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Background: Recent research has shown that the adhesion G protein-coupled receptor F1 (Adgrf1; also known as GPR110; PGR19; KPG_012; hGPCR36) is an oncogene. The evidence is mainly based on high expression of Adgrf1 in numerous cancer types, and knockdown Adgrf1 can reduce the cell migration, invasion, and proliferation. Adgrf1 is, however, mostly expressed in the liver of healthy individuals. The function of Adgrf1 in liver has not been revealed. Interestingly, expression level of hepatic Adgrf1 is dramatically decreased in obese subjects. Here, the research examined whether Adgrf1 has a role in liver metabolism. Methods: We used recombinant adeno-associated virus-mediated gene delivery system, and antisense oligonucleotide was used to manipulate the hepatic Adgrf1 expression level in diet-induced obese mice to investigate the role of Adgrf1 in hepatic steatosis. The clinical relevance was examined using transcriptome profiling and archived biopsy specimens of liver tissues from non-alcoholic fatty liver disease (NAFLD) patients with different degree of fatty liver. Results: The expression of Adgrf1 in the liver was directly correlated to fat content in the livers of both obese mice and NAFLD patients. Stearoyl-coA desaturase 1 (Scd1), a crucial enzyme in hepatic de novo lipogenesis, was identified as a downstream target of Adgrf1 by RNA-sequencing analysis. Treatment with the liver-specific Scd1 inhibitor MK8245 and specific shRNAs against Scd1 in primary hepatocytes improved the hepatic steatosis of Adgrf1-overexpressing mice and lipid profile of hepatocytes, respectively. Conclusions: These results indicate Adgrf1 regulates hepatic lipid metabolism through controlling the expression of Scd1. Downregulation of Adgrf1 expression can potentially serve as a protective mechanism to stop the overaccumulation of fat in the liver in obese subjects. Overall, the above findings not only reveal a new mechanism regulating the progression of NAFLD, but also proposed a novel therapeutic approach to combat NAFLD by targeting Adgrf1. Funding: This work was supported by the National Natural Science Foundation of China (81870586), Area of Excellence (AoE/M-707/18), and General Research Fund (15101520) to CMW, and the National Natural Science Foundation of China (82270941, 81974117) to SJ.
Being overweight or obese increases the risk of developing numerous medical conditions including non-alcoholic fatty liver disease (NAFLD), where excess fat accumulates in the liver. NAFLD is a major global health issue affecting about 25% of the world's population and, if left untreated, can lead to liver inflammation as well as serious complications such as type 2 diabetes, heart disease, and liver cancer. Currently, there are no medications which specifically treat NFALD. Instead, only medications which help to manage the associated health complications are available. Therefore, a better understanding of NFALD is required to help to develop new strategies for diagnosing and treating the progression of this disease. A family of proteins known as GPCRs have crucial roles in regulating various bodily processes and are therefore commonly targeted for the treatment of disease. By identifying the GPCRs specifically involved in liver fat accumulation, new treatments for NFALD could be identified. Previous studies identified a GPCR known as Adgrf1 that is mainly found in liver cells, but its role remained unclear. To investigate the function of Adgrf1 in the liver, Wu et al. studied obese mice and human patients with NAFLD. The experiments showed that elevated levels of Adgrf1 in human and mouse livers led to increased fat accumulation. On the other hand, livers with lower levels of Adgrf1 exhibited reduced fat levels. A technique called RNA sequencing revealed that Adgrf1 induces expression of enzymes involved in fat synthesis, including a key regulator called Scd1. Treating mice with high levels of liver fat with molecules that inhibit Scd1 decreased the symptoms of Adgrf1-mediated fatty liver disease. These findings suggest therapies that decrease the levels of Adgrf1 may help to stop too much fat accumulating in the liver of human patients who are at risk of developing NAFLD. Further research is needed to confirm the effectiveness and safety of targeting Adgrf1 in humans and to develop suitable candidate drugs for the task.
