 60, 1324–1335.
13. Chen, ; Shalom-Feuerstein, R.; Riley, J.; Zhang, S.-D.; Tucci, P.; Agostini, M.; Aberdam, D.; Knight, R.A.; Genchi, G.; Nicotera, P.; et al. miR-7 and miR-214 are specifically expressed during neuroblastoma differentiation, cortical development and embryonic stem cells differentiation, and control neurite outgrowth in vitro. Biochem. Biophys. Res. Commun. 2010, 394, 921–927.
14. Xin, ; Liu, L.; Liu, C.; Zhou, L.; Zhou, Q.; Yuan, Y.; Li, S.; Zhang, H. DNA-methylation-mediated silencing of miR-7-5p promotes gastric cancer stem cell invasion via increasing Smo and Hes1. J. Cell. Physiol. 2020, 235, 2643–2654.
15. Masuda, ; Miki, Y.; Hata, S.; Takagi, K.; Sakurai, M.; Ono, K.; Suzuki, K.; Yang, Y.; Abe, E.; Hirakawa, H.; et al. An induction of microRNA, miR-7 through estrogen treatment in breast carcinoma. J. Transl. Med. 2012, 10, S2.
16. Duex, E.; Comeau, L.; Sorkin, A.; Purow, B.; Kefas, B. Usp18 Regulates Epidermal Growth Factor (EGF) Receptor Expression and Cancer Cell Survival via MicroRNA-7. J. Biol. Chem. 2011, 286, 25377–25386.
17. Jeong, D.; Ham, J.; Park, ; Lee, S.; Lee, H.; Kang, H.-S.; Kim, S.J. MicroRNA-7-5p mediates the signaling of hepatocyte growth factor to suppress oncogenes in the MCF-10A mammary epithelial cell. Sci. Rep. 2017, 7, 15425.
18. Blume, J.; Hotzwagenblatt, A.; Hullein, J.; Sellner, L.; Jethwa, A.; Stolz, T.; Slabicki, M.; Lee, K.; Sharathchandra, A.; Benner, A.; et al. p53-dependent non-coding RNA networks in chronic lymphocytic leukemia. Leukemia 2015, 29, 2015–2023.
19. Pollock, ; Bian, S.; Zhang, C.; Chen, Z.; Sun, T. Growth of the Developing Cerebral Cortex Is Controlled by MicroRNA-7 through the p53 Pathway. Cell Rep. 2014, 7, 1184–1196.
20. Gou, ; Wu, K.; Zhou, J.-K.; Xie, Y.; Liu, L.; Peng, Y. Profiling and bioinformatic analysis of circular RNA expression regulated by c-Myc. Oncotarget 2017, 8, 71587–71596.
21. Wang, ; Vogel, G.; Yu, Z.; Richard, S. The QKI-5 and QKI-6 RNA Binding Proteins Regulate the Expression of MicroRNA 7 in Glial Cells. Mol. Cell. Biol. 2013, 33, 1233–1243.
22. Li, -J.; Wang, C.-H.; Zhou, Y.; Liao, Z.-Y.; Zhu, S.-F.; Hu, Y.; Chen, C.; Luo, J.-M.; Wen, Z.-K.; Xu, L. TLR9 signaling repressed tumor suppressor miR-7 expression through up-regulation of HuR in human lung cancer cells. Cancer Cell Int. 2013, 13, 90.
23. Hansen, B.; Jensen, T.I.; Clausen, B.H.; Bramsen, J.B.; Finsen, B.; Damgaard, C.K.; Kjems, J. Natural RNA circles function as efficient microRNA sponges. Nat. Cell Biol. 2013, 495, 384–388.
24. Memczak, ; Jens, M.; Elefsinioti, A.; Torti, F.; Krueger, J.; Rybak, A.; Maier, L.; Mackowiak, S.D.; Gregersen, L.H.; Munschauer, M.; et al. Circular RNAs are a large class of animal RNAs with regulatory potency. Nat. Cell Biol. 2013, 495, 333–338.
25. Rajman, ; Schratt, G. MicroRNAs in neural development: From master regulators to fine-tuners. Development 2017, 144, 2310–2322.
26. Kleaveland, ; Shi, C.Y.; Stefano, J.; Bartel, D.P. A Network of Noncoding Regulatory RNAs Acts in the Mammalian Brain. Cell 2018, 174, 350–362.
