Glucose Transporter 1 Overexpression Research Articles

The impact of glucose conjugation on the activity and uptake of zinc phthalocyanine in HaCaT keratinocytes stimulated with proinflammatory cytokines

SignificanceGlucose metabolism has been proven as an essential process for proliferating keratinocytes, which highlights the importance of glucose transporter-1 (GLUT1) not only in the onset of psoriasis but also in the progression and severity of this inflammation-driven disease. Recent evidence showed that overexpressed GLUT1 transporter may be a potential target for the treatment of psoriasis and other hyperproliferative skin diseases. ApproachFor this reason, we attempted to synthesize and evaluate the photocytotoxic activity and intracellular uptake of glucose-conjugated zinc phthalocyanine (Glu-ZnPc), in order to prove its preferential accumulation in highly proliferative psoriatic keratinocytes. HaCaT cells stimulated with exogenous cytokines (TNF-α, IL-6, IL-17, IL-23, IL-36) were used as in vitro model. ResultsWe managed to synthesize Glu-ZnPc that is stable, water soluble, cytotoxic, and has a more efficient transport system than unconjugated ZnPc. ConclusionsWe believe that GLUT1 overexpression could potentially be utilized by using selective glucose- conjugated photosensitizers against psoriasis.

Xanthatin induce DDP-resistance lung cancer cells apoptosis through regulation of GLUT1 mediated ROS accumulation.

Chemoresistance to cisplatin (DDP) therapy is a major obstacle that needs to be overcome in treating lung cancer patients. Xanthatin has been reported to exhibit an antitumor effect on various cancers, but the function of xanthatin in DDP-resistance lung cancer remains unclear. The study aimed to explore the effect and mechanisms of xanthatin on proliferation, apoptosis, and migration in DDP-resistance lung cancer cells. In the present study, xanthatin suppresses the expression of glucose transporter 1 (GLUT1), attenuates the pentose phosphate pathway (PPP), and causes ROS accumulation and apoptosis, thereby mitigating the antioxidative capacity in DDP-resistance cells. Previous studies have shown that GLUT1 is associated with resistance to platinum drugs. We found that GLUT1 was significantly increased in the DDP-resistant lung cancer cell line compared to the parental cell line, and xanthatin significantly downregulated GLUT1 expression in DDP-resistant lung cancer cells. Notably, overexpression of GLUT1 significantly reduced the production of ROS and increased cellular NADPH/NADP+ and GSH/GSSG ratios. Thus, these results suggest that xanthatin induces DDP-resistance lung cancer cells apoptosis through regulation of GLUT1-mediated ROS accumulation. These findings might provide a possible strategy for the clinical treatment of DDP-resistant lung cancer.

Assessment of the Expression of GLUT1 in Renal Cell Carcinoma and its Various Subtypes

BACKGROUND: Renal cell carcinoma is one of the most common tumors of the kidney. Glucose transporters, transport glucose, and increased expression of these transporters have been reported in various tumor types. Glucose transporter 1 (GLUT1), the best-known glucose transporter, has an important role at several stages in cancer progression. The overexpression of GLUT1 in the tumor cells indicates an increased proliferation and invasive behavior of the tumor. AIM: This study aims to investigate the expression of GLUT1 in renal cell carcinoma and its subtypes. METHODS: This study is a descriptive cross-sectional study that was performed on patients with renal cell carcinoma. Seventy reports of formalin fixed; paraffin-embedded blocks of renal cell carcinoma were selected from pathology archives. The samples included: clear cell type renal cell carcinoma, RCC clear cell type with sarcomatoid feature, papillary renal cell carcinoma, and chromophobe renal cell carcinoma. RESULTS: In this study, 50 male and 20 female samples (71.4% and 28.6%) with the mean age of 57.9 ± 13.1 years were studied. Forty-three samples (61.4%) were positive for GLUT1 and 27 (38.9%) were negative for it. For the GLUT1 expression being positive or negative between the two groups, was not significantly affected by the age, sex, and the grade of the tumor, </AQ17>while the difference between the two groups was statistically significant in terms of stage and type of tumor (p < 0/001, p = 0.039). CONCLUSION: Renal cell carcinoma of ccRCC type is associated with increased GLUT1 expression. Therefore, the GLUT1 immunohistochemistry marker can be a useful marker for diagnosis of RCC, specifically ccRCC type.