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Enfermedad del Hígado Graso no Alcohólico , Receptores Acoplados a Proteínas G , Animales , Ratones , Dieta Alta en Grasa , Metabolismo de los Lípidos , Hígado/metabolismo , Ratones Endogámicos C57BL , Ratones Obesos , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Obesidad/metabolismo , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismoRESUMEN
The G protein-coupled receptors (GPCR) sensing nutritional signals (amino acids, fatty acids, glucose, etc.) are not fully understood. In this research, we used transcriptome sequencing to analyse differentially expressed genes (DEG) in mouse mammary gland tissues at puberty, lactation and involution stages, in which eight GPCR were selected out and verified by qRT-PCR assay. It was further identified the role of GPR110-mediating nutrients including palmitic acid (PA) and methionine (Met) to improve milk synthesis using mouse mammary epithelial cell line HC11. PA but not Met affected GPR110 expression in a dose-dependent manner. GPR110 knockdown decreased milk protein and fat synthesis and cell proliferation and blocked the stimulation of PA on mechanistic target of rapamycin (mTOR) phosphorylation and sterol-regulatory element binding protein 1c (SREBP-1c) expression. In summary, these experimental results disclose DEG related to lactation and reveal that GPR110 mediates PA to activate the mTOR and SREBP-1c pathways to promote milk protein and fat synthesis.
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Lactancia , Glándulas Mamarias Animales , Proteínas de la Leche , Animales , Femenino , Ratones , Células Epiteliales/metabolismo , Lactancia/genética , Lactancia/metabolismo , Glándulas Mamarias Animales/efectos de los fármacos , Glándulas Mamarias Animales/metabolismo , Metionina/metabolismo , Proteínas de la Leche/metabolismo , Ácido Palmítico/farmacología , Receptores Acoplados a Proteínas G/genética , Maduración Sexual , Proteína 1 de Unión a los Elementos Reguladores de Esteroles/genética , Proteína 1 de Unión a los Elementos Reguladores de Esteroles/metabolismo , Serina-Treonina Quinasas TOR/genética , Serina-Treonina Quinasas TOR/metabolismo , TranscriptomaRESUMEN
Adhesion G protein-coupled receptors (aGPCRs) play a pivotal role in human immune responses, cellular communication, organ development, and other processes. GPR110 belongs to the aGPCR subfamily VI and was initially identified as an oncogene involved in lung and prostate cancers. GPR110 contains tandem adhesion domains at the extracellular region that mediate inter-cellular signaling. However, the structural organization and signaling mechanism for these tandem domains remain unclear. Here, we report the crystal structure of a GPR110 fragment composing the SEA, HormR, and GAIN domains at 2.9 Å resolution. The structure together with MD simulations reveal rigid connections between these domains that are stabilized by complementary interfaces. Strikingly, we found N-linked carbohydrates attached to N389 of the GAIN domain form extensive contacts with the preceding HormR domain. These interactions appear to be critical for folding, as removal of the glycosylation site greatly decreases expression of the GPR110 extracellular fragment. We further demonstrate that the ligand synaptamide fits well within the hydrophobic pocket occupied by the Stachel peptide in the rest state. This suggests that the agonist may function by removing the Stachel peptide which in turn redocks to the orthosteric pocket for receptor activation. Taken together, our structural findings and analyses provide novel insights into the activation mechanism for aGPCRs.
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Proteínas Oncogénicas , Receptores Acoplados a Proteínas G , Humanos , Masculino , Ligandos , Péptidos/química , Receptores Acoplados a Proteínas G/agonistas , Receptores Acoplados a Proteínas G/química , Transducción de Señal , Proteínas Oncogénicas/agonistas , Proteínas Oncogénicas/química , Etanolaminas/química , Dominios Proteicos , Cristalografía por Rayos X , Simulación de Dinámica MolecularRESUMEN
