Abstract
The G-protein-coupled receptor (GPCR) family is the largest family of cell-surface receptors involved in signal transduction. Aberrant expression of GPCRs and G proteins are frequently associated with prevalent human diseases, including cancer. In fact, GPCRs represent the therapeutic targets of more than a quarter of the clinical drugs currently on the market. MiRNAs (miRNAs) are also aberrantly expressed in many human cancers, and they have significant roles in the initiation, development and metastasis of human malignancies. Recent studies have revealed that dysregulation of miRNAs and their target genes expression are associated with cancer progression. The emerging information suggests that miRNAs play an important role in the fine tuning of many signaling pathways, including GPCR signaling. We summarize our current knowledge of the individual functions of miRNAs regulated by GPCRs and GPCR signaling-associated molecules, and miRNAs that regulate the expression and activity of GPCRs, their endogenous ligands and their coupled heterotrimeric G proteins in human cancer.
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Introduction
More than 20 years ago, the first microRNA (miRNA), lin-4, was discovered in Caenorhabditis elegans (C. elegans) in 1993 by two research groups,1, 2 the second C. elegans miRNA, let-7, was identified in 2000.3 This 7-year time gap could be considered to be related to the immaturity of the genetics and molecular biology methods used to discover miRNAs at that time. However, this delay in advancing the field could be also due to the lack of appreciation of the significant roles of miRNAs in biology among most scientists, who previously regarded miRNA as a worm-specific curiosity. However, the field of miRNA research has remarkably expanded to date with over 28 000 miRNAs discovered in 223 species, including more than 2500 in humans.4 The key word of 'microRNA' currently pulls more than 47 000 publications from PubMed. MiRNAs have been the most characterized of the non-coding RNAs. MiRNAs are a class of small non-coding RNA molecules 19–25 nucleotides in length, which play pivotal roles in normal biological processes, such as development, differentiation, apoptosis, senescence and cell proliferation through gene expression regulation at post-transcriptional levels.5 MiRNA genes are transcribed by RNA polymerase II (Pol II). The transcribed long RNA is capped with a specially modified nucleotide at the 5′ end, poly-adenylated with multiple adenosines (Poly-A) and then spliced. This product is called primary miRNA. Drosha ribonuclease type III processes primary miRNA into precursor-miRNA. Exportin 5 exports Hairpin-shaped precursor-miRNAs from the nucleus to the cytoplasm. In the cytoplasm, the precursor-miRNA hairpin is cleaved by the RNase III enzyme Dicer, and one strand is taken into the RNA-induced silencing complex (RISC), where the miRNA and its target mRNA interact. MiRNAs that bind to the 3′ untranslated region (UTR) of targets with perfect match induce mRNA cleavage, whereas translational repression, and hence reduced protein expression, is induced when matching is imperfect.6 Aberrant miRNA alterations have been identified in a number of human diseases, such as cardiac disorders, immune-related and neurodegenerative diseases, and cancers, to name but a few.7, 8 The direct link between miRNAs and human cancer was first recognized with the observation that tumor-suppressive miR-15 and miR-16 genes were frequently deleted or downregulated in B-cell chronic lymphocytic leukemia samples in 2002.9 A recent explosion of studies have revealed that miRNAs are aberrantly expressed in many cancers.10, 11
The G-protein-coupled receptor (GPCR) family is the largest family of cell-surface receptors involved in signal transduction. The GPCR family of proteins comprises approximately 4% of the protein-coding human genes with over 800 members.12 GPCRs are characterized by a seven-transmembrane domain structure with an extracellular amino terminus and an intracellular carboxyl terminus. Some important functions of GPCRs include regulation of cellular motility, growth, differentiation and gene expression.12 At the physiological level, GPCRs are involved in many processes, such as cardiac function, hormone regulation, immune responses, neurotransmission and sensory functions. Thus, their aberrant activity or expression is deeply associated with some of the most prevalent human diseases.13 Many independent studies have revealed that GPCRs play crucial roles in the malignant transformation of human cancers.13 In 1986, the first direct connection between tumorigenesis and GPCRs was demonstrated by the discovery of the MAS1 proto-oncogene, which encodes a typical GPCR, inducing foci of transformation in NIH3T3 cells.14 Initially considered to represent a cloning anomaly, subsequent studies established that GPCRs are overexpressed in multiple types of cancer, and contribute to cell growth when they are activated by their respective circulating or locally available ligands.13, 15
