Role of microRNA-7 in liver diseases: a comprehensive review of the mechanisms and therapeutic applications

Abstract

MicroRNA-7 (miR-7) is a small non-coding RNA, which plays critical roles in regulating gene expression of multiple key cellular processes. MiR-7 exhibits a tissue-specific pattern of expression, with abundant levels found in the brain, spleen, and pancreas. Although it is expressed at lower levels in other tissues, including the liver, miR-7 is involved in both the development of organs and biological functions of cells. In this review, we focus on the mechanisms by which miR-7 controls cell growth, proliferation, invasion, metastasis, metabolism, and inflammation. We also summarize the specific roles of miR-7 in liver diseases. MiR-7 is considered as a tumor suppressor miRNA in hepatocellular carcinoma and is involved in the pathogenesis of hepatic steatosis and hepatitis. Future studies to further define miR-7 functions and its mechanism in association with other types of liver diseases should be explored. An improved understanding from these studies will provide us a useful perspective leading to mechanism-based intervention by targeting miR-7 for the treatment of liver diseases.

INTRODUCTION

MicroRNAs (miRNAs) are endogenous, small non-coding, single-stranded RNAs, 18–24 nucleotides in length, which regulate target gene expression after transcription.¹ miRNAs bind to messenger RNAs (mRNAs) by partial base pairing (partial complementarity) at the 3’-untranslated regions (UTRs), however, there are few reports of its interaction at 5’-UTR and thereby interfere with the process of translation, repressing translation, or inducing mRNA degradation.^{2 3} It also can upregulate translation.⁴ Genes that encode miRNAs are transcribed by RNA polymerase II or III, to a primary transcript (pri-miRNAs). The pri-miRNAs are cleaved into precursor miRNAs (pre-miRNA) by nuclear RNase III Drosha, and then exported to the cytoplasm with the help of nuclear transport receptor exportin. In the cytoplasm, the pre-miRNAs are further processed by cytoplasmic RNase III Dicer into short RNA duplexes or miRNA duplexes which are further processed to form the mature miRNAs.⁵ The biogenesis of miRNAs can be regulated by specific transcription factors and changes in processing at the post-transcriptional level.³ Single nucleotide polymorphisms in miRNA genes also modulate miRNA activity and function.⁶ There are around 1400 mammalian miRNAs and each miRNA can influence hundreds of gene transcripts in regulating cellular biological processes.⁷

MicroRNA-7 (miR-7), first identified in 2001 in Caenorhabditis elegans, is an evolutionarily conserved miRNA.⁸ In humans, miR-7 is encoded by three different genomic loci 9q21, 15q26, and 19q13. The products of the three corresponding sequences are pri-miR-7-1, pri-miR-7-2, and pri-miR-7-3 respectively, and can be processed into the mature miR-7 with 23 nucleotides in length.^{9 10} The biogenesis of miR-7 involves a multistep process (figure 1). Mature miR-7 can be derived from either the 5’ or 3’ arm of the pre-miR-7 and is referred to as miR-7-5p or miR-7-3p, respectively. MiR-7-5p (commonly referred to as miR-7) is the most widely studied mature miR-7 with the sequence (5’ to 3’): UGGAAGACUAGUGAUUUUGUUGU. MiR-7 exhibits a tissue-specific pattern of expression, with abundant levels found in the brain, spleen, and endocrine pancreas.^{11 12} Although it is also expressed at lower levels in other tissues, including the liver, miR-7 is involved in both the development of organs and biological functions of cells.^{13 14} Many studies have shown that miR-7 plays an important role in growth, migration, and invasion of multiple cancers.^15–18

Figure 1.

Biogenesis and structure of the human microRNA-7 (miR-7). The pri-miRNAs are cleaved into precursor miRNAs (pre-miRNA) by nuclear RNase III Drosha, and then exported to the cytoplasm with the help of nuclear transport receptor exportin. In the cytoplasm, the pre-miRNAs are further processed by cytoplasmic RNase III Dicer into short RNA duplexes or miRNA duplexes which are further processed to form the mature miRNAs (see more detail in text). The resulting mature miR-7 is incorporated into the RNA-induced silencing complex (RISC), which can bind and downregulate target messenger RNAs (mRNAs).