Purpose To explore the differential expression of GPR110,an adherent G protein-coupled receptor,and its role in the differential diagnosis of acinar and solid adenocarcinoma of the lung.Methods The expression level of GPR110 was de-termined by immunohistochemistry(IHC),qRT-PCR and ELISA,and ROC and area under the curve(AUC)were ana-lyzed to distinguish the acinar predominant and solid predomi-nant of lung adenocarcinoma,so as to evaluate the role of differ-ential GPR110 expression in the differential diagnosis of these two histopathological subtypes with different prognosis.Results The expression of GPR110 in lung adenocarcinoma tumor tis-sue was significantly higher than that in adjacent tissue,and its expression in solid predominant lung adenocarcinoma was signifi-cantly higher than that in acinar predominant.The average con-centrations of GPR110 protein in 100 pairs of acinar predominant lung adenocarcinoma tumor tissues and its adjacent tissues were 430.53 and 313.26 ng/L by ELISA.The average concentrations of GPR110 protein in 53 pairs of solid predominant lung adeno-carcinoma tumor tissues and its adjacent tissues were 716.56 and 368.46 ng/L,and the differences were statistically signifi-cant(P＜0.001).At the same time,the ROC curve showed that the GPR110 protein had a sensitivity of 77.36％,a speci-ficity of 83.00％,an optimal Cut-off value of 582.27 ng/L,and an AUC of 0.865(0.802-0.927).Conclusion GPR110 has potential application value in the differential diagnosis of acinar type and solid type of adenocarcinoma of the lung,and it is ex-pected to become a new biomarker for differential diagnosis
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Bone remodeling is precisely regulated mainly by osteoblasts and osteoclasts. Although some G-protein coupled receptors (GPCRs) were reported to play roles in osteoblast function, little is known about the roles in osteoclasts. In this study, we found, for the first time, that the expression of GPR110 increased during osteoclastogenesis. GPR110 belongs to adhesion GPCR and was the functional receptor of N-docosahexaenoyl ethanolamine (also called synaptamide). Synaptamide suppressed osteoclastogenesis induced by receptor activator of nuclear factor-kappa B ligand. Considering that synaptamide is the endogenous metabolite of DHA, we hypothesized that DHA may inhibit osteoclastogenesis by affecting synaptamide/GPR110 signaling. But GPR110 knockout and subsequent rescue experiments revealed a pivotal role of GPR110 in the attenuation of osteoclastogenesis by synaptamide but not by DHA. These results suggest that synaptamide/GPR110 signaling negatively regulates osteoclastogenesis. Our study suggested that ligands of GPR110, such as synaptamide, might be a useful drug for osteoporotic patients.
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Osteoclastos , Osteogénesis , Proteínas Portadoras/metabolismo , Diferenciación Celular , Etanolaminas , Humanos , Osteoblastos/metabolismoRESUMEN
The neurodevelopmental and neuroprotective actions of docosahexaenoic acid (DHA) are mediated by mechanisms involving membrane- and metabolite-related signal transduction. A key characteristic in the membrane-mediated action of DHA results from the stimulated synthesis of neuronal phosphatidylserine (PS). The resulting DHA-PS-rich membrane domains facilitate the translocation and activation of kinases such as Raf-1, protein kinase C (PKC), and Akt. The activation of these signaling pathways promotes neuronal development and survival. DHA is also metabolized in neural tissues to bioactive mediators. Neuroprotectin D1, a docosatriene synthesized by the lipoxygenase activity, has an anti-inflammatory property, and elovanoids formed from DHA elongation products exhibit antioxidant effects in the retina. Synaptamide, an endocannabinoid-like lipid mediator synthesized from DHA in the brain, promotes neurogenesis and synaptogenesis and exerts anti-inflammatory effects. It binds to the GAIN domain of the GPR110 (ADGRF1) receptor, triggers the cAMP/protein kinase A (PKA) signaling pathway, and activates the cAMP-response element binding protein (CREB). The DHA status in the brain influences not only the PS-dependent signal transduction but also the metabolite formation and expression of pre- and post-synaptic proteins that are downstream of the CREB and affect neurotransmission. The combined actions of these processes contribute to the neurodevelopmental and neuroprotective effects of DHA.