GPCRs are key transducers of cell signaling from the extracellular environment to the inside of the cell. Many ligands, such as sensory signal mediators (e.g., light and olfactory stimulatory molecules), chemokines, Wnts, hormones, and many others, are capable of inducing conformational changes that promote receptor activation, by altering the position of its transmembrane helices and intracellular loops.16 Members of the large family of GPCRs transduce signaling by activating one or more members of the family of heterotrimeric G proteins, namely α-, β- and γ-subunit of G proteins. The β- and γ-subunits are able to form a stable dimer which is called the βγ complex. Many GPCRs mutually couple to more than one G-protein. For example, rhodopsin preferentially couples to transducing, while β2 adrenergic receptor preferentially couples to Gαs. In addition, both are also capable of coupling with Gαi (GNAI).17 Typically, Gαs (GNAS) stimulates adenylyl cyclase (AC) and increases levels of cyclic AMP (cAMP), whereas Gαi (GNAI) inhibits AC and decreases cAMP levels. The Gαq (GNAQ) members bind to and activate phospholipase C (PLC), which degrades phosphatidylinositol bisphosphate (PIP2) into diacylglycerol and inositol triphosphate. Gα12 (GNA12) and Gαq (GNAQ) members can regulate the activity of key intracellular signaling molecules, such as small GTPases of the Ras and Rho families and members of the mitogen-activated protein kinase family. These effectors in turn activate each cascade of downstream signaling events that eventually results in an alteration of cell function.18
microRNAs targeting chemokine receptors
In this article, we focus on regulatory mechanisms resulting from the interaction between miRNAs and their mRNA targets, involving the inhibition of mRNA expression by promoting its degradation or translational repression of the encoded protein by sequence-specific binding at 3′ UTR of the mRNA, unless otherwise noted. Chemokine receptors are seven-transmembrane cytokine receptors, which interact with extracellular chemokines. There have been 20 distinct chemokine receptors expressed in mammals. Chemokine receptors are divided into four distinct families, CXC chemokine receptors, CC chemokine receptors, CX3C chemokine receptors and XC chemokine receptors. They correspond to the respective subfamilies of chemokines which they can bind to. Among them, CXCR4, a C-X-C motif chemokine receptor, has received considerable attention, as it is overexpressed in a number of cancer types and involved in cell migration towards distant organs during cancer metastasis.19 miR-146 is a direct regulator of CXCR4 expression in several cancers, such as breast cancer,20 Kaposi’s sarcoma (KS)21 and acute myeloid leukemia.22 Wang et al.20 reported that TRAIL-induced miR-146a expression suppresses CXCR4-mediated breast cancer cell migration. Punj et al.21 demonstrated that KS-associated herpesvirus (KSHV)-encoded viral FLICE inhibitory protein (vFLIP) K13 upmodulates miR-146a expression via NF-kappaB activation, which leads to suppression of CXCR4 expression. In gastric cancer, miR-139 is suppressed by CD44 bound to HER2 directly,14 which promotes CXCR4 overexpression.23 miR-139 is also downregulated in laryngeal squamous cell carcinoma (SCC), and Luo et al.24 showed the direct regulation of CXCR4 by miR-139 in laryngeal SCC cells. Multiple additional miRNAs have been reported as direct CXCR4 suppressors, including miR-9 which regulates CXCR4 as a potential tumor suppressor in nasopharyngeal carcinoma25 and oral SCC.26 In addition, in colon cancer miR-12627 and miR-133b28 regulate CXCR4; miR-494-3p in prostate29 and breast cancer;30 miR-302a in breast cancer;31 the miR-302-367 cluster in glioblastoma multiforme;32 and miR-150 in pancreatic cancer,33 together supporting that CXCR4 represent a frequent target for miRNAs in human malignancies.