Pathological significance of GLUT-1 expression in breast cancer cells in diabetic and obese patients: The French Guiana study

The prevalence of obesity and type 2 diabetes is higher in French Guiana compared to mainland France. These metabolic disorders are associated with an increased risk of cancer. One of the factors involved is hyperinsulinemia that promotes the action of glucose transporter 1 (GLUT-1). The objective of this study is to characterize the expression of GLUT-1 in breast cancers cells in diabetic and obese patients compared to those who are not and to describe the clinical and histological prognostic factors of breast cancer in this population. We conducted a monocentric study between 2014 and 2020. Patients were classified into three groups: diabetes, obesity, and control group. The GLUT-1 expression was assessed by immunohistochemistry. In total, 199 patients were included in this study. The median age was 53.5 years, and the median tumor size was 2.8 cm. Luminal A was the most frequent molecular type (58.1%), followed by the triple-negative type (19.9%). The breast cancer in our population was characterized by a younger age at diagnosis, more aggressive molecular types, and larger tumor size. Thus, we suggest the advancement of the age of breast cancer screening in this territory. Overexpression of GLUT-1 was observed in 60.4% of cases and in all carcinoma in situ lesions. GLUT-1 overexpression was associated with more aggressive cancers. This overexpression is correlated with high histological grade, high proliferation index, and aggressive molecular types. Our study found no difference in GLUT-1 expression between the diabetic or obese patients and the control group.

Aroylhydrazone Glycoconjugate Prochelators Exploit Glucose Transporter 1 (GLUT1) to Target Iron in Cancer Cells.

Glycoconjugation strategies in anticancer drug discovery exploit the high expression of glucose transporters in malignant cells to achieve preferential uptake and hence attractive pharmacological characteristics of increased therapeutic windows and decreased unwanted toxicity. Here we present the design of glycoconjugated prochelators of aroylhydrazone AH1, an antiproliferative scavenger that targets the increased iron demand of rapidly proliferating malignant cells. The constructs feature a monosaccharide (d-glucose, d-glucosamine, or glycolytic inhibitor 2-deoxy-d-glucose) connected at the C2 or C6 position via a short linker, which masks the chelator through a disulfide bond susceptible to intracellular reduction. Cellular assays showed that the glycoconjugates rely on the GLUT1 transporter for uptake, lead to intracellular iron deprivation, and present antiproliferative activity. Ectopic overexpression of GLUT1 in malignant and normal cells increased the uptake and toxicity of the glycoconjugated prochelators, demonstrating that these compounds are well suited for targeting cells overexpressing glucose transporters and therefore for selective iron sequestration in malignant cells.

The inhibition of GLUT1-induced glycolysis in macrophage by phloretin participates in the protection during acute lung injury

The increased level of glycolysis in macrophage aggravates lipopolysaccharide (LPS)-induced acute lung injury (ALI). Glucose transporter 1 (GLUT1) serves as a ubiquitously expressed glucose transporter, which could activate inflammatory response by mediating glycolysis. Phloretin (PHL), an apple polyphenol, is also an inhibitor of GLUT1, possessing potent anti-inflammatory effects in various diseases. However, the potential role of PHL in ALI remains unclear till now. This study aims to investigate the impacts of PHL on ALI as well as its possible mechanisms. A mouse ALI model was established via intratracheal injection of LPS. LPS-induced primary macrophages were used to mimic in vitro ALI. Mice were pretreated with low or high dosage of PHL for 7 days via intragastric administration once a day before LPS injection. The results showed that PHL pretreatment significantly prevented LPS-induced lung pathological injury and inflammatory response. Meantime, PHL pretreatment also decreased the level of glycolysis in macrophage during ALI. In terms of mechanism, PHL inhibited the mRNA and protein expression of GLUT1. In vitro experiments further showed GLUT1 overexpression in macrophage by infection with lentivirus could abolish the inhibition of inflammation and glycolysis mediated by PHL, suggesting that GLUT1 was essential for the protection of PHL. Taken together, PHL pretreatment may protect against LPS-induced ALI by inhibiting glycolysis in macrophage in a GLUT1-dependent manner, which may be a candidate against ALI in the future.