In this review, we summarize the current knowledge of miR-7 regarding its functions and implications in disease pathogenesis, the regulation of miR-7, and the roles of miR-7 in liver diseases.

Functional roles of miR-7 in disease pathogenesis

MiRNAs regulate several biological processes in almost all cell types. Specific miRNAs have shown to be principal regulators that control cellular functions and involve in disease pathogenesis. In this section, we summarized the roles of miR-7 and its implications in disease pathogenesis.

Role of miR-7 in regulating lipid and glucose metabolism

MiR-7 plays an important role in lipid metabolism through its effect on transcription factors that are involved in fatty acid oxidation and synthesis. Endoplasmic reticulum lipid raft associated 2 (ERLIN2) is an important protein-coding gene that promotes the retention of sterol response element-binding protein (SREBP), a key regulator in fatty acid synthesis, at the endoplasmic reticulum and prevents the proteolysis required for its activation.¹⁹ MiR-7 can suppress ERLIN2 and activate SREBP, thus increase intra-cellular lipid accumulation.²⁰ The increase in lipid accumulation by miR-7 is accompanied by the enlargement of lipid droplet size through the activation of the cell death-inducing DFF45-like effector (CIDE) protein family.²⁰ Interestingly, miR-7 itself can also be regulated by a transcription factor responsible for fatty acid oxidation, peroxisome proliferator-activated receptor alpha (PPAR-α). Treating Huh7.5 cells with GW6471, a potent PPAR-α antagonist, led to a significant reduction in miR-7 levels, suggested that PPAR-α signaling represses mature miR-7 abundance.²⁰ MiR-7 also exerts its effect on AMP-activated protein kinase (AMPK), a key cellular energy homeostasis.²¹ In this study, miR-7 significantly reduced the 3’-UTR activity of liver kinase B1 (LKB1), the upstream kinase, responsible for phosphorylation of AMPK. Moreover, when THP-1 macrophages were transfected with miR-7 mimic, it significantly decreased the LKB1, AMPK phosphorylation, and the expression of downstream targets such as PPARγ, liver X receptor-alpha and cholesterol efflux regulatory protein (ABCA1), leading to the accumulation of lipid.²¹

MiR-7 also plays an important role in glucose metabolism and insulin signaling pathway. It is essential in the development of the pancreas and regulation of its endocrine function. Inhibition of miR-7 using antisense miR-7 morpholinos during early embryonic life results in an overall downregulation of insulin production, decreased β-cell numbers, and glucose intolerance in the postnatal period. The in vitro inhibition of miR-7 in explanted pancreatic buds also led to β-cell death and lower insulin expression by β-cells.²² Overexpression of miR-7 downregulated the expression of insulin receptor substrate 1 as well as inhibited insulin-stimulated Akt phosphorylation and glucose uptake.^{23 24} MiR-7 is a negative regulator of glucose-stimulated insulin secretion in β cells.²⁵ In a loss-of-function study using Rip-Cre crossed conditional miR-7a2 deficient mice, it demonstrated that selectively ablate miR-7a2 in β cell interfered with late stages of insulin granule fusion with the plasma membrane and affected β cell function.²⁵ Transgenic mice overexpressing miR-7a in β cells developed diabetes due to impaired insulin secretion and β cell dedifferentiation; the process that did not affect β cells proliferation and apoptosis.²⁵ The level of miR-7a was markedly reduced in mouse models with obesity/diabetes as well as in human islets from individuals with obesity and moderate diabetes with compensated β cell function.²⁵ Lastly, the circulating plasma level of miR-7 can also be used as a non-invasive biomarker indicative of glycemic control.²⁶ In addition to miR-7, other miRNAs have also been shown to regulate lipid and glucose metabolism, such as miR-122, miR-33, miR-34, miR-103, miR-104, and miR-370.²⁷

Role of miR-7 in regulating mitochondrial function

The mitochondrial permeability transition pore (PTP) is a conductance channel responsible for maintaining the mitochondrial membrane potential. It consists of three proteins: cyclophilin D, voltage-dependent anion channel 1 (VDAC1), and adenine nucleotide transporter.²⁸ MiR-7 can regulate the expression of mitochondrial proteins and function of PTP and modulate mitochondrial morphology.²⁹ Depolarization of the mitochondria in response to cytotoxic stimuli occurs due to the opening of the mitochondrial PTP.³⁰ MiR-7 significantly inhibited mitochondrial depolarization and the opening of the mitochondrial PTP by targeting VDAC1, following the treatment with 1-methyl-4-phenylpyridinium (MPP⁺), which inhibits complex I of the electron transport chain leading to the depletion of arsenic trioxide and cell death.²⁹ MiR-7-induced mitochondrial dysfunction may have an impact on lipid metabolism as fatty acid β-oxidation is the major pathway for the degradation of fatty acids.