27. Zhang, ; Niu, W.; Mu, M.; Hu, S.; Niu, C. Long non-coding RNA LPP-AS2 promotes glioma tumorigenesis via miR-7- 5p/EGFR/PI3K/AKT/c-MYC feedback loop. J. Exp. Clin. Cancer Res. 2020, 39, 1–20.
28. Zhang, ; Zhao, X.; Li, Y.; Zhou, Y.; Zhang, Z. Long noncoding RNA SOX21-AS1 promotes cervical cancer progression by competitively sponging miR-7/VDAC1. J. Cell. Physiol. 2019, 234, 17494–17504.
29. Hu, ; Yang, L.; Li, L.; Zeng, C. Long non-coding RNA KCNQ1OT1 modulates oxaliplatin resistance in hepatocellular carcinoma through miR-7-5p/ ABCC1 axis. Biochem. Biophys. Res. Commun. 2018, 503, 2400–2406.
30. Liu, ; Fu, Q.; Li, S.; Liang, N.; Li, F.; Li, C.; Sui, C.; Dionigi, G.; Sun, H. LncRNA FOXD2-AS1 Functions as a Competing Endogenous RNA to Regulate TERT Expression by Sponging miR-7-5p in Thyroid Cancer. Front. Endocrinol. 2019, 10.
31. Yang, ; Shi, X.; Li, C.; Wang, X.; Hou, K.; Li, Z.; Zhang, X.; Fan, Y.; Qu, X.; Che, X.; et al. Long non-coding RNA UCA1 upregulation promotes the migration of hypoxia-resistant gastric cancer cells through the miR-7-5p/EGFR axis. Exp. Cell Res. 2018, 368, 194–201.
32. Shu, ; Zhang, W.; Huang, C.; Huang, G.; Su, G.; Xu, J. lncRNA ANRIL protects H9c2 cells against hypoxia-induced injury through targeting the miR-7-5p/SIRT1 axis. J. Cell. Physiol. 2020, 235, 1175–1183.
33. Zheng, ; Nie, P.; Xu, S. Long noncoding RNA CASC21 exerts an oncogenic role in colorectal cancer through regulating miR-7-5p/YAP1 axis. Biomed. Pharmacother. 2020, 121, 109628.
34. Valluy, ; Bicker, S.; Aksoy-Aksel, A.; Lackinger, M.; Sumer, S.; Fiore, R.; Wüst, T.; Seffer, D.; Metge, F.; Dieterich, C.; et al. A coding-independent function of an alternative Ube3a transcript during neuronal development. Nat. Neurosci. 2015, 18, 666–673.
35. Chen, ; Guo, H.; Li, L.; Bao, D.; Gao, F.; Li, Q.; Huang, Q.; Duan, X.; Xiang, Z. Long Non-Coding RNA (lncRNA) Small Nucleolar RNA Host Gene 15 (SNHG15) Alleviates Osteoarthritis Progression by Regulation of Extracellular Matrix Homeostasis. Med. Sci. Monit. 2020, 26.
36. Yu, ; Huangyang, P.; Yang, X.; Han, X.; Yan, R.; Jia, H.; Shang, Y.; Sun, L. microRNA-7 Suppresses the Invasive Potential of Breast Cancer Cells and Sensitizes Cells to DNA Damages by Targeting Histone Methyltransferase SET8. J. Biol. Chem. 2013, 288, 19633–19642.
37. Cheng, ; Guo, S.; Chen, S.; Mastriano, S.J.; Liu, C.; D’Alessio, A.C.; Hysolli, E.; Guo, Y.; Yao, H.; Megyola, C.M.; et al. An Extensive Network of TET2-Targeting MicroRNAs Regulates Malignant Hematopoiesis. Cell Rep. 2013, 5, 471–481.
38. Hong, -F.; Lin, S.-Y.; Chou, Y.-T.; Wu, C.-W. MicroRNA-7 Compromises p53 Protein-dependent Apoptosis by Controlling the Expression of the Chromatin Remodeling Factor SMARCD1. J. Biol. Chem. 2016, 291, 1877–1889.
39. De Chevigny, ; Coré, N.; Follert, P.; Gaudin, M.; Barbry, P.; Beclin, C.; Cremer, H. miR-7a regulation of Pax6 controls spatial origin of forebrain dopaminergic neurons. Nat. Neurosci. 2012, 15, 1120–1126.
40. López-Beas, ; Capilla-González, V.; Aguilera, Y.; Mellado, N.; Lachaud, C.C.; Martín, F.; Smani, T.; Soria, B.; Hmadcha, A. miR-7 Modulates hESC Differentiation into Insulin-Producing Beta-like Cells and Contributes to Cell Maturation. Mol.