Recently, the involvement of CXCR6 and its ligand CXCL16 (C-X-C motif chemokine 16) in tumor progression is becoming more evident.34 The CXCR6/CXCCL16 axis act as a positive promoter of cell growth and metastasis in some types of cancer.35 miR-361-5p suppressed CXCR6 expression in hepatocellular carcinoma (HCC).36
CXCR7 is also highly expressed in many malignancies, suggesting CXCR7 is a potential therapeutic target for cancers.37 CXCR7 was firstly thought to be an orphan receptor. However, it is now classified as a member of chemokine receptors which is able to bind CXCL1238 and CXCL11.39 Tumor-suppressive miR-101, which is epigenetically repressed by polycomb repressive complex 2 (PRC2), regulates CXCR7 in HCC.40 In bladder cancer, decreased miR-430 functions as a tumor suppressor by suppressing CXCR7 expression, which leads to downregulation of oncogenic ERK, metalloproteinase-2 (MMP-2) and MMP-9 activity.41
CC chemokine receptor 6 (CCR6) is a C-C motif chemokine receptor protein that is preferentially expressed in dendritic cells, NK cells, B-cells and T-cells.42 CCR6 is a specific receptor for the ligand CCL20,42 and has been reported as a specific marker of Th17 cells and regulatory T-cells segregating from other helper T-cells.43, 44 In cancer cells, CCR6 is regulated by miR-150 in cutaneous T-cell lymphoma,45 and is regulated by miR-518a-5p in colorectal cancer.46
CCR7 is another C-C motif chemokine receptor protein that was identified as a gene induced by Epstein-Barr virus.47 CCR7 is also expressed by many cancers.48 The CCL21–CCR7 chemokine ligand–receptor axis promotes cancer cell metastasis specifically to the lymph nodes.49 In breast cancer cells, decreased let-7a acts as a tumor suppressor by suppressing CCR7 expression.50
microRNAs targeting frizzled homolog proteins
Frizzled homolog proteins (FZDs) are seven-transmembrane receptors, and are activated by the wingless/int1 (WNT) family of lipoglycoproteins.51 Eleven members of FZD (FZD1–FZD10, and SMO) have been identified in humans.51 Intracellular signaling mediated by WNTs/FZDs pathway plays pivotal roles in normal embryonic development, stem cell differentiation, organogenesis and patterning.51 In many cancers, expressions of some FZDs are aberrantly up-modulated, therefore activating the Wnt signaling pathway, which is associated with cancer malignancy and poor patient prognosis.52 FZD7, which is frequently overexpressed in several cancer,52 is regulated by several miRNAs, such as miR-1 in breast cancer,53 miR-23b in colon cancer,54 miR-27a and miR-199a-5p in HCC,55, 56 miR-27b in gastric cancer57 and miR-613 in prostate cancer.58 Besides, it has been reported that FZD2 expression is inhibited by miR-203 in lung cancer,59 FZD4 by miR-493 in bladder cancer,60 FZD5 by miR-124 in renal cell carcinoma,61 FZD6 by miR-199a-5p in colorectal cancer62 and FZD8 by miR-100 in breast cancer,63 all of which may represent direct binding interaction. MiR-338-3p suppresses several oncogenic activities by targeting smoothened (SMO), a component of the hedgehog signaling pathway which is conserved from flies to humans,64 in HCC65 and colorectal cancer.66 MiR-320 also regulates SMO in glioma biological behaviors and stemness.67
microRNAs targeting adhesion-GPCRs