Role of miR-7 in regulating inflammation

A number of miRNAs have been implicated in inflammatory responses such as miR-21, miR-132, miR-125b, miR-146a, miR-150, miR-155, miR-181, miR-132, miR-125b, miR-146a, miR-150, miR-181, and miR-let-7.^{27 31} The role of miR-7-mediated inflammation has been reported primarily in brain tissue. MiR-7 was upregulated in the brain tissue of lipopolysaccharide-induced murine brain tissue inflammation model.³² The induction of miR-7 is believed to be a protective mechanism against inflammation, as in the loss-of-function study using miR-7 deficient mice, miR-7 deficiency aggravates the pathology of brain tissue inflammation.³² MiR-7-5p can also inhibit microglial activation and translational repression of caspase 3, following cerebral ischemia.³³

In vitro experiments showed that miR-7 downregulated the levels of inflammatory cytokines such as interleukin (IL)-1β, IL-8, and tumor necrotic factor-α. Mechanistically, miR-7 can bind to the 3’-UTR of toll-like receptor-4 and inhibits its protein expression.³⁴ MiR-7 negatively regulates the NOD-containing, LRR-containing and pyrin domain-containing protein 3 (NLRP3) inflammasome activation induced by a variety of stimuli via different pathway.³⁵

Role of miR-7 in regulating cellular stress, autophagy, and apoptosis

MiR-7 is considered as a hypoxia-associated miRNA, which is critical to mediate the cellular response to hypoxia. Regulated in development and DNA damage response 1 (REDD1), a negative regulator of mammalian target of rapamycin (mTOR) signaling, is upregulated under hypoxia.^{36 37} During the hypoxic state, miR-7 expression was downregulated in parallel with the upregulation of REDD1 and inhibition of mTOR signaling.³⁷ On the other hand, overexpression of miR-7 reversed the hypoxia-induced inhibition of mTOR.³⁷ It has been reported that miR-7 can regulate autophagy by targeting mTOR. Overexpression of miR-7 is accompanied by increased autophagy in hepatocellular carcinoma (HCC).³⁸ The potential mechanism is that mTOR is a negative regulator of autophagy, while miR-7 targets mTOR and exerts the negative influence.

MiR-7 can regulate cellular apoptosis. It inhibits neuronal apoptosis in a cellular model of Parkinson’s disease by targeting Bax and Sirt2.³⁹ In lung cancer cell lines, miR-7 compromises p53 protein-dependent apoptosis by controlling the expression of the chromatin remodeling factor SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily D member 1.⁴⁰ MiR-7 also targets X-Ray Repair Cross Complementing 2 and p21 activated kinase 2 in regulating cellular apoptosis.^{41 42}

Role of miR-7 in regulating cellular proliferation and cell cycle

Dysregulated miRNAs can function as either tumor suppressors or oncogenes and regulate cellular proliferation and tumorigenesis. In colorectal cancer, miR-7 expression is downregulated, while overexpression of miR-7 remarkably suppresses cell proliferation, migration, and invasion.⁴³ The mechanism of miR-7 in the pathogenesis of colorectal cancer is likely related to miR-7 targeting thyroid hormone receptor-interacting protein 6 (TRIP6), a member of LIM family, which acts as an adaptor protein being overexpressed in several tumor types and oncogene Krueppel-like factor 4 (KLF4).^43–45 MiR-7-5p regulates the proliferation and migration of colorectal cancer cells by negatively regulating the expression of KLF4.⁴⁵ MiR-7 also functions as a negative regulator of many oncogenic genes. For example, Yin Yang 1 (YY1) is coded by an oncogenic gene, which results in the inhibition of p53 and activation of Wnt signaling pathways.⁴⁶ By interacting with YY1, miR-7 has tumor suppressive functions of reducing cell proliferation, activating cell-cycle checkpoint in vitro and diminishing xenograft tumor growth.⁴⁶