    Definition

    miR-7 is an ancient miRNA involved in the fine-tuning of several signaling pathways, acting mainly as tumor suppressor. Through downregulation of PI3K and MAPK pathways, its dominant role is the suppression of proliferation and survival, stimulation of apoptosis and inhibition of migration. Besides these functions, it has numerous additional roles in the differentiation process of several cell types, protection from stress and chromatin remodulation. In the brain, one of the most investigated tissues, its downregulation is linked to glioblastoma cell proliferation. miR-7 deregulation is found also in other tumor types, such as liver, lung and pancreas. In some types of lung and oral carcinoma, it can act as oncomir. However, the miR-7 roles in cell fate determination and maintenance of cell homeostasis are still to be fully discovered, as well as the possibilities of its use as a specific biotherapeutic.

    1. Introduction

    MicroRNAs are short non-coding RNAs (ncRNA) involved in the regulation of specific mRNA translation. Through this process, they regulate numerous cellular functions, participate in signaling circuits and fine-tune cellular differentiation.

    miRNAs (miRs) have a complex pathway of biogenesis and regulation of their function. While mature miRNAs are short single-stranded noncoding RNAs of 20–23 nt, they start as pri-miRNAs, several hundred base pairs long with a complex formation pathway. These primary miRNAs are first processed by a microprocessor containing Drosha, an enzyme that cleaves the stem of a hairpin structure formed by future miR sequence and producing pre-miRNA. After nuclear export, further processing is completed by the Dicer enzyme in the cytoplasm, which removes the loop region and produces a miRNA duplex. Only one strand of the duplex is chosen to become the mature miRNA, loaded on the RNA-induced silencing complex (RISC) containing the Argonaute protein. RISC complex with specific miR targets complementary mRNAs and fully complementary mRNA are degraded. Since mature miRNAs of higher eukaryotic cells most often are not fully complementary to their target mRNA, they could cause a translation inhibition [1].

    Usually, one mRNA can be targeted by several miRNAs on its 3’UTR. It is supposed that the target site spacing can influence cooperative repression. Although a great number of genes can be influenced by a single miR, in general, miRs act according to the cellular program in a specific cell type and therefore target only a subset of transcripts [2].

    One of the first known, and also most investigated miRNAs is miR-7. The seed sequence GGAAGA is evolutionarily conserved and is found in Nematodes, Insects as well as Vertebrates [3]. In Mammals miR-7 dominantly acts as a tumor suppressor and regulates several basic cellular processes, which include proliferation, differentiation, apoptosis, migration and expression of stem cell features. Most discoveries are in regard to its role in the brain and sensory cell differentiation in man and Drosophila, respectively. miRs-7 may stabilize different regulatory networks depending on the conditions of environmental fluctuation during development such as participating in Notch and Epidermal growth factor receptor (EGFR) coherent and incoherent feedforward loops during photoreceptor determination in Drosophila [4].

    miR-7 is encoded in three different sites in the human genome. MIR7-1 sequence is present inside the last intron of the heterogeneous nuclear ribonucleoprotein K (hnRNPK) gene, on chromosome 9 (9q21.32) and is considered to be the dominant gene responsible for miR-7 expression. MIR7-2 sequence is present in the intergenic region on chromosome 15, and MIR7-3 in the intron of pituitary gland specific factor 1 gene (PGSF1) or MIR-7 host gene on chromosome 19 [5].

    2. Regulation of MiR-7 Expression

    miRNA genes' transcription is regulated by their promoters and their products are members of signaling circuits of different cellular processes. miRs are also regulated at several steps during processing into their active form by means of binding to different proteins [6]. miRs can bind different long non-coding RNAs and circular RNAs either to be degraded or to be “preserved” for later function.

    As a tumor suppressor, miR-7 expression is often downregulated in different cancer cells (i.e., in brain, lung and colon cancer cells [7-9]). It is also involved in signaling circuits directing differentiation in different tissues and it is regulated by specific transcription factors [10-13]. The miR-7 promoter was found to be silenced by DNA methylation in cancer stem cells [14]. In breast carcinoma, its expression is estrogen-dependent [15]. miR-7 was found to be engaged in a signaling loop with EGFR through Usp18 (Ubp43), a ubiquitin-specific peptidase, whose downregulation raises miR-7 levels [16]. It is also regulated by hepatocyte growth factor (HGF) in breast cells [17]. miR-7 was found to belong to a p53-dependent non-coding RNA network [18,19], as well as the Myc signaling circuit [20].