Long Non-Coding RNA TMPO-AS1 Promotes GLUT1-Mediated Glycolysis and Paclitaxel Resistance in Endometrial Cancer Cells by Interacting With miR-140 and miR-143.

Increased glycolysis in tumor cells is frequently associated with drug resistance. Overexpression of glucose transporter-1 (GLUT1) promotes the Warburg effect and mediates chemoresistance in various cancers. Aberrant GLUT1 expression is considered as an essential early step in the development of endometrial cancer (EC). However, its role in EC glycolysis and chemoresistance and the upstream mechanisms underlying GLUT1 overexpression, remain undefined. Here, we demonstrated that GLUT1 was highly expressed in EC tissues and cell lines and that high GLUT1 expression was associated with poor prognosis in EC patients. Both gain-of-function and loss-of-function studies showed that GLUT1 increased EC cell proliferation, invasion, and glycolysis, while also making them resistant to paclitaxel. The long non-coding RNA TMPO-AS1 was found to be overexpressed in EC tissues and to be negatively associated with EC patient outcomes. RNA-immunoprecipitation and luciferase reporter assays confirmed that TMPO-AS1 elevated GLUT1 expression by directly binding to two critical tumor suppressor microRNAs (miR-140 and miR-143). Downregulation of TMPO-AS1 remarkably reduced EC cell proliferation, invasion, glycolysis, and paclitaxel resistance in EC cells. This study established that dysregulation of the TMPO-AS1-miR-140/miR-143 axis contributes to glycolysis and drug resistance in EC cells by up-regulating GLUT1 expression. Thus, inhibiting TMPO-AS1 and GLUT1 may prove beneficial in overcoming glycolysis-induced paclitaxel resistance in patients with EC.

The Impact of Proinflammatory Cytokines and Imiquimod on GLUT1 in HaCaT Keratinocytes - a Potential Anti-Psoriatic Therapeutic Target?

Glucose metabolism has been proven as an essential process for proliferating keratinocytes, which highlights the importance of glucose transporter-1 (GLUT1) not only in the onset of psoriasis but also in the progression and severity of this inflammation-driven disease. In this study, we attempted to find a connection between proinflammatory cytokines (IL-6, IL-17, IL-23, IL-36, TNF-α), a skin inflammation inducing agent - imiquimod (IMQ) and GLUT1 expression. Human keratinocyte HaCaT cell line was incubated with exogenous cytokines: IL-6, IL-17A, IL-23, IL-36, TNF-α at a final concentration of 100 ng/ml, or with 1 µM of IMQ, for 48 h. Following the stimulation, glucose uptake and GLUT1 expression were evaluated. The activity of GLUT1 was measured in the presence of a selective GLUT1 inhibitor, BAY-876. The expression of GLUT1 was examined by immunofluorescence and quantified by qPCR, Western blotting and densitometry. The results from qPCR analysis showed that the administration of exogenous IL-6, IL-17, IL-23 and IL-36 to HaCaT cells resulted in upregulation of GLUT1-encoding SLC2A1 gene, while TNF-α had no significant effect. The same results were confirmed by immunofluorescence analysis, as the fluorescent intensity of GLUT1 was elevated following cytokine and IMQ stimulation. Western blot and densitometry showed that all examined cytokines, as well as IMQ, increased GLUT1 expression. HaCaT cells displayed an improved intracellular 2-deoxy-D-glucose (2-DG) uptake and GLUT1 activity after stimulation by exogenous cytokines and IMQ. The highest uptake of 2-DG was observed after IL-23 stimulation (1.93x) and the lowest after TNF-α stimulation (1.07x). BAY-876 inhibited the 2-DG uptake compared to control. Our findings suggest that cytokines and IMQ may play a key role in regulating GLUT1 expression in HaCaT cells. We believe that GLUT1 overexpression could potentially be utilized in the targeted treatment of psoriasis.