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Ácidos Docosahexaenoicos , Neuroprotección , Antiinflamatorios/farmacología , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismo , Ácidos Docosahexaenoicos/metabolismo , Ácidos Docosahexaenoicos/farmacología , Endocannabinoides/metabolismo , Transducción de SeñalRESUMEN
BACKGROUND: Repetitive mild traumatic brain injury (mTBI) can result in chronic visual dysfunction. G-protein receptor 110 (GPR110, ADGRF1) is the target receptor of N-docosahexaenoylethanolamine (synaptamide) mediating the anti-neuroinflammatory function of synaptamide. In this study, we evaluated the effect of an endogenous and a synthetic ligand of GPR110, synaptamide and (4Z,7Z,10Z,13Z,16Z,19Z)-N-(2-hydroxy-2-methylpropyl) docosa-4,7,10,13,16,19-hexaenamide (dimethylsynaptamide, A8), on the mTBI-induced long-term optic tract histopathology and visual dysfunction using Closed-Head Impact Model of Engineered Rotational Acceleration (CHIMERA), a clinically relevant model of mTBI. METHODS: The brain injury in wild-type (WT) and GPR110 knockout (KO) mice was induced by CHIMERA applied daily for 3 days, and GPR110 ligands were intraperitoneally injected immediately following each impact. The expression of GPR110 and proinflammatory mediator tumor necrosis factor (TNF) in the brain was measured by using real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR) in an acute phase. Chronic inflammatory responses in the optic tract and visual dysfunction were assessed by immunostaining for Iba-1 and GFAP and visual evoked potential (VEP), respectively. The effect of GPR110 ligands in vitro was evaluated by the cyclic adenosine monophosphate (cAMP) production in primary microglia isolated from adult WT or KO mouse brains. RESULTS: CHIMERA injury acutely upregulated the GPR110 and TNF gene level in mouse brain. Repetitive CHIMERA (rCHIMERA) increased the GFAP and Iba-1 immunostaining of glia cells and silver staining of degenerating axons in the optic tract with significant reduction of N1 amplitude of visual evoked potential at up to 3.5 months after injury. Both GPR110 ligands dose- and GPR110-dependently increased cAMP in cultured primary microglia with A8, a ligand with improved stability, being more effective than synaptamide. Intraperitoneal injection of A8 at 1 mg/kg or synaptamide at 5 mg/kg significantly reduced the acute expression of TNF mRNA in the brain and ameliorated chronic optic tract microgliosis, astrogliosis, and axonal degeneration as well as visual deficit caused by injury in WT but not in GPR110 KO mice. CONCLUSION: Our data demonstrate that ligand-induced activation of the GPR110/cAMP system upregulated after injury ameliorates the long-term optic tract histopathology and visual impairment caused by rCHIMERA. Based on the anti-inflammatory nature of GPR110 activation, we suggest that GPR110 ligands may have therapeutic potential for chronic visual dysfunction associated with mTBI.
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Conmoción Encefálica/complicaciones , Etanolaminas/metabolismo , Etanolaminas/farmacología , Gliosis/tratamiento farmacológico , Gliosis/metabolismo , Tracto Óptico/efectos de los fármacos , Tracto Óptico/patología , Receptores Acoplados a Proteínas G/metabolismo , Animales , Encéfalo/metabolismo , Encéfalo/patología , Conmoción Encefálica/patología , Técnicas de Cultivo de Célula , AMP Cíclico/metabolismo , Modelos Animales de Enfermedad , Electrorretinografía , Potenciales Evocados Visuales , Gliosis/complicaciones , Inflamación , Ligandos , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Microglía/metabolismo , Tracto Óptico/lesiones , Factor de Necrosis Tumoral alfa/metabolismo , Visión OcularRESUMEN
While G protein-coupled receptors (GPCRs) are known to be excellent drug targets, the second largest family of adhesion-GPCRs is less explored for their role in health and disease. ADGRF1 (GPR110) is an adhesion-GPCR and has an important function in neurodevelopment and cancer. Despite serving as a poor predictor of survival, ADGRF1's coupling to G proteins and downstream pathways remain unknown in cancer. We evaluated the effects of ADGRF1 overexpression on tumorigenesis and signaling pathways using two human epidermal growth factor receptor-2-positive (HER2+) breast cancer (BC) cell-line models. We also interrogated publicly available clinical datasets to determine the expression of ADGRF1 in various BC subtypes and its impact on BC-specific survival (BCSS) and overall survival (OS) in patients. ADGRF1 overexpression in HER2+ BC cells increased secondary mammosphere formation, soft agar colony formation, and % of Aldefluor-positive tumorigenic population in vitro and promoted tumor growth in vivo. ADGRF1 co-immunoprecipitated with both Gαs and Gαq proteins and increased cAMP and IP1 when overexpressed. However, inhibition of only the Gαs pathway by SQ22536 reversed the pro-tumorigenic effects of ADGRF1 overexpression. RNA-sequencing and RPPA analysis revealed inhibition of cell cycle pathways with ADGRF1 overexpression, suggesting cellular quiescence, as also evidenced by cell cycle arrest at the G0/1 phase and resistance to chemotherapy in HER2+ BC. ADGRF1 was significantly overexpressed in the HER2-enriched BC compared to luminal A and B subtypes and predicted worse BCSS and OS in these patients. Therefore, ADGRF1 represents a novel drug target in HER2+ BC, warranting discovery of novel ADGRF1 antagonists.