     

    Different proteins can regulate pri-miR degradation [1]. There are also several proteins, which influence miR-7 maturation, such as protein quaking isoforms (QKI), Musashi homolog 2 (MSI2) and Hu antigen R (HuR) [21,22]. Hansen et al. described the existence of circular RNAs, which contain multiple target sites complementary to a specific miR and consequently influence its activities by binding toit. They can function as miR “sponges” that keep them out of function. The first such molecule was detected in neurons, the cerebellar degeneration-related protein 1 Cdr1 antisense RNA which has many binding sites for miR7 and Hansen et al. named it  as ciRS-7. It contains miR-7 sequences transcribed in the antisense orientation from the CDR1 gene, forming circular RNA (circRNA) Cdr1as with more than 70 binding sites for miR-7 and one perfectly complementary site for miR-671 [23-25]. It seems that Cdr1as binds miR-7s and serves as their reservoir, and their release is regulated with miR-671, which causes cleavage of Cdr1as and liberation of miR-7s to exert their activities. Furthermore, miR-7 was found to be a member of a regulatory network consisting of four ncRNAs: one long ncRNA, one circular and two microRNAs, in the mouse cerebellum [26]. Cyrano is a long ncRNA, which pairs with miR-7 and triggers its destruction. At the same time, this long ncRNA enables upregulation of circular Cdr1as, otherwise downregulated by miR-7. miR-671 was found to be involved in Cdr1as destruction. There are several other circular RNAs, beside ciRS, which downregulate miR-7 activities, and numerous long noncoding RNAs which bind to miR-7 [27-33] as well as other types of RNA:  3′UTR Ube3a-1 mRNA [34] and Small Nucleolar RNA Host Gene 15 (SNHG15) regulating Klf4 through miR-7 [35].

    3. MiR-7 and Chromatin Regulation

    miR-7 was found to regulate a number of genes involved in chromatin modulation. It can downregulate histone methyl-transferase gene, SETDB1 in different types of cancer cells [36], as well as TET2 and SMARCD1 [37, 38].

     

    4. MiR-7 in signaling pathways

     

    miR-7 regulation is tightly connected with differentiation processes in the pancreas, brain and some other organs (Fig.1.) [10, 39]. It can also influence global cellular expression through the regulation of master transcription factors, such as KLF4, and thus impact the fate of human embryonic stem cells [40]. miR-7 downregulation is linked to the cell proliferation in many tumors, such as glioblastoma, gastric and lung cancer, as its target genes are EGFR and PI3K and pathways inhibited MAPK, PI3K/Akt, and  NF-κB [7,8,41,42,43]. Some of the miR-7 target genes are involved in cell migration, such as PAK and FAK [7,42,44], and others are involved in apoptosis and protection from stress, such as BCL-2, XIAP and PARP [45,46,47]. miR-7 also interferes with several pathways involved in differentiation, such as Hedgehog, wnt and Hox [48, 49, 50]. It targets numerous mRNAs depending on the intracellular milieu. Its role could be to buffer cellular processes under stress conditions and to coordinate cell proliferation with other functions.

    Figure 1. Effects of miR-7 on carcinogenesis in different types of tissues. blue: tumor suppressor’s activities; red: activities as oncomirs.

                                                                                                                                