In gastric cancer, miR-7/nuclear factor kappa B (NF-κB) signaling regulatory feedback circuit regulates gastric carcinogenesis.⁴⁷ A recent study shows that loss of miR-7 promotes p65-mediated aberrant NF-κB activation, facilitating gastric cancer metastasis.⁴⁸ In human clinical specimens, mTOR was highly expressed in gastric cancer tissues compared with adjacent normal tissues. MiR-7 can target mTOR, a key downstream effector of the phosphoinositide 3-kinase (PI3K)/AKT signaling pathway.⁴⁹ MiR-7 also sensitizes gastric cancer cells to cisplatin by targeting mTOR.⁴⁹ In HCC, ectopic overexpression of TRIP6 dramatically promoted the proliferation of hepatocellular carcinoma cells via downregulates FOXO3a transactivity and activates AKT signaling pathway.⁵⁰ In pancreatic cancer, mitogen-activated protein kinase kinase kinase 9 (MAP3K9) significantly enhances cell proliferation and inhibits cell apoptosis partly through activation of the MEK/ERK pathway and NF-κB pathway.^{51 52} MiR-7 suppresses tumor progression by directly targeting MAP3K9 and interleukin enhancer binding factor 2 in pancreatic cancer.^{53 54} MiR-7 is also implicated in glioblastoma by targeting SATB Homeobox 1 (SATB1) and Raf-1 Proto-Oncogene, Serine/Threonine Kinase (RAF1). SATB1 functions to promote cell migration and invasion and RAF1 plays a role in vascular endothelial cell proiferation.^{18 55}

MiR-7 also plays an important role in cell cycle regulation. It causes cell cycle arrest in the G1 phase by directly targeting cyclin E1 (CCNE1) in a study in hepatoma cell line.⁵⁶ Using the loss-of-function approach by silencing of CCNE1, the effect on cell cycle mimics that of miR-7 overexpression, whereas enforced expression of CCNE1 reversed the suppressive effects of miR-7 in cell cycle regulation.⁵⁶ In addition to CCNE1, miR-7 can also target other genes including S-Phase kinase associated protein 2 and proteasome activator complex subunit 3 and trigger cell cycle arrest at the G1/S transition.^{57 58} Upregulation of miR-7 also inhibits cellular growth, suppresses migration and invasion, and leads to a G0/G1 arrest by targeting CDC28 protein kinase regulatory subunit 2.⁵⁹

Role of miR-7 in regulating epithelial-mesenchymal transition and differentiation

The epithelial-mesenchymal transition (EMT) is a process by which epithelial cells lose their cell polarity and cell-cell adhesion, and gain migratory and invasive properties to become mesenchymal stem cells. Aberrant EMT homeostasis in the human placenta contributes to various pregnancy complications, such as pre-eclampsia and fetal growth restriction. One study unveils the role of miR-7 in linking transforming growth factor (TGF)-β-Smad-mediated EMT with negative regulation of trophoblast invasion.⁶⁰ Attenuated expression of TGF-β type 1 receptor with RNA interference in trophoblastic cells can significantly enhance the trophoblastic invasion.⁶⁰ Loss of E-cadherin expression has been identified as a critical event in EMT.⁶¹ Snail is a strong repressor of E-cadherin expression and a potent EMT effector.⁶² One study shows that suppression of Snail by miR-7, through targeting insulin-like growth factor 1 receptor precursor, increases E-cadherin expression and partially reverses the EMT.⁶³ AXL is a member of the TAM (Tyro3, Axl, Mer) family of receptor tyrosine kinases, which plays a role in the EMT and the initiation of metastasis.^{64 65} AXL expression is mediated by inhibition of miR-34a and miR-7 representing another pathway in the regulation of EMT by miR-7.⁶⁶ The functional roles of miR-7 and its targets are demonstrated in figure 2 and tables 1 and 2.

Figure 2.

Functional roles of microRNA-7 (miR-7) in disease pathogenesis. MiR-7 involves the regulation of lipid and glucose metabolism, mitochondrial function, inflammation, cellular stress, autophagy and apoptosis, cellular proliferation and cell cycle, epithelial-mesenchymal transition, and differentiation.