So far, 33 adhesion-GPCRs are identified in humans, and are classified in nine families characterized by the molecular structure of their seven-transmembrane domains and extracellular domain.68 Unlike the classic GPCRs, adhesion-GPCRs have an unusual long N-terminal extracellular domain.69 Many adhesion-GPCRs are still orphan receptors. Recently, several members of the adhesion-GPCRs have received considerable attention, as their functions are often associated with tumorigenesis.70 For example, CD97/ADGRE5 belonging to the EGF-TM7 family71 is overexpressed in several cancers, such as oral,72 esophageal,73 gastric,73 pancreatic73 and colorectal cancers.74 CD97/ADGRE5 is reported as a direct target of tumor-suppressive miRNA-126 in breast cancer cells.75 GPR124/ADGRA2 contributes to gefitinib (EGFR-TKI) resistance in non-small cell lung cancer cells.76 miR-138-5p recovers gefitinib sensitivity in non-small cell lung cancer cells by regulating GPR124/ADGRA2.76
microRNAs regulating sphingosine-1-phosphate (S1P) receptors
Sphingosine-1-phosphate (S1P) is a pleiotropic bioactive lipid mediator. Five isoforms of cell-surface GPCRs, S1P1–S1P5, mediate the actions of S1P in many types of cell. A large number of studies have demonstrated that S1P-associated signaling pathways regulate many processes important for cancer development, such as cell proliferation, survival, migration, invasion, angiogenesis and lymphangiogenesis.77 MiRNA-148a inhibits migration and invasion of ovarian cancer78 and HCC79 cells via targeting S1P1. MiRNA-363-mediated downregulation of S1P1 suppresses the proliferation of HCC cells.80
Additional GPCRs targeted by microRNAs
The renin–angiotensin system is not only an important regulator of cardiovascular and hydro-electrolyte homeostasis, but also has been reported to be involved in some cancer development.81, 82 The effects of angiotensin II (Ang II) are mediated by Ang II type 1 (AGTR1) and Ang II type 2 (AGTR2) receptors.82 AGTR1 is regulated by miR-155 in endometrial cancer,83 and by miR-410 in pancreatic cancer.84
Endothelin receptors are activated by the small bioactive peptides of 21 residues, endothelins 1–3 (ET1–ET3).85 ET1 receptors (ETAR and ETBR) can activate several signaling pathways in both G-protein-dependent and G-protein-independent manner via complexes with β-arrestin (β-arr)-1 or -2.85 ETAR and ETBR are aberrantly overexpressed in many cancers.86 MiR-30a regulates ETAR expression, and reverses chemoresitance in epithelial ovarian cancer cells.87
The G-protein-coupled estrogen receptor-1 (GPER1) participates in the physiology of the reproductive, cardiovascular and central nerve system, but GPER1 is also involved in many estrogen-related diseases, including cancers of the reproductive system, male fertility, cardiovascular disorder and autoimmune diseases.88 MiR-424 regulates GPER1 expression, and suppresses E2 (17β-estradiol)-induced cell proliferation in endometrial cancer cells.89
Many studies have showed that kinin receptors are involved in cancer progression.90 Both kinin receptors, BDKRB1 and BDKRB2, are aberrantly expressed in a variety of cancers and cancer cells.90 MiR-129-1-3p regulates BDKRB2 expression, which leads to suppress cell migration activity in gastric cancer cells.91 Gastrin-releasing peptide (GRP) appears to be involved in the growth of several neoplasms. GRP receptors (GRP-Rs) are expressed in a variety of cancer cells and have limited distribution in normal human tissue.92 MiR-335 and miR-363 can contribute to neuroblastoma tumorigenesis and metastasis via regulating GRPR.93
MiR-103a-3p targets the 5′ UTR, not 3′ UTR, of GPRC5A (class C) in pancreatic cancer cells.94 So far, the findings that the miRNA negatively regulates the expression of the target mRNA in a seed-sequence-dependent manner for the 5′ UTR of mRNAs are quite few.94
These microRNAs targeting G-protein-coupled receptors are summarized in Table 1.