    References

    1. Treiber, ; Treiber, N.; Meister, G. Regulation of microRNA biogenesis and its crosstalk with other cellular pathways. Nat. Rev. Mol. Cell Biol. 2019, 20, 5–20.
    2. Oliveira, C.; Bovolenta, L.A.; Alves, L.; Figueiredo, L.; Ribeiro, A.O.; Campos, V.F.; Lemke, N.; Pinhal, D. Understanding the Modus Operandi of MicroRNA Regulatory Clusters. Cells 2019, 8, 1103.
    3. Zhao, ; Zhou, Y.; Guo, M.; Yue, D.; Chen, C.; Liang, G.; Xu, L. MicroRNA-7: Expression and function in brain physiological and pathological processes. Cell Biosci. 2020, 10, 1–12.
    4. Li, ; Cassidy, J.J.; Reinke, C.A.; Fischboeck, S.; Carthew, R.W. A MicroRNA Imparts Robustness against Environmental Fluctuation during Development. Cell 2009, 137, 273–282.
    5. Horsham, L.; Ganda, C.; Kalinowski, F.C.; Brown, R.A.; Epis, M.R.; Leedman, P.J. MicroRNA-7: A miRNA with expanding roles in development and disease. Int. J. Biochem. Cell Biol. 2015, 69, 215–224.
    6. Choudhury, R.; Alves, F.D.L.; De Andrés-Aguayo, L.; Graf, T.; Cáceres, J.F.; Rappsilber, J.; Michlewski, G. Tissue-specific control of brain-enriched miR-7 biogenesis. Genes Dev. 2013, 27, 24–38.
    7. Saydam, ; Senol, O.; Würdinger, T.; Mizrak, A.; Ozdener, G.B.; Stemmer-Rachamimov, A.O.; Yi, M.; Stephens, R.M.; Krichevsky, A.M.; Saydam, N.; et al. miRNA-7 Attenuation in Schwannoma Tumors Stimulates Growth by Upregulating Three Oncogenic Signaling Pathways. Cancer Res. 2011, 71, 852–861.
    8. Zhao, ; Wang, K.; Liao, Z.; Li, Y.; Yang, H.; Chen, C.; Zhou, Y.; Tao, Y.; Guo, M.; Ren, T.; et al. Promoter mutation of tumor suppressor microRNA-7 is associated with poor prognosis of lung cancer. Mol. Clin. Oncol. 2015, 3, 1329–1336.
    9. Zhang, ; Li, X.; Wu, C.W.; Dong, Y.; Cai, M.; Mok, M.T.S.; Wang, H.; Chen, J.; Ng, S.S.M.; Chen, M.; et al. microRNA-7 is a novel inhibitor of YY1 contributing to colorectal tumorigenesis. Oncogene 2012, 32, 5078–5088.
    10. Kredo-Russo, ; Mandelbaum, A.D.; Ness, A.; Alon, I.; Lennox, K.A.; Behlke, M.A.; Hornstein, E. Pancreas-enriched miRNA refines endocrine cell differentiation. Development 2012, 139, 3021–3031.
    11. Midgley, ; Morris, G.; Phillips, A.O.; Steadman, R. 17β-estradiol ameliorates age-associated loss of fibroblast function by attenuating IFN-γ/STAT1-dependent miR-7 upregulation. Aging Cell 2016, 15, 531–541.
    12. Marzioni, ; Agostinelli, L.; Candelaresi, C.; Saccomanno, S.; De Minicis, S.; Maroni, L.; Mingarelli, E.; Rychlicki, C.; Trozzi, L.; Banales, J.M.; et al. Activation of the developmental pathway neurogenin-3/microRNA-7a regulates cholangiocyte proliferation in response to injury. Hepatology 2014, 60, 1324–1335.
    13. Chen, ; Shalom-Feuerstein, R.; Riley, J.; Zhang, S.-D.; Tucci, P.; Agostini, M.; Aberdam, D.; Knight, R.A.; Genchi, G.; Nicotera, P.; et al. miR-7 and miR-214 are specifically expressed during neuroblastoma differentiation, cortical development and embryonic stem cells differentiation, and control neurite outgrowth in vitro. Biochem. Biophys. Res. Commun. 2010, 394, 921–927.
    14. Xin, ; Liu, L.; Liu, C.; Zhou, L.; Zhou, Q.; Yuan, Y.; Li, S.; Zhang, H. DNA-methylation-mediated silencing of miR-7-5p promotes gastric cancer stem cell invasion via increasing Smo and Hes1. J. Cell. Physiol. 2020, 235, 2643–2654.
    15. Masuda, ; Miki, Y.; Hata, S.; Takagi, K.; Sakurai, M.; Ono, K.; Suzuki, K.; Yang, Y.; Abe, E.; Hirakawa, H.; et al. An induction of microRNA, miR-7 through estrogen treatment in breast carcinoma. J. Transl. Med. 2012, 10, S2.