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Resistencia a Antineoplásicos/genética , Proteínas Oncogénicas/genética , Receptor ErbB-2/genética , Receptores Acoplados a Proteínas G/genética , Animales , Neoplasias de la Mama/genética , Carcinogénesis/genética , Puntos de Control del Ciclo Celular/genética , Línea Celular Tumoral , Proliferación Celular/genética , Femenino , Fase G1/genética , Humanos , Ratones , Ratones Desnudos , Fase de Descanso del Ciclo Celular/genética , Transducción de Señal/genéticaRESUMEN
Recovery from axonal injury is extremely difficult, especially for adult neurons. Here, we demonstrate that the activation of G-protein coupled receptor 110 (GPR110, ADGRF1) is a mechanism to stimulate axon growth after injury. N-docosahexaenoylethanolamine (synaptamide), an endogenous ligand of GPR110 that promotes neurite outgrowth and synaptogenesis in developing neurons, and a synthetic GPR110 ligand stimulated neurite growth in axotomized cortical neurons and in retinal explant cultures. Intravitreal injection of GPR110 ligands following optic nerve crush injury promoted axon extension in adult wild-type, but not in gpr110 knockout, mice. In vitro axotomy or in vivo optic nerve injury rapidly induced the neuronal expression of gpr110. Activating the developmental mechanism of neurite outgrowth by specifically targeting GPR110 that is upregulated upon injury may provide a novel strategy for stimulating axon growth after nerve injury in adults.
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Axones/metabolismo , Etanolaminas/farmacología , Regeneración Nerviosa , Receptores Acoplados a Proteínas G/metabolismo , Animales , Femenino , Ligandos , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Microfluídica , Simulación del Acoplamiento Molecular , Compresión Nerviosa , Neurogénesis , Neuronas/metabolismo , Nervio Óptico/metabolismo , Retina/metabolismoRESUMEN
BACKGROUND: G protein-coupled receptors (GPCRs) are involved in several signaling pathways. However, the roles of many GPCRs in tumor oncogenesis and progression are not fully understood. In our previous study, we concluded that the absence of Gpr110 decelerates the development of liver brosis/cirrhosis into tumorigenesis. In our current study, the role of GPR110 in the oncogenesis and progression of lung cancer was observed. METHODS: After collecting tumor tissues from lung cancer patients, the expression of GPR110 was analyzed by both Western blotting and real-time PCR. Immunofluorescence was used to observe GPR110 expression in human lung cancer cells. A CCK8 kit was used to analyze the proliferation of human lung cancer cells transfected with Gpr110. Changes in cell migration were evaluated with wound healing and Transwell assays. A nude mouse xenograft model was constructed. Lung cancer model was induced in Gpr110-/- mice with urethane. RESULTS: GPR110 mRNA and protein expression was significantly higher in lung cancer tissue. GPR110 was barely expressed in H460, A549, H1299, and SPC-A1 cells, but its expression in PC-9 and QG56 cells was significantly higher. Overexpression of GPR110 promoted the proliferation and cell aggregation of H1299 cells and H1299 cell migration was also enhanced. Overexpression of GPR110 in H1299 cells significantly promoted tumor development in the nude mice tumor xenograft model. There was no statistical significance between the Gpr110+/+ and Gpr110-/- mice despite the lesions in the Gpr110-/- mice group decreasing at 35 and 40 weeks after the initial injection of urethane. CONCLUSIONS: Our findings indicate that GPR110 promotes the progression of lung cancer through accelerating cell proliferation and migration.