microRNAs regulating GPCR ligands
Chemokines
C-X-C motif chemokine 12 (CXCL12/SDF-1), which is a ligand for CXCR4 and CXCR7, is frequently overexpressed in various cancer types, and its aberrant expression promotes proliferation, migration and invasion through multiple signal pathways.95 CXCL12 is regulated by miR-1 in thyroid cancer,96 miR-101 in cancer-associated fibroblast in lung cancer,97 exosomal miR-126 in chronic myelogenous leukemia98 and miR-126/miR-126* in breast cancer.99 C-X-C motif chemokine 1 (CXCL1), also known as melanoma growth stimulatory activity, is secreted by human melanoma cells, which was found in 1988.100 CXCL1 has tumorigenic potential and is implicated in melanoma pathogenesis.101 Overexpression of CXCL1 is reported in HCC,102 gastric,103 breast,104 bladder105 and prostate cancer.106 MiR-141 regulates CXCL1 expression, which attenuates CXCR2-dependent signaling and then suppresses tumor growth and metastasis mediated by the recruitment of regulatory T-cells in non-small cell lung cancer.107
Interleukin-8 (IL-8/CXCL8) is one of the major mediators of the inflammatory response. IL-8 activates multiple intracellular signaling pathways via two cell-surface GPCRs, CXCR1 and CXCR2. IL-8 induces tumor angiogenesis, tumorigenesis and metastasis of cancer cells in numerous xenograft and orthotopic in vivo models.108 IL-8 is regulated by miR-520b in breast cancer,109 miR-23a in nasopharyngeal carcinoma110 and the miR-302 cluster in gastric cancer.111
The CXCL16 interacts with the chemokine receptor CXCR6.112 Trans-membranous CXCL16 inhibits cell proliferation while soluble CXCL16 promotes cell proliferation and migration.35 MiR-451 inhibits cell growth and invasion activity by regulating CXCL16 in osteosarcoma.113
CC chemokine cysteine motif chemokine ligand 20 (CCL20), also known as liver and activation-regulated chemokine (LARC), or macrophage inflammatory protein-3alpha (MIP-3α), is the only chemokine interacting with CC chemokine receptor 6 (CCR6).114 A number of studies have drawn attention to the CCL20/CCR6 pathway to play a role in the initiation, progression of various cancer entities.115 CCL20 is regulated by miR-21 in colorectal116 and cervical cancer cells.117 RGS16 functions as GTP-activating proteins for Gα subunits, promoting the inactivation of Gα-GTP. RGS16 is a negative regulator of SDF-1-CXCR4 signaling.118 miR-181a regulates RGS16 expression, and promotes tumor angiogenesis and metastasis in chondrosarcoma.119
Wnt ligands and Wnt-associated molecules
Wnt ligands (Wnts) comprise a large family of secreted glycoproteins.120 Wnts are cysteine-rich and highly hydrophobic.120 In the well-known canonical Wnt signaling pathway, Wnt binding to Fzd and low-density lipoprotein receptor-related protein-5 or -6 (LRP5/6) co-receptors stabilizes β-Catenin protein, followed by the β-Catenin is shuttled into the nucleus where it affects the transcription of target genes.120 Dickkopf-related proteins (Dkks) antagonize the canonical Wnt signaling pathway by inhibiting the interaction between Wnt and LRP5/6.121 The receptor tyrosine kinase-like orphan receptors (RORs) are transmembrane proteins that are part of the receptor tyrosine kinase (RTK) family.122 Wnt-5a and ROR2 mediate non-canonical Wnt signaling pathway.123
Wnt-1 is negatively regulated by miR-200b and miR-22 in gastric cancer,124 and by miR-148a in HCC125 and breast cancer cells.126 Mir-26a regulates Wnt-5a, and inhibits cell proliferation, metastasis and epithelial mesenchymal transition and induces G1 phase arrest in prostate cancer cells.127 miR-329 and miR-410, within the chromosome 14q32.2 miRNA cluster, regulate Wnt-7a resulting in the attenuation of the Wnt-β-Catenin signaling pathway in oral SCC.128 Wnt-16 is regulated by miR-374b in T-cell lymphoblastic lymphoma, where Wnt-16 signaling is involved in cell proliferation and antiapoptotic activity.129 LRP6 is regulated by multiply microRNAs including miR-126 in thyroid cancer130 and HCC,131 miR-183 in retinoblastoma,132 miR-202 in HCC,133 miR-513c in glioblastoma134 and miR-610 in HCC.135 LRP1 interaction with the FZD1 is regulated by miR-205 in dermatofibrosarcoma protuberans.136 Dkk-3, which is considered to act as a tumor suppressor, is regulated by miR-183 in prostate cancer,137 miR-582-3p in lung cancer138 and miR-17-92 in neuroblastoma.139, 140 ROR1, a non-canonical Wnt receptor, is regulated by miR-382 in ovarian cancer,141 whereas ROR2 is regulated by miR-124 in osteosarcoma.142