    16. Duex, E.; Comeau, L.; Sorkin, A.; Purow, B.; Kefas, B. Usp18 Regulates Epidermal Growth Factor (EGF) Receptor Expression and Cancer Cell Survival via MicroRNA-7. J. Biol. Chem. 2011, 286, 25377–25386.
    17. Jeong, D.; Ham, J.; Park, ; Lee, S.; Lee, H.; Kang, H.-S.; Kim, S.J. MicroRNA-7-5p mediates the signaling of hepatocyte growth factor to suppress oncogenes in the MCF-10A mammary epithelial cell. Sci. Rep. 2017, 7, 15425.
    18. Blume, J.; Hotzwagenblatt, A.; Hullein, J.; Sellner, L.; Jethwa, A.; Stolz, T.; Slabicki, M.; Lee, K.; Sharathchandra, A.; Benner, A.; et al. p53-dependent non-coding RNA networks in chronic lymphocytic leukemia. Leukemia 2015, 29, 2015–2023.
    19. Pollock, ; Bian, S.; Zhang, C.; Chen, Z.; Sun, T. Growth of the Developing Cerebral Cortex Is Controlled by MicroRNA-7 through the p53 Pathway. Cell Rep. 2014, 7, 1184–1196.
    20. Gou, ; Wu, K.; Zhou, J.-K.; Xie, Y.; Liu, L.; Peng, Y. Profiling and bioinformatic analysis of circular RNA expression regulated by c-Myc. Oncotarget 2017, 8, 71587–71596.
    21. Wang, ; Vogel, G.; Yu, Z.; Richard, S. The QKI-5 and QKI-6 RNA Binding Proteins Regulate the Expression of MicroRNA 7 in Glial Cells. Mol. Cell. Biol. 2013, 33, 1233–1243.
    22. Li, -J.; Wang, C.-H.; Zhou, Y.; Liao, Z.-Y.; Zhu, S.-F.; Hu, Y.; Chen, C.; Luo, J.-M.; Wen, Z.-K.; Xu, L. TLR9 signaling repressed tumor suppressor miR-7 expression through up-regulation of HuR in human lung cancer cells. Cancer Cell Int. 2013, 13, 90.
    23. Hansen, B.; Jensen, T.I.; Clausen, B.H.; Bramsen, J.B.; Finsen, B.; Damgaard, C.K.; Kjems, J. Natural RNA circles function as efficient microRNA sponges. Nat. Cell Biol. 2013, 495, 384–388.
    24. Memczak, ; Jens, M.; Elefsinioti, A.; Torti, F.; Krueger, J.; Rybak, A.; Maier, L.; Mackowiak, S.D.; Gregersen, L.H.; Munschauer, M.; et al. Circular RNAs are a large class of animal RNAs with regulatory potency. Nat. Cell Biol. 2013, 495, 333–338.
    25. Rajman, ; Schratt, G. MicroRNAs in neural development: From master regulators to fine-tuners. Development 2017, 144, 2310–2322.
    26. Kleaveland, ; Shi, C.Y.; Stefano, J.; Bartel, D.P. A Network of Noncoding Regulatory RNAs Acts in the Mammalian Brain. Cell 2018, 174, 350–362.
    27. Zhang, ; Niu, W.; Mu, M.; Hu, S.; Niu, C. Long non-coding RNA LPP-AS2 promotes glioma tumorigenesis via miR-7- 5p/EGFR/PI3K/AKT/c-MYC feedback loop. J. Exp. Clin. Cancer Res. 2020, 39, 1–20.
    28. Zhang, ; Zhao, X.; Li, Y.; Zhou, Y.; Zhang, Z. Long noncoding RNA SOX21-AS1 promotes cervical cancer progression by competitively sponging miR-7/VDAC1. J. Cell. Physiol. 2019, 234, 17494–17504.
    29. Hu, ; Yang, L.; Li, L.; Zeng, C. Long non-coding RNA KCNQ1OT1 modulates oxaliplatin resistance in hepatocellular carcinoma through miR-7-5p/ ABCC1 axis. Biochem. Biophys. Res. Commun. 2018, 503, 2400–2406.
    30. Liu, ; Fu, Q.; Li, S.; Liang, N.; Li, F.; Li, C.; Sui, C.; Dionigi, G.; Sun, H. LncRNA FOXD2-AS1 Functions as a Competing Endogenous RNA to Regulate TERT Expression by Sponging miR-7-5p in Thyroid Cancer. Front. Endocrinol. 2019, 10.
    31. Yang, ; Shi, X.; Li, C.; Wang, X.; Hou, K.; Li, Z.; Zhang, X.; Fan, Y.; Qu, X.; Che, X.; et al. Long non-coding RNA UCA1 upregulation promotes the migration of hypoxia-resistant gastric cancer cells through the miR-7-5p/EGFR axis. Exp. Cell Res. 2018, 368, 194–201.