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BACKGROUND: Neuroinflammation is a widely accepted underlying condition for various pathological processes in the brain. In a recent study, synaptamide, an endogenous metabolite derived from docosahexaenoic acid (DHA, 22:6n-3), was identified as a specific ligand to orphan adhesion G-protein-coupled receptor 110 (GPR110, ADGRF1). Synaptamide has been shown to suppress lipopolysaccharide (LPS)-induced neuroinflammation in mice, but involvement of GPR110 in this process has not been established. In this study, we investigated the possible immune regulatory role of GPR110 in mediating the anti-neuroinflammatory effects of synaptamide under a systemic inflammatory condition. METHODS: For in vitro studies, we assessed the role of GPR110 in synaptamide effects on LPS-induced inflammatory responses in adult primary mouse microglia, immortalized murine microglial cells (BV2), primary neutrophil, and peritoneal macrophage by using quantitative PCR (qPCR) and enzyme-linked immunosorbent assay (ELISA) as well as neutrophil migration and ROS production assays. To evaluate in vivo effects, wild-type (WT) and GPR110 knock-out (KO) mice were injected with LPS intraperitoneally (i.p.) or TNF intravenously (i.v.) followed by synaptamide (i.p.), and expression of proinflammatory mediators was measured by qPCR, ELISA, and western blot analysis. Activated microglia in the brain and NF-kB activation in cells were examined microscopically after immunostaining for Iba-1 and RelA, respectively. RESULTS: Intraperitoneal (i.p.) administration of LPS increased TNF and IL-1ß in the blood and induced pro-inflammatory cytokine expression in the brain. Subsequent i.p. injection of the GPR110 ligand synaptamide significantly reduced LPS-induced inflammatory responses in wild-type (WT) but not in GPR110 knock-out (KO) mice. In cultured microglia, synaptamide increased cAMP and inhibited LPS-induced proinflammatory cytokine expression by inhibiting the translocation of NF-κB subunit RelA into the nucleus. These effects were abolished by blocking synaptamide binding to GPR110 using an N-terminal targeting antibody. GPR110 expression was found to be high in neutrophils and macrophages where synaptamide also caused a GPR110-dependent increase in cAMP and inhibition of LPS-induced pro-inflammatory mediator expression. Intravenous injection of TNF, a pro-inflammatory cytokine that increases in the circulation after LPS treatment, elicited inflammatory responses in the brain which were dampened by the subsequent injection (i.p.) of synaptamide in a GPR110-dependent manner. CONCLUSION: Our study demonstrates the immune-regulatory function of GPR110 in both brain and periphery, collectively contributing to the anti-neuroinflammatory effects of synaptamide under a systemic inflammatory condition. We suggest GPR110 activation as a novel therapeutic strategy to ameliorate inflammation in the brain as well as periphery.
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Antiinflamatorios/farmacología , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Etanolaminas/farmacología , Inflamación/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Animales , Femenino , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones NoqueadosRESUMEN
BACKGROUND: GPR110 is a member of the adhesion G protein-coupled receptor family, which has been identified as an oncogene in various cancers, including hepatocellular carcinoma, lung cancer, prostatic cancer and glioma. Whereas the expression and the clinical relevance of GPR110 in gastric cancer has not been investigated. The research purpose of this study was to explore the expression pattern of GPR110 and evaluate its clinical-pathological and prognostic value in gastric cancer. METHODS: In this study, the expression of GPR110 was detected in 117 paired gastric cancer tissues and adjacent non-tumorous tissues by using qRT-PCR and immunohistochemical assays. Univariate Kaplan-Meier and multivariate Cox analysis were used to determine the prognostic value of GPR110 in GC. RESULTS: We demonstrated that the mRNA and protein levels of GPR110 in GC tissues were overexpressed than the adjacent non-tumorous tissues. Furthermore, elevated GPR110 protein expression was correlated with decreased overall and recurrence-free survival (P = 0.001 and P = 0.000, respectively). Univariate and multivariate analysis indicated that GPR110 protein level may serve as an independent prognostic indicator for determining prognosis of GC patients. CONCLUSIONS: Our study revealed that high expression of GPR110 predicts the poor prognosis of GC patients, and GPTR110 may function as a potential biomarker for the diagnosis of GC.
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Biomarcadores de Tumor/análisis , Proteínas Oncogénicas/biosíntesis , Receptores Acoplados a Proteínas G/biosíntesis , Neoplasias Gástricas/patología , Adulto , Anciano , Femenino , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Pronóstico , Modelos de Riesgos Proporcionales , Neoplasias Gástricas/mortalidadRESUMEN
PURPOSE: G protein-coupled receptors (GPCRs) represent the largest family of druggable targets in human genome. Although several GPCRs can cross-talk with the human epidermal growth factor receptors (HERs), the expression and function of most GPCRs remain unknown in HER2+ breast cancer (BC). In this study, we aimed to evaluate gene expression of GPCRs in tumorigenic or anti-HER2 drug-resistant cells and to understand the potential role of candidate GPCRs in HER2+ BC. METHODS: Gene expression of 352 GPCRs was profiled in Aldeflur+ tumorigenic versus Aldeflur- population and anti-HER2 therapy-resistant derivatives versus parental cells of HER2+ BT474 cells. The GPCR candidates were confirmed in 7 additional HER2+ BC cell line models and publicly available patient dataset. Anchorage-dependent and anchorage-independent cell growth, mammosphere formation, and migration/invasion were evaluated upon GPR110 knockdown by siRNA in BT474 and SKBR3 parental and lapatinib+ trastuzumab-resistant (LTR) cells. RESULTS: Adhesion and class A GPCRs were overexpressed in Aldeflur+ and anti-HER2 therapy-resistant population of BT474 cells, respectively. GPR110 was the only GPCR overexpressed in Aldeflur+ and anti-HER2 therapy-resistant population in BT474, SKBR3, HCC1569, MDA-MB-361, AU565, and/or HCC202 cells and in HER2+ BC subtype in patient tumors. Using BT474 and SKBR3 parental and LTR cells, we found that GPR110 knockdown significantly reduced anchorage-dependent/independent cell growth as well as migration/invasion of parental and LTR cells and mammosphere formation in LTR derivatives and not in parental cells. CONCLUSION: Our data suggest a potential role of GPR110 in tumorigenicity and in tumor cell dissemination in HER2+ BC.