Table 1.

MicroRNA-7 (miR-7) targeted genes and functions in non-liver-specific diseases

Target mRNA	Gene name	Main function	Cell type or disease	Reference
AXL	anexelekto	Epithelial-mesenchymal transition	Prostate cancer	66
CKS2	Cyclin-dependent kinases regulatory subunit 2	Regulate cell circle	Thyroid papillary cancer cells	59
IGF1R	Insulin-like growth factor 1 receptor precursor	Epithelial-mesenchymal transition	Gastric cancer	63
ILF2	Interleukin enhancer binding factor 2	Carcinogenesis and tumor progression	Pancreatic cancer	54
KLF4	Krüppel-like factor 4	Carcinogenesis and tumor progression	Colorectal cancer cells	45
MAP3K9	Mitogen-activated protein kinase kinase kinase 9	Promotes cell proliferation	Pancreatic cancer	53
mTOR	Mammalian target of rapamycin	Regulates cell growth, cell proliferation, cell motility, and survival	Gastric cancer cells	49
NF-κB	Nuclear factor kappa-light-chain-enhancer of activated B cells	Regulate the immune response to infection, cell migration, and invasion	Gastric cancer	47 48
NLRP3	nod-like receptor protein 3	Microglial activation and neuroinflammation	Parkinson’s disease	35
PAK2	p21 activated kinases 2	Regulate actin cytoskeleton remodeling, motility, differentiation, and attachment	Non-small cell lung cancer	42
PSME3	Proteasome activator complex subunit 3	Regulate cell circle	Chinese hamster ovary cells	57
RAF1	Proto-oncogene c-RAF	Carcinogenesis and tumor progression	Glioblastoma	18
REDD1	Regulated in development and DNA damage response 1	Repress cell growth in hypoxia	HeLa cells	37
RORα	RAR-related orphan receptor alpha	Development of cerebellum, inflammatory pathways	Neuronal cells	32
SATB1	Special AT-rich sequence binding protein 1	Promote cell migration and invasion	Glioblastoma	55
SMARCD1	SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily d, member 1	Cancer developmental processes and tumor repression	Lung cancer cell lines	40
TGFBR1	TGF-β type 1 receptor	Epithelial-mesenchymal transition	Trophoblast	60
TLR4	Toll-like receptor 4	Pathogen recognition and activation of innate immunity	Rat cerebral hemorrhage model	34
TRIP6	Thyroid receptor interactor protein 6	Oncogene in tumorigenesis and cancer progression	Colorectal cancer cells	43
VDAC1	Voltage-dependent anion-selective channel protein 1	Regulate the function of mitochondrial permeability transition pore	Human neuroblastoma SH-SY5Y cells; mouse primary neurons	29
XRCC2	X-ray repair cross complementing 2	Homologous recombination to maintain chromosome stability and repair DNA damage.	Colorectal cancer	41
YY1	Yin Yang 1	Tumor suppressive functions	Colorectal cancer	46

Table 2.

MicroRNA-7 (miR-7) targeted genes and functions specifically to liver diseases

Target mRNA	Gene name	Main function	Cell type and disease	Reference
CCNE1	Cyclin E1	Promote cell survival	HCC	56
HNF4α	Hepatocyte nuclear factor 4α	Carcinogenesis and tumor progression	HCC	107
mTOR	Mammalian target of rapamycin	Promote autophagy	HCC	38
PIK3CD	Phosphoinositide 3-kinase catalytic subunit delta	Carcinogenesis and tumor progression	HCC	105
SKP2	S-phase kinase-associated protein 2	Regulate cell circle	Hepatocytes	58
TRIP6	Thyroid receptor interactor protein 6	Promotes cell proliferation	HCC	50
VDAC1	Voltage-dependent anion-selective channel protein 1	Promote hepatocellular carcinoma proliferation and metastasis	HCC	104
YY1	Yin Yang 1	Regulate lipid metabolism	NAFLD and NASH	110

HCC, hepatocellular carcinoma; NAFLD, non-alcoholic fatty liver disease; NASH, non-alcoholic steatohepatitis.