    32. Shu, ; Zhang, W.; Huang, C.; Huang, G.; Su, G.; Xu, J. lncRNA ANRIL protects H9c2 cells against hypoxia-induced injury through targeting the miR-7-5p/SIRT1 axis. J. Cell. Physiol. 2020, 235, 1175–1183.
    33. Zheng, ; Nie, P.; Xu, S. Long noncoding RNA CASC21 exerts an oncogenic role in colorectal cancer through regulating miR-7-5p/YAP1 axis. Biomed. Pharmacother. 2020, 121, 109628.
    34. Valluy, ; Bicker, S.; Aksoy-Aksel, A.; Lackinger, M.; Sumer, S.; Fiore, R.; Wüst, T.; Seffer, D.; Metge, F.; Dieterich, C.; et al. A coding-independent function of an alternative Ube3a transcript during neuronal development. Nat. Neurosci. 2015, 18, 666–673.
    35. Chen, ; Guo, H.; Li, L.; Bao, D.; Gao, F.; Li, Q.; Huang, Q.; Duan, X.; Xiang, Z. Long Non-Coding RNA (lncRNA) Small Nucleolar RNA Host Gene 15 (SNHG15) Alleviates Osteoarthritis Progression by Regulation of Extracellular Matrix Homeostasis. Med. Sci. Monit. 2020, 26.
    36. Yu, ; Huangyang, P.; Yang, X.; Han, X.; Yan, R.; Jia, H.; Shang, Y.; Sun, L. microRNA-7 Suppresses the Invasive Potential of Breast Cancer Cells and Sensitizes Cells to DNA Damages by Targeting Histone Methyltransferase SET8. J. Biol. Chem. 2013, 288, 19633–19642.
    37. Cheng, ; Guo, S.; Chen, S.; Mastriano, S.J.; Liu, C.; D’Alessio, A.C.; Hysolli, E.; Guo, Y.; Yao, H.; Megyola, C.M.; et al. An Extensive Network of TET2-Targeting MicroRNAs Regulates Malignant Hematopoiesis. Cell Rep. 2013, 5, 471–481.
    38. Hong, -F.; Lin, S.-Y.; Chou, Y.-T.; Wu, C.-W. MicroRNA-7 Compromises p53 Protein-dependent Apoptosis by Controlling the Expression of the Chromatin Remodeling Factor SMARCD1. J. Biol. Chem. 2016, 291, 1877–1889.
    39. De Chevigny, ; Coré, N.; Follert, P.; Gaudin, M.; Barbry, P.; Beclin, C.; Cremer, H. miR-7a regulation of Pax6 controls spatial origin of forebrain dopaminergic neurons. Nat. Neurosci. 2012, 15, 1120–1126.
    40. López-Beas, ; Capilla-González, V.; Aguilera, Y.; Mellado, N.; Lachaud, C.C.; Martín, F.; Smani, T.; Soria, B.; Hmadcha, A. miR-7 Modulates hESC Differentiation into Insulin-Producing Beta-like Cells and Contributes to Cell Maturation. Mol. Ther. Nucleic Acids 2018, 12, 463–477.
    41. Xu, ; Wen, Z.; Zhou, Y.; Liu, Z.; Li, Q.; Fei, G.; Luo, J.; Ren, T. MicroRNA-7–regulated TLR9 signaling–enhanced growth and metastatic potential of human lung cancer cells by altering the phosphoinositide-3-kinase, regulatory subunit 3/Akt pathway. Mol. Biol. Cell 2013, 24, 42–55.
    42. Liu, ; Jiang, Z.; Huang, J.; Huang, S.; Li, Y.; Yu, S.; Yu, S.; Liu, X. miR-7 inhibits glioblastoma growth by simultaneously interfering with the PI3K/ATK and Raf/MEK/ERK pathways. Int. J. Oncol. 2014, 44, 1571–1580.
    43. Zhao, -D.; Lu, Y.-Y.; Guo, H.; Xie, H.-H.; He, L.-J.; Shen, G.-F.; Zhou, J.-F.; Li, T.; Hu, S.-J.; Zhou, L.; et al. MicroRNA-7/NF-κB signaling regulatory feedback circuit regulates gastric carcinogenesis. J. Cell Biol. 2015, 210, 613–627.
    44. Kong, ; Li, G.; Yuan, Y.; He, Y.; Wu, X.; Zhang, W.; Wu, Z.; Chen, T.; Wu, W.; Lobie, P.E.; et al. MicroRNA-7 Inhibits Epithelial- to-Mesenchymal Transition and Metastasis of Breast Cancer Cells via Targeting FAK Expression. PLoS ONE 2012, 7, e41523.
    45. Xiong, ; Zheng, Y.; Jiang, P.; Liu, R.; Liu, X.; Chu, Y. MicroRNA-7 Inhibits the Growth of Human Non-Small Cell Lung Cancer A549 Cells through Targeting BCL-2. Int. J. Biol. Sci. 2011, 7, 805–814.