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Neoplasias de la Mama/metabolismo , Proteínas Oncogénicas/metabolismo , Receptor ErbB-2/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Animales , Antineoplásicos/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Resistencia a Antineoplásicos , Femenino , Técnicas de Silenciamiento del Gen , Humanos , Ratones , Terapia Molecular Dirigida , Proteínas Oncogénicas/genética , ARN Interferente Pequeño/genética , Receptor ErbB-2/genética , Receptores Acoplados a Proteínas G/genética , Reproducibilidad de los Resultados , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
N-Docosahexaenoylethanolamine (synaptamide) is an endocannabinoid-like metabolite endogenously synthesized from docosahexaenoic acid (DHA, 22:6n-3), the major omega-3 polyunsaturated fatty acid present in the brain. Although its biosynthetic mechanism has yet to be established, there is a closely linked relationship between the levels of synaptamide and its precursor DHA in the brain. Synaptamide at nanomolar concentrations promotes neurogenesis, neurite outgrowth and synaptogenesis in developing neurons. Synaptamide also attenuates the lipopolysaccharide-induced neuroinflammatory response and reduces the deleterious effects of ethanol on neurogenic differentiation of neural stem cells (NSCs). These actions are mediated by a specific target receptor of synaptamide GPR110 (ADGRF1), a G-protein coupled receptor that is highly expressed in NSCs and the brain during development. Synaptamide binding to GPR110 induces cAMP production and phosphorylation of protein kinase A (PKA) and the cAMP response element binding protein (CREB). This signaling pathway leads to the expression of neurogenic and synaptogenic genes and suppresses the expression of proinflammatory genes. The GPR110-dependent cellular effects of synaptamide are recapitulated in animal models, suggesting that synaptamide-derived mechanisms may have translational implications. The synaptamide bioactivity transmitted by newly deorphanized GPR110 provides a novel target for neurodevelopmental and neuroprotective control as well as new insight into mechanisms for DHA's beneficial effects on the central nervous system.
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Encéfalo/metabolismo , Ácidos Docosahexaenoicos/metabolismo , Etanolaminas/metabolismo , Proteínas Oncogénicas/genética , Receptores Acoplados a Proteínas G/genética , Animales , Encéfalo/patología , Diferenciación Celular/genética , AMP Cíclico/genética , Proteínas Quinasas Dependientes de AMP Cíclico/genética , Endocannabinoides/genética , Endocannabinoides/metabolismo , Etanolaminas/uso terapéutico , Ácidos Grasos Omega-3/genética , Ácidos Grasos Omega-3/metabolismo , Humanos , Células-Madre Neurales/efectos de los fármacos , Células-Madre Neurales/metabolismo , Neuronas/metabolismoRESUMEN
Glioma is the most common type of malignancy in the central nervous system, which has a poor prognosis due to its rapid progression and diffuse invasion. Identification of novel biomarkers for glioma would be invaluable for studying disease mechanism and improving prognosis. Orphan G protein-coupled receptor 110 (GPR110) belongs to the subfamily VI of adhesion GPCR. The knowledge of the ligand, signaling pathway or physiology function of GPR110 is poorly elucidated. The potential role of GPR110 as an oncogene in mouse has been recently reported by mutagenesis screen. However, its expression and role in human glioma hasn't been identified. Here in the current study, we initially explored the RNA and protein expression of GPR110 in patients with glioma. Statistical analysis proved that GPR110 was highly expressed in some patients, which was correlated with advanced disease stages. Furthermore, univariate and multivariate analyses revealed its role as an independent prognostic biomarker for the overall survival of glioma patients. Interestingly, cellular studies showed that overexpression or knockdown of GPR110 in U87 cells didn't affect cell proliferation and migration. However, the invasion of U87 cells was significantly enhanced by GPR110-overepxression, while inhibited by GPR110-knockdown. The detailed mechanisms remain further investigation although our results suggested the possible participation of STAT3 instead of ERK in the GPR110 signaling pathways.