Regulation of miR-7 by other non-coding RNAs

Regulation of miR-7 by lncRNAs

Long non-coding RNAs (lncRNAs) are commonly defined as a non-protein-coding RNA molecule longer than 200 nucleotides, which can act like a sponge that binds a targeted miRNA to suppress its functions.⁶⁷ LncRNAs are involved in several biological processes such as the shaping of chromatin, replication, transcription, splicing, translation, and post-translational modification of proteins.^{68 69} The sponge of miRNA is an approach to block a specific miRNA’s activity, using a non-coding transcript (lncRNA or 3’-UTR of a reporter gene) which contains multiple binding sites to compete for the interaction of the miR and its mRNA targets.⁷⁰ The mechanism of lncRNA as miR-7 sponge is shown in figure 3.

Figure 3.

The mechanism of microRNA-7 (miR-7) exerting its function by binding with messenger RNA (mRNA), long non-coding RNA (lncRNA) as well as circular RNA (circRNA). (A) miR-7 represses the translation of mRNA. (B) miR-7 induces targeted mRNA to decay. (C) lncRNA competes to binding miR-7 as a sponge. (D) circRNA competes to binding miR-7 as a sponge.

The antisense RNA of SRY-box transcription factor (SOX21), SOX21-AS1, was associated with the progression and prognosis of HCC.⁷¹ High expression of SOX21-AS1 promotes proliferation and invasion through sponging miR-7, ultimately increasing the expression of VDAC1.⁷² Antisense non-coding RNA in the INK4 locus (ANRIL) protects H9c2 cells against hypoxia-induced injury through targeting the miR-7-5p/SIRT1 axis.⁷³ ANRIL downregulates miR-7 to protect human trabecular meshwork cells in an experimental model for glaucoma. This process may activate mTOR and MEK/ERK pathways.⁷⁴

Maternally expressed 3 (MEG3) is a paternally imprinted lncRNA. Its expression is lost in many cancer types.⁷⁵ Overexpression of MEG3 accelerates apoptosis; inhibits cell proliferation, migration, and invasion; and induces G0/G1 phase cell cycle arrest in clear cell renal cell carcinoma (CCRCC). MiR-7 directly binds to MEG3 in the CCRCC tissues, inhibits apoptosis, and promotes the migration and invasion of CCRCC cells.⁷⁶ FOXD2 adjacent opposite strand RNA 1 (FOXD2-AS1) has been widely reported to be implicated in the progression and recurrence of several cancers.^77–79 Further study indicates that lncRNA FOXD2-AS1 functions as a competing endogenous RNA to regulate TERT expression by sponging miR-7-5p in thyroid cancer.⁸⁰ Terminal differentiation-induced non-coding RNA overexpression contributes to colorectal cancer progression by sponging miR-7-5p⁸¹. LncRNA urothelial cancer associated 1 (lncRNA-UCA1) upregulation promotes the migration of hypoxia-resistant gastric cancer cells through the miR-7-5p/EGFR axis.⁸²

Small nucleolar RNA host gene 1 (SNHG1) is widely distributed in the many types of cancer including HCC and indicated poor survival for those patients.⁸³ Downregulation of SNHG1 elevates miR-7 expression, suppresses microglial activation, and NLRP3 inflammasome.⁸⁴ LncRNA KCNQ1OT1 (KCNQ1 overlapping transcript 1) is only expressed from the paternal allele, while the coding gene, KCNQ1 was expressed from the maternal allele. Studies showed that lncRNA KCNQ1OT1 is significantly upregulated in oxaliplatin-resistant HepG2 and Huh7 cells and serves as an endogenous sponge of miR-7-5p.⁸⁵