Circ_0001955 plays a carcinogenic role in breast cancer via positively regulating GLUT1 via decoying miR-1299.

BackgroundBreast cancer is widespread in females. The role of circular RNA (circRNA) in breast cancer has aroused much attention. However, the function of several circRNAs remain unclear. The aim of our study was to determine the role of circ_0001955 in breast cancer.MethodsQuantitative real‐time PCR (qPCR) and western blot was employed for expression analysis of circ_0001955, miR‐1299 and glucose transporter 1 (GLUT1). Cell functions including proliferation, apoptosis, migration, invasion and angiogenesis, were assessed using EdU, flow cytometry, transwell and tube formation assays. Glycolysis metabolism was assessed according to glucose consumption, lactate production and ATP content. Dual‐luciferase reporter assay and RIP assay were utilized to validate the binding between miR‐1299 and circ_0001955 or GLUT1. The effects of circ_0001955 in vivo were observed by animal study.ResultsUpregulation of circ_0001955 was detected in breast cancer. Knockdown of circ_0001955 inhibited breast cancer cell proliferation, migration, invasion, angiogenesis and glycolysis. MiR‐1299 was a target of circ_0001955, and its repression reversed the effects of circ_0001955 knockdown. Moreover, circ_0001955 targeted miR‐1299 to positively regulate GLUT1 expression. GLUT1 overexpression reversed the effects of miR‐1299 enrichment. GLUT1 knockdown was verified to block tumor growth in vivo.ConclusionsCirc_0001955 was found to promote breast cancer malignant development via targeting of the miR‐1299/GLUT1 pathway, which contributes to our understanding of the pathogenesis of breast cancer.

Pathological Significance of GLUT-1 Expression in Breast Cancer Cells in Diabetic and Obese Patients: The French Guiana Study.

Simple SummaryThis study describes the clinical, histological, and molecular features of breast cancer in French Guiana, and characterizes the expression of the tumor metabolic marker GLUT-1 in breast cancers cells in diabetic and obese patients compared to a control group. This study reveals an overall overexpression of GLUT-1 in 60% of invasive breast carcinomas and in all medullary pattern and carcinoma in situ lesions. Our results highlight the potential role of GLUT-1 as a tumor metabolic prognostic marker and also as an interesting target therapy, independently of patient metabolic disorder.The prevalence of obesity and type 2 diabetes is higher in French Guiana compared to mainland France. These metabolic disorders are associated with an increased risk of cancer. One of the factors involved is hyperinsulinemia that promotes the action of glucose transporter 1 (GLUT-1). The objective of this study is to characterize the expression of GLUT-1 in breast cancers cells in diabetic and obese patients compared to those who are not and to describe the clinical and histological prognostic factors of breast cancer in this population. We conducted a monocentric study including patients with breast cancer diagnosed between 2014 and 2020. Patients were classified into three groups: diabetes, obesity, and control group. The GLUT-1 expression was assessed by immunohistochemistry. In total, 199 patients were included in this study. The median age was 53.5 years, and the median tumor size was 2.8 cm. Luminal A was the most frequent molecular type (58.1%), followed by the triple-negative type (19.9%). The breast cancer in our population was characterized by a younger age at diagnosis, more aggressive molecular types, and larger tumor size. Thus, we suggest the advancement of the age of breast cancer screening in this territory. A total of 144 patients (31 diabetes, 22 obese, and 91 control group) were included for the study of GLUT-1 expression. Overexpression of GLUT-1 was observed in 60.4% of cases and in all carcinoma in situ lesions. GLUT-1 overexpression was associated with more aggressive cancers. This overexpression is correlated with high histological grade, high proliferation index, and aggressive molecular types. Our study found no difference in GLUT-1 expression between the diabetic or obese patients and the control group. These results highlight the potential role of GLUT-1 as a tumor metabolic prognostic marker and also as an interesting target therapy, independently of patient metabolic disorder.