microRNAs regulating Shpk1
S1P is produced intracellularly by two sphingosine kinase isoenzymes, sphingosine kinase type 1 (SphK1) and type 2 (SphK2).143 Of the two SphKs, SphK1 has been shown to be involved in multiple important processes contributing to cancer progression.144 On the other hand, little is known of the biological functions of SphK2, especially in cancer.144 Sphk1 is regulated by miR-124 in gastric145 and ovarian cancer,146 miR-101 in colorectal cancer,147 miR-506 in HCC148 and miR-125 in bladder cancer.149
microRNAs regulating heterotrimeric G proteins
Heterotrimeric G proteins play essential roles when the ligand-GPCR-mediated signaling happens, such as the sensation of smell, light and taste to chemotaxis, inflammation and the coordination of immune responses.150 These signaling reactions commonly occur in fast and short-lived manner. Recent advanced technologies on cancer genome sequencing have revealed an unexpected high frequency of mutations and aberrant expression in G proteins in most tumor types.13 Among the coding genes of Gαi subunits, GNAI1 acts as a suppressor of cell migration and invasion activity in vitro, and it is regulated by miR-320a/c/d in HCC cells.151 miR-138 downregulate GNAI2 expression, resulting in a reduction of cell proliferation and induction of cell cycle arrest and apoptosis in tongue SCC.152 On the contrary, GNAI2 act as metastasis suppressor in HCC, and is regulated by miR-30d.153 GNAI3 also functions as a metastasis suppressor in HCC, and is controlled by miR-222.154 Oncogenic GNA13 is also regulated by multiple microRNAs, including miR-182 and miR-200, which act synergistically in prostate cancer,155 miR-31 in breast cancer156 and miR-29c in colorectal cancer.157
These microRNAs targeting GPCR signaling-associated molecules are summarized in Table 2.
microRNAs regulated by G proteins and GPCR signaling
An increasing number of reports have revealed regulatory mechanisms controlling the expression of miRNAs. Specifically, some miRNAs are under the control of GPCRs and G proteins, functioning as downstream targets of GPCRs. For example, multiple studies have used array-based genome-wide approaches to interrogate miRNAs whose abundance is affected after stimulating GPCRs.
In breast cancers, regulation of miR-148a through GPER has been reported.158, 159 The tumor-suppressive role of miR-148a was documented in both estrogen receptor-positive breast cancers and triple negative breast cancers.158, 159 Interestingly, it was observed that E2-GPER downregulates miR-148a, and that miR-148a in turn downregulates another non-coding RNA, HOTAIR.158 Consequently, E2-GPER upregulates HOTAIR, promoting breast cancer migration. Another study found that miR-144 is induced by GPER through the PI3K/ERK1/2/Elk1 pathway in breast cancer, HCC and cancer-associated fibroblasts.160 As for HCC, the upregulation of oncogenic miR-21 is induced by dehydroepiandrosterone-GPER signaling through mitogen-activated protein kinase or the PI3K/AKT pathway.161
miR-518c-5p and let-7a are under the regulation of CXCL12 (SDF-1)–CXCR4 signaling in oral cancer and acute myeloid leukemia, respectively.162, 163 Detailed experiments were performed to show CXCR4–Yin Yang 1 (YY1)–let-7a–Myc/BCLXL signaling induced chemoresistance in acute myeloid leukemia cells.163
CCL5 promotes angiogenesis in chondrosarcoma by downregulating miR-199 or miR-200b, which target VEGF.164, 165 As for miR-200b, the downregulation is induced via PI3K/Akt signaling.164 This can in turn contribute as in the progression of this highly malignant tumor.