    46. Liu, ; Zhang, P.; Chen, Z.; Liu, M.; Li, X.; Tang, H. MicroRNA-7 downregulates XIAP expression to suppress cell growth and promote apoptosis in cervical cancer cells. FEBS Lett. 2013, 587, 2247–2253.]
    47. Lai, ; Yang, H.; Zhu, Y.; Ruan, M.; Huang, Y.; Zhang, Q. MiR-7-5p-mediated downregulation of PARP1 impacts DNA homologous recombination repair and resistance to doxorubicin in small cell lung cancer. BMC Cancer 2019, 19, 1–9.
    48. Zhang, ; Mubarak, T.; Chen, Y.; Lee, T.; Pollock, A.; Sun, T. Counter-Balance Between Gli3 and miR-7 Is Required for Proper Morphogenesis and Size Control of the Mouse Brain. Front. Cell. Neurosci. 2018, 12, 259.
    49. Adusumilli, ; Facchinello, N.; Teh, C.; Busolin, G.; Le, M.T.; Yang, H.; Beffagna, G.; Campanaro, S.; Tam, W.L.; Argenton, F.; et al. miR-7 Controls the Dopaminergic/Oligodendroglial Fate through Wnt/β-catenin Signaling Regulation. Cells 2020, 9, 711.]
    50. Li, ; Zhu, F.; Chen, P. miR-7 and miR-218 epigenetically control tumor suppressor genes RASSF1A and Claudin-6 by targeting HoxB3 in breast cancer. Biochem. Biophys. Res. Commun. 2012, 424, 28–33.
    Ther. Nucleic Acids 2018, 12, 463–477.
41. Xu, ; Wen, Z.; Zhou, Y.; Liu, Z.; Li, Q.; Fei, G.; Luo, J.; Ren, T. MicroRNA-7–regulated TLR9 signaling–enhanced growth and metastatic potential of human lung cancer cells by altering the phosphoinositide-3-kinase, regulatory subunit 3/Akt pathway. Mol. Biol. Cell 2013, 24, 42–55.
42. Liu, ; Jiang, Z.; Huang, J.; Huang, S.; Li, Y.; Yu, S.; Yu, S.; Liu, X. miR-7 inhibits glioblastoma growth by simultaneously interfering with the PI3K/ATK and Raf/MEK/ERK pathways. Int. J. Oncol. 2014, 44, 1571–1580.
43. Zhao, -D.; Lu, Y.-Y.; Guo, H.; Xie, H.-H.; He, L.-J.; Shen, G.-F.; Zhou, J.-F.; Li, T.; Hu, S.-J.; Zhou, L.; et al. MicroRNA-7/NF-κB signaling regulatory feedback circuit regulates gastric carcinogenesis. J. Cell Biol. 2015, 210, 613–627.
44. Kong, ; Li, G.; Yuan, Y.; He, Y.; Wu, X.; Zhang, W.; Wu, Z.; Chen, T.; Wu, W.; Lobie, P.E.; et al. MicroRNA-7 Inhibits Epithelial- to-Mesenchymal Transition and Metastasis of Breast Cancer Cells via Targeting FAK Expression. PLoS ONE 2012, 7, e41523.
45. Xiong, ; Zheng, Y.; Jiang, P.; Liu, R.; Liu, X.; Chu, Y. MicroRNA-7 Inhibits the Growth of Human Non-Small Cell Lung Cancer A549 Cells through Targeting BCL-2. Int. J. Biol. Sci. 2011, 7, 805–814.
46. Liu, ; Zhang, P.; Chen, Z.; Liu, M.; Li, X.; Tang, H. MicroRNA-7 downregulates XIAP expression to suppress cell growth and promote apoptosis in cervical cancer cells. FEBS Lett. 2013, 587, 2247–2253.]
47. Lai, ; Yang, H.; Zhu, Y.; Ruan, M.; Huang, Y.; Zhang, Q. MiR-7-5p-mediated downregulation of PARP1 impacts DNA homologous recombination repair and resistance to doxorubicin in small cell lung cancer. BMC Cancer 2019, 19, 1–9.
48. Zhang, ; Mubarak, T.; Chen, Y.; Lee, T.; Pollock, A.; Sun, T. Counter-Balance Between Gli3 and miR-7 Is Required for Proper Morphogenesis and Size Control of the Mouse Brain. Front. Cell. Neurosci. 2018, 12, 259.
49. Adusumilli, ; Facchinello, N.; Teh, C.; Busolin, G.; Le, M.T.; Yang, H.; Beffagna, G.; Campanaro, S.; Tam, W.L.; Argenton, F.; et al. miR-7 Controls the Dopaminergic/Oligodendroglial Fate through Wnt/β-catenin Signaling Regulation. Cells 2020, 9, 711.]
50. Li, ; Zhu, F.; Chen, P. miR-7 and miR-218 epigenetically control tumor suppressor genes RASSF1A and Claudin-6 by targeting HoxB3 in breast cancer. Biochem. Biophys. Res. Commun. 2012, 424, 28–33.