Regulation of miR-7 by circular RNAs

Circular RNAs (circRNAs) are closed long non-coding RNAs, in which the 5’ and 3’ termini are covalently linked by back splicing of exons from a single pre-mRNA.⁸⁶ CircRNAs have been identified as naturally occurring RNAs that are highly represented in the eukaryotic transcriptome, which exert many effects on cellular biological activities.⁸⁷ Functionally, some circRNAs harbor miRNA binding sites and usually act as miRNA sponges.⁸⁸ MiR-7 is also sponged and regulated by several circRNAs. The mechanism is shown in figure 3. CDR1 antisense RNA (CDR1as), also known as ciRS-7, is the first circRNA with proven biological functions, which contains 70 conserved miR-7 binding sites and acts as a miR-7 sponge.⁸⁹ CDR1as can act as an oncogenic circRNA, which was involved in human tumorigenesis and dysregulated in various kinds of cancers.^{90 91} Recent studies show that silencing CDR1as enhances the sensitivity of breast cancer cells to therapy.⁹² In this context, CDR1as acts as a miR-7 sponge to downregulate REGγ, a member of the 11S proteasome activators.⁹³ REGγ has been found was associated with poor prognosis in breast cancer.⁹⁴ Silencing CDR1as may inhibit the expression of REGγ by removing the competitive inhibitory effect on miR-7 and thus enhance the sensitivity of drug-resistant breast cancer cells.⁹² Some studies demonstrate that the CDR1as/miR-7 axis can possibly serve as a regulator in mediating proliferation, apoptosis, and inflammation in chondrocytes in the process of osteoarthritis development.⁹⁵ For example, CDR1as promotes the proliferation and metastasis of pancreatic cancer by regulating miR-7-mediated EGFR/STAT3 signaling pathway.⁹⁶ CDR1as also triggers the migration and invasion of esophageal squamous cell carcinoma via miR-7/KLF4, miR-7/HOXB13, and NF-κB/p65 pathway.^{79 97} In cellular development, CDR1as regulates osteoblastic differentiation of periodontal ligament stem cells via the miR-7/GDF5/SMAD and p38 MAPK signaling pathway.⁹⁸ In pancreatic islet cells, CDR1as, via miR-7 and its targets, regulates insulin transcription and secretion.⁹⁹

A newly identified circRNA, circ_0015756, is highly expressed in hepatoblastoma.¹⁰⁰ Circ_0015756 promotes proliferation, invasion, and migration by miR-7 dependent inhibition of focal adhesion kinase (FAK) in HCC.¹⁰¹ The high expression level of FAK is associated with tumor progression in HCC.^{102 103} The main sponge of miR-7 and their functions are listed in table 3.

Table 3.

Regulation of miR-7 by other non-coding RNAs

Target lncRNA and circRNA	Gene name	Axis and pathway	Mainly function	Cell type or disease	Reference
SOX21-AS1	SOX21 antisense RNA 1	miR-7/VDAC1	Promote proliferation and invasion	Cervical cancer	72
ANRIL	lncRNA antisense noncoding RNA in the INK4 locus	miR‐7‐5 p/SIRT1	Protect against hypoxia-induced injury	H9c2 cells	73
		mTOR and MEK/ERK pathways	Attenuate oxidative injury	Human trabecular meshwork cells	74
CDR1as	Antisense to the cerebellar degeneration-related protein 1 transcript	miR-7/REGγ	Mediate breast cancer occurrence and its sensitivity to cisplatin	Breast cancer	92
		EGFR/STAT3 signaling pathway	Cell proliferation and tumor invasion	Pancreatic ductal adenocarcinoma	96
		miR-7/KLF4	Carcinogenesis and tumor progression	Esophageal squamous cell carcinoma	97
		NF-κB/p65 signaling pathway	Regulate the immune response to infection, carcinogenesis, and tumor progression	Esophageal squamous cell carcinoma	97
		miR-7/GDF5/SMAD	Differentiation of stem cell	Osteoblastic cells	98
		miR-7/HOXB13	Regulate the immune response to infection, carcinogenesis, and tumor progression	Esophageal squamous cell carcinoma	79
		miR-7/Myrip	Regulates insulin granule secretion	Pancreatic islet cells	99
MEG3	Maternally expressed gene 3	miR-7/RASL11B	Inhibit the apoptosis and promote the migration and invasion	CCRCC	76
FOXD2-AS1	FOXD2 Adjacent Opposite Strand RNA 1	miR-7/TERT	Progression and recurrence of cancers	Thyroid cancer	80
TINCR	Terminal differentiation-induced non coding RNA	PI3K/Akt/mTOR signaling pathway	Cell proliferation, migration, and invasion	Colorectal cancer	81
SNHG1	Small nucleolar RNA host gene 1	miR-7/NLRP3 pathway	Promotes neuroinflammation	Parkinson’s disease	84
KCNQ1OT1	KCNQ1 overlapping transcript 1	miR-7-5p/ABCC1 axis	Resistance to chemotherapy	HCC	85
UCA1	Urothelial cancer associated 1	miR-7-5p/EGFR axis	Promote tumor metastasis	Gastric cancer cells	82
Circ_0015756	circRNA_0015756	miR-7/FAK	Promote proliferation, invasion, and migration	HCC	101

CCRCC, clear cell renal cell carcinoma; HCC, hepatocellular carcinoma.