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Biomarcadores de Tumor/genética , Neoplasias Encefálicas/diagnóstico , Regulación Neoplásica de la Expresión Génica , Glioma/diagnóstico , Proteínas Oncogénicas/genética , Receptores Acoplados a Proteínas G/genética , Factor de Transcripción STAT3/genética , Adulto , Anciano , Biomarcadores de Tumor/metabolismo , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/mortalidad , Neoplasias Encefálicas/cirugía , Línea Celular Tumoral , Movimiento Celular , Proliferación Celular , Femenino , Glioma/genética , Glioma/mortalidad , Glioma/cirugía , Humanos , Masculino , Persona de Mediana Edad , Clasificación del Tumor , Invasividad Neoplásica , Proteínas Oncogénicas/metabolismo , Pronóstico , Receptores Acoplados a Proteínas G/metabolismo , Estudios Retrospectivos , Factor de Transcripción STAT3/metabolismo , Transducción de Señal , Análisis de SupervivenciaRESUMEN
Hepatocarcinogenesis is a complex process that includes pronounced necroinflammation, unregulated hepatocyte damage, subsequent extensive fibrosis, and carcinogenesis. GPR110 was an adhesion G protein-coupled receptor. Analysis of the expression pattern of Gpr110 in mice displayed that Gpr110 was expressed highly in liver, implicating the tissue compartments where Gpr110 could execute its functions, the role of Gpr110 in the physiological and pathological state of liver remains unclear. Based on a Gpr110 knockout mouse model, we evaluated the role of Gpr110 in hepatocarcinogenesis by using a carbon tetrachloride (CCl4)-induced liver injury and fibrosis model, as well as diethylnitrosamine (DEN) plus CCl4-induced liver cancer model. In this study, we found subdued chronic liver injury, reduced compensatory proliferation, lower liver fibrosis, but enhanced inflammation occurred in Gpr110-/- mice during CCl4 challenge. In addition, Gpr110-/- mice were resistant to liver tumorigenesis induced by DEN plus CCl4 injection. Molecular mechanisms underlying these differences correlated with augmented activation of the IL-6/STAT3 pathway, which exerted hepatoprotective effects during liver damage, fibrosis, and oncogenesis in Gpr110-/- mice. Furthermore, pharmacological inhibition of the activation of the IL-6/STAT3 pathway enhanced hepatic fibrosis and promoted DEN plus CCl4-induced carcinogenesis in Gpr110-/- mice. In summary, absence of Gpr110 decelerates liver fibrosis/cirrhosis progressing into tumorigenesis, due to strengthening activation of the IL-6/STAT3 pathway, leading to a weaker liver injury and fibrosis microenvironment. It is indicated that targeting Gpr110 and activating the IL-6/STAT3 pathway may be considered to be preventive methods for some cirrhosis transition.
RESUMEN
The large class of adhesion G protein-coupled receptors (aGPCRs) bind extracellular matrix or neighboring cell-surface ligands to regulate organ and tissue development through an unknown activation mechanism. We examined aGPCR activation using two prototypical aGPCRs, GPR56 and GPR110. Active dissociation of the noncovalently bound GPR56 or GPR110 extracellular domains (ECDs) from the respective seven-transmembrane (7TM) domains relieved an inhibitory influence and permitted both receptors to activate defined G protein subtypes. After ECD displacement, the newly revealed short N-terminal stalk regions of the 7TM domains were found to be essential for G protein activation. Synthetic peptides comprising these stalks potently activated GPR56 or GPR110 in vitro or in cells, demonstrating that the stalks comprise a tethered agonist that was encrypted within the ECD. Establishment of an aGPCR activation mechanism provides a rational platform for the development of aGPCR synthetic modulators that could find clinical utility toward aGPCR-directed disease.