Neurotensin (NTS) and its high affinity receptor (NTSR1) are involved in the progression of several malignant tumors and could represent a potential target for cancer treatment.166 NTS/NTSR1 signaling activates the transcription factor c-Myc in glioblastoma cells, which results in negative regulation of tumor-suppressive miR-29b-1.167
COX2 elevates oncogenic miR-526b in breast cancer by activation of the prostaglandin E2 (PGE2) receptor EP4 (PTGER4).168 Stable overexpression of miR-526b in non-metastatic breast cancer cell lines resulted in increased cellular migration, invasion and epithelial mesenchymal transition phenotype.168 COX2 expression and PGE2 production also upregulates oncogenic miR-17-92 via c-Myc activation in non-small cell lung cancer cells.169
MiRNAs under the regulation of GNA12 have been analyzed in HCC. Activated GNA12 downregulates miR-122 via HNF4α ubiquitination, and downregulation of miR-122 upregulates c-Met, a potent growth factor receptor in the liver, which can contribute to the progression of this cancer type.170 In parallel, activated mutants of GNA12 (Gα12QL) upregulate miR-135b via JunB/AP-1, and miR-135b regulates FOXO1 directly.171 Furthermore, Gα12QL downregulates miR-194, regulating MDM2, which destabilizes FOXO1.171 The FOXO1 transcription factor functions as a regulator of cell cycle progression. Taken together, Gα12QL inhibits the tumor-suppressive role of FOXO1 by miRNA-mediated signals.171
KS is currently a major global health problem as an AIDS-defining angioproliferative neoplasm.172 As previously mentioned, KSHV-encoded vFLIP K13 induces NF-kappaB activity, then upmodulates miR-146a expression, which results in CXCR4 suppression.21 The KSHV-encoded chemokine receptor vGPCR (KSHV-vGPCR) acts as an oncogene in KS development.173 KSHV-vGPCR induces upregulation of miR-34a, which induces genomic instability.174
These microRNAs regulated by G proteins and GPCR signaling are summarized in Table 3.
Conclusion
The availability of large expression data sets of miRNAs and bioinformatics tools to analyze patterns of changes in their relative abundance has contributed to an increased understanding of the role of miRNAs in cancer biology, and in the control of tumor-associated pathways. Dysregulation of G-protein and GPCR signaling leads to the initiation and progression of malignant tumor growth and their metastatic spread. Here, we have reviewed the individual functions of miRNAs that are regulated by GPCRs and GPCR signaling-associated molecules, or that regulate the expression and activity of GPCRs, their endogenous ligands, or their coupled heterotrimeric G proteins. To illustrate the molecular mechanism involved in the interplay between GPCRs and miRNAs in cancer, we provide a scheme depicting the CXCL12–CXCR4–Gi signaling network and miRNAs regulating this signaling system in Figure 1, as an example. An emerging body of evidence shows a plethora of miRNAs that act as fine tuners of GPCR signaling pathways in multiple human cancers. Therefore, understanding the novel mechanism involved and the interplay between GPCRs and miRNAs might be exploited in the future for cancer diagnosis, prevention and treatment.
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Acknowledgements
This work was partially supported by funds provided by the UCSD Moores Cancer Center, and the Office of the Dean, Medical School, UCSD (to JSG) and the KAKENHI Grant Number 15K20071 (to YG).
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Nohata, N., Goto, Y. & Gutkind, J. Onco-GPCR signaling and dysregulated expression of microRNAs in human cancer. J Hum Genet 62, 87–96 (2017). https://doi.org/10.1038/jhg.2016.124
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DOI: https://doi.org/10.1038/jhg.2016.124
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