GLUT1 Regulates the Tumor Immune Microenvironment and Promotes Tumor Metastasis in Pancreatic Adenocarcinoma via ncRNA-mediated Network.

Pancreatic adenocarcinoma (PAAD) is a digestive tumor with extremely high malignancy. Previous studies have reported that Glucose transporter 1 (GLUT1) contributes to the aggressive tumor progression in various cancer types and indicates an unfavorable prognosis. However, the function of GLUT1 in PAAD remains largely unclear. Through pan-cancer analysis of GLUT1 expression, GLUT1 expression was significantly higher in several cancer types including PAAD. Survival analysis based on the GLUT1 expression showed that GLUT1 could serve as a predictor of poor prognosis. We further predicted and screened the candidate non-coding RNAs (ncRNAs) upstream of the GLUT1 mRNA through correlation analysis, and found that the CASC19/miR-140-5p axis contributing to the regulation of GLUT1 expression. Our study suggested a link exists between GLUT1 expression and selected immunity-related indicators. Subsequent analysis revealed overexpression of GLUT1 in pancreatic cancer specimens and patients with highly expressed GLUT1 expression had worse prognosis. Based on the significantly different expression of GLUT1, the possibility that GLUT1 participated in tumor progression was identified. Using online public databases, genes co-expressed with GLUT1 were screened and enriched to metastasis-related pathways by enrichment analysis. Additionally, functional assays verified that GLUT1 could function in the metastatic process of PAAD cancer cells. Therefore, we proposed that GLUT1 might serve as a role in tumor immunity and tumor metastasis, and was expected to be a prognostic factor in PAAD.

LINC00839 Regulates Proliferation, Migration, Invasion, Apoptosis and Glycolysis in Neuroblastoma Cells Through miR-338-3p/GLUT1 Axis.

BackgroundLong noncoding RNAs (lncRNAs) are related to the development and treatment of neuroblastoma. The lncRNA LINC00839 is dysregulated in neuroblastoma, while its function and mechanism in neuroblastoma development remain largely unclear.MethodsThe tumor and adjacent noncancerous tissues were collected from 48 neuroblastoma patients. LINC00839, glucose transporter 1 (GLUT1) and microRNA-338-3p (miR-338-3p) abundances were examined via quantitative reverse transcription polymerase chain reaction or Western blot. Cell proliferation, apoptosis, migration, invasion and glycolysis were assessed via Cell Counting Kit-8, colony formation, flow cytometry, wound healing, transwell, glucose uptake and lactate production. The target relationship of miR-338-3p and LINC00839 or GLUT1 was tested via dual-luciferase reporter analysis and RNA immunoprecipitation. The function of LINC00839 on neuroblastoma cell growth in vivo was tested via a xenograft model.ResultsLINC00839 and GLUT1 abundances were increased in neuroblastoma tissues and cell lines. The high expression of LINC00839 and GLUT1 indicated the lower overall survival. LINC00839 interference constrained neuroblastoma cell proliferation, migration, invasion and glycolysis, and facilitated apoptosis. GLUT1 overexpression or miR-338-3p knockdown could mitigate the influence of LINC00839 silence on neuroblastoma cell processes. LINC00839 could regulate GLUT1 expression via miR-338-3p. LINC00839 knockdown reduced neuroblastoma cell growth in xenograft model.ConclusionLINC00839 silence repressed neuroblastoma cell proliferation, migration, invasion and glycolysis and promoted apoptosis via regulating miR-338-3p/GLUT1 axis.