Role of miR-7 in the pathogenesis of liver diseases

MiR-7 in HCC

Growing evidence has demonstrated that the aberrant expression of miRNA is a hallmark of malignancies, indicating the important roles of miRNA in the development and progression of cancer. MiR-7 is considered as a tumor suppressor miRNA in multiple types of cancer, including HCC. For example, miR-7 exerts tumor-suppressive effects in hepatocarcinogenesis through the suppression of oncogene CCNE1 (cyclin E1) expression.⁵⁶ Another study showed that miR-7 downregulates the oncogene VDAC1 to influence hepatocellular carcinoma proliferation and metastasis.¹⁰⁴ Phosphoinositide 3-kinase catalytic subunit delta (PIK3CD) is another target of miR-7. By targeting PIK3CD and mTOR, miR-7 efficiently regulates the PI3K/Akt pathway. Therefore, miR-7 functions as a tumor suppressor and plays a substantial role in inhibiting tumorigenesis and reversing the metastasis of HCC.¹⁰⁵

MiR-7 is also associated with sorafenib resistance in HCC. Tyrosine-protein kinase receptor (TYRO3) is a new functional target of miR-7, which regulates proliferation, migration, and invasion of Huh-7 cells through the PI3K/protein kinase B pathway and is markedly elevated with the acquisition of sorafenib resistance.¹⁰⁶ HNF4α is a liver-enriched transcription factor and is indispensable for liver development. Recently, an HNF4α-NF-κB feedback circuit including miR-7 was identified in HCC. MiR-7 is transcriptionally upregulated by HNF4α, which represses RelA expression by way of interaction with RelA-3’-UTR.¹⁰⁷ Nuclear factor 90-nuclear factor 45 complex (NF90-NF45) inhibits the pri-miR-7-1 processing step through the binding of NF90-NF45 to pri-miR-7-1. Therefore, suppression of miR-7 biogenesis by NF90-NF45 also controls cell proliferation in HCC.¹⁰⁸

MiR-7 in NAFLD and NASH

Non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) have been associated with the function and changes in expression levels of miRNAs.¹⁰⁹ Few studies are exploring the role of miR-7 in NAFLD and NASH. The only related study is in a zebrafish model. The author first generated a transgenic miR-7a-sponge model (hC7aSP) in zebrafish. The activities of hepatic miR-7a were disrupted and resulted in the early onset of NAFLD and NASH. The mechanistic study revealed miR-7a-sponge can stabilize YY1 expression, a new miR-7a target, and increase hepatic triglycerides accumulation by reducing the C/EBP homologous protein (CHOP) expression and inducing the transactivation of C/EBP-α and PPAR-γ expression. Furthermore, miR-7a mimic treatment rescued NASH phenotypes. This finding indicated that miR-7a overexpression suppressed liver steatosis and steatohepatitis in the transgenic miR-7a-sponge model, which suggests a novel potential therapeutic application of NAFLD and NASH in humans.¹¹⁰

PERSPECTIVE AND CONCLUSIONS

We now have a much better understanding of the role of miR-7 in human diseases. MiR-7 plays an important role in regulating cell growth, proliferation, lipid metabolism, inflammatory process, and tumorigenesis. MiR-7 can be regulated by other non-coding RNAs and exerts its function by controlling various target genes. MiR-7 is implicated in various types of liver diseases, notably NAFLD and HCC, through various mechanisms. These regulations subsequently trigger a downstream signaling pathway to control tumorigenesis and lipid metabolism. Future studies to further define miR-7 functions and its mechanism in association with other types of liver diseases should be explored. An improved understanding from these studies will provide us a useful perspective leading to mechanism-based intervention by targeting miR-7 for the treatment of liver diseases.