MicroRNA-140-5p is Downregulated in Osteosarcoma and Overexpression of MicroRNA-140-5p Inhibits Cancer Cell Proliferation by Downregulating GLUT-1.

BackgroundMicroRNA-140-5p plays pivotal role in different types of human malignancies, while its involvement in osteosarcoma is unknown.ObjectiveOur study aimed to investigate the functionality of microRNA-140-5p in osteosarcoma.MethodsPlasma levels of microRNA-140-5p and glucose transporter 1 (GLUT-1) in both osteosarcoma and healthy controls were measured by qRT-PCR and ELISA, respectively. Correlation between plasma levels of microRNA-140-5p and GLUT-1 was analyzed by Pearson correlation coefficient. Correlation between plasma levels of microRNA-140-5p and clinical data of patients with osteosarcoma was analyzed by Chi-square test. MicroRNA-140-5p mimic and GLUT-1 expression vector were transfected into cells of human osteosarcoma cell lines, and the effects on microRNA-140-5p expression, GLUT-1 expression and cell proliferation were analyzed by qRT-PCR, Western-blot and CCK-8 assay, respectively.ResultsPlasma levels of microRNA-140-5p were significantly lower and plasma levels of GLUT-1 were significantly higher in osteosarcoma patients than that in healthy controls. Levels of plasma microRNA-140-5p and GLUT-1 were reversely correlated in osteosarcoma patients. Plasma levels of microRNA-140-5p were correlated with tumor size but not with other clinical data of patients. MicroRNA-140-5p mimic significantly inhibited cancer cell proliferation, while GLUT-1 overexpression significantly promoted cancer cell proliferation. MicroRNA-140-5p mimic significantly downregulated GLUT-1 expression.ConclusionGLUT-1 overexpression showed no significant effect on microRNA-140-5p expression but attenuated the inhibitory effects of microRNA-140-5p mimic on cell proliferation. We therefore conclude that microRNA-140-5p is downregulated in osteosarcoma and overexpression of microRNA-140-5p may inhibit cancer cell proliferation by downregulating GLUT-1.

MiR‑218 inhibits glucose metabolism in non‑small cell lung cancer via the NF‑κB signaling pathway

High glucose metabolism is recognized as one of the hallmarks of cancer and increased expression levels of several key factors involved in glucose metabolism have been reported in non-small cell lung cancer (NSCLC). Previous studies showed that microRNA (miR)-218 is reduced in NSCLC, but its function in glucose metabolism in NSCLC is not fully understood. The present study aimed to investigate the effect of miR-218 on glucose metabolism in NSCLC cell lines and the underlying molecular mechanism. The present results suggested that miR-218 reduced glucose consumption, the mechanism of glycolysis and activity in the pentose phosphate pathway. In addition, glucose transporter 1 (GLUT1) was identified to be a direct target of miR-218, while overexpression of GLUT1 did not abolish the effect of miR-218 on glucose metabolism. The present results indicated that phosphorylation of NF-κB p65 was significantly decreased by miR-218 in NSCLC cells and that activation of NF-κB led to the inhibition of miR-218 regulation of glucose metabolism. In conclusion, the present results suggested that miR-218 downregulated glucose metabolism in NSCLC not only by directly targeting GLUT1, but also via the NF-κB signaling pathway.

The Interaction of GLUT1 and FOXM1 Leads to a Poor Prognosis in Colorectal Cancer.

Colorectal Cancer (CRC) is one of the most common fatal diseases with high morbidity. Alteration of glucose metabolism is one of the hallmarks in the development of CRC. Glucose Transporter 1 (GLUT1) is a key rate-limiting protein in hyperactive glucose metabolism and up-regulated in CRC, however, the underlying mechanism of the altered metabolism in CRC is still unknown. In this study, immunohistochemical staining was used to evaluate the expression of GLUT1 and FOXM1 in 135 paired CRC and adjacent normal tissues. The association between the expression of GLUT1/FOXM1 and clinicopathological factors was determined and the correlation between GLUT1 and FOXM1 in CRC was investigated. Our results revealed that regardless of tumor location, GLUT1 and FOXM1 were overexpressed in CRC tissues, especially in patients with positive lymph node metastasis and TNM stage III-IV. Furthermore, GLUT1 showed a significantly strong link with FOXM1 in CRC tissue. Overexpression of GLUT1 and FOXM1 may play critical roles in CRC leading to a poor prognosis.

MicroRNA-125b reduces glucose uptake in papillary thyroid carcinoma cells.

Previous studies have shown that microRNA (miR)-125b plays important roles in several human cancer types. The aim of the present study was to analyze the potential roles of miR-125b in papillary thyroid carcinoma (PTC). It was found that miR-125b was downregulated in PTC and its expression was affected by clinical stages. Glucose transporter 1 (GLUT1) was upregulated in PTC and was negatively correlated with miR-125b. In PTC cells, overexpression of miR-125b suppressed glucose uptake and downregulated GLUT1. Furthermore, GLUT1 overexpression reduced the effects of miR-125b overexpression on glucose uptake. Moreover, miR-125b overexpression suppressed PTC cell proliferation. GLUT1 overexpression promoted the proliferation of PTC cells and reduced the effects of miR-125b overexpression on cancer cell proliferation. Overall, miR-125b decreased glucose uptake in PTC cells by downregulating GLUT1.

Circular RNA circDENND4C facilitates proliferation, migration and glycolysis of colorectal cancer cells through miR-760/GLUT1 axis.

Colorectal cancer is a common malignant tumor of the digestive tract, and its incidence is closely related to lifestyle inheritance and colorectal adenoma. Circular RNA (circRNA) has been proved to participate in the progression of colorectal cancer cells. Our study aimed to investigate the function and the underlying mechanism of circRNA circDENND4C in colorectal cancer cells. The expression of circDENND4C, glucose transporter 1 (GLUT1), and miR-760 was detected by quantitative Real Time-Polymerase Chain Reaction (qRT-PCR). Western blot was used to measure the protein levels of GLUT1, the proliferation-related protein (Cyclin D1) and matrix metallopeptidase 9 (MMP-9). Cell Counting Kit-8 (CCK-8) assay and transwell assay were performed to evaluate cell proliferation and migration. The glucose uptake and lactate production were detected by the corresponding kits. The targets between circDENND4C and miR-760 and miR-760 and GLUT1 were predicted by starBase 3.0 and TargetScan, and then confirmed by Dual-Luciferase reporter assay. Animal experiment revealed the effect of circDENND4C on colorectal cancer cells in vivo. The expression of circDENND4C and GLUT1 was upregulated in colorectal cancer tissues and cells. Functionally, the knockdown of circDENND4C suppressed proliferation, migration, and glycolysis of colorectal cancer cells. Similarly, silence of GLUT1 also inhibited cell proliferation, migration, and glycolysis. Notably, the overexpression of GLUT1 reversed the functional effects of circDENND4C knockdown on colorectal cancer cells. More importantly, miR-760 acted as a direct target of circDENND4C, and miR-760 could bind to GLUT1, and circDENND4C regulated GLUT1 by sponging miR-760. Finally, circDENND4C knockdown decreased the growth of colorectal cancer cells in vivo. CircRNA circDENND4C accelerated proliferation, migration, and glycolysis of colorectal cancer cells through regulating GLUT1 by sponging miR-760.

IFN-γ/mTORC1 decreased Rab11 in Schwann cells of diabetic peripheral neuropathy, inhibiting cell proliferation via GLUT1 downregulation.

Diabetic peripheral neuropathy (DPN) is the most common complication of diabetes mellitus. Rab11 is conserved gene-regulating vesicle traffic and reported to be involved in the pathogenesis of diabetes mellitus by affecting insulin sensitivity. We aimed to investigate the role of Rab11 in the pathogenesis of DPN. In this study, Rab11 expression decreased in the sciatic nerves of diabetic mice with impaired conduction function versus those of normal mice. In vitro experiment revealed interferon-γ (IFN-γ), not high glucose and interleukin 1β was the main factor to lead to Rab11 downregulation in RSC96 cells. Again, both Rab11 knockdown and IFN-γ treatment caused cell viability inhibition and the decrease in BrdU-positive cells. In contrast, overexpression of Rab11 reversed IFN-γ-reduced cell proliferation. Furthermore, mTORC1 not mTORC2 was proven to be suppressed by IFN-γ treatment in RSC96 cells, indicated in decreased phospho-p70S6K. Inhibition of the mTORC1 pathway resulted in Rab11 expression downregulation in RSC96 cells. Activation of the mTORC1 pathway effectively prevented IFN-γ-reduced Rab11 expression in RSC96 cells. Also, glucose transporter 1 (GLUT1) was found to be downregulated in RSC96 cells with Rab11 silence and overexpression of GLUT1 reversed Rab11 blocking-caused proliferation inhibition. Taken together, our findings suggest that IFN-γ decreases Rab11 expression via the inhibition of the mTORC1 signaling pathway, causing reduced cell proliferation in Schwann cells of DPN by GLUT1 downregulation.

Differential effect of GLUT1 overexpression on survival and tumor immune microenvironment of human papilloma virus type 16-positive and -negative cervical cancer

Glucose transporter-1 (GLUT1) has been proposed as a prognosticator in various cancers associated with therapeutic resistance and immune evasion; however little data is available on the role of GLUT1 in cervical cancer. Most cervical cancers are caused by human papilloma virus (HPV), but studies on the treatment response and prognosis depending on the HPV subtype, are conflicting. This hypothesis-generating study aims to investigate the prognostic impact of GLUT1 in cervical cancer, in conjunction with HPV subtype. Clinicopathologic factors, along with mRNA expression data were obtained using The Cancer Genome Atlas database. Tumor HPV status and immune cell scores were extracted from previous publications. In total, 298 patients were analyzed. High GLUT1 expression was associated with old age, squamous cell carcinoma, high tumor stage, pelvic lymph node metastases, and low hysterectomy rate. Multivariate survival analysis revealed that high GLUT1 expression (Hazard ratio (HR) 2.57, p = 0.002) and HPV16 subtype (HR 0.56, p = 0.033) were independent prognostic factors for overall survival. In the subgroup analysis, poor prognostic impact of high GLUT1 expression was maintained in HPV16-positive group (p < 0.001), but not in HPV16-negative group (p = 0.495). Decreased immune cell scores of CD8+ T cells, B cells, and Th1 cells by high GLUT1 expression were observed only in HPV16-positive group. In conclusion, these results suggested that GLUT1 expression and HPV16 subtype might have an independent prognostic value in cervical cancer. GLUT1-mediated immunomodulation might be an important cause of treatment failure, especially in HPV16-positive group.

Differential Effect of GLUT1 Overexpression on Survival and Tumor Immune Microenvironment of Human Papilloma Virus Type 16-Positive and -Negative Cervical Cancer

Glucose transporter-1 (GLUT1) has been reported as a poor prognosticator associated with radioresistance and immune evasion through metabolic communication in various cancers, but little data is available on cervical cancer. Meanwhile, most cervical cancer is known to be caused by human papilloma virus (HPV), but treatment response and prognosis according to the HPV subtype are also unknown. This hypothesis-generating study was conducted to investigate the prognostic impact of GLUT1 in cervical cancer, in conjunction with HPV subtype. Clinicopathologic factors along with mRNA expression data were obtained using The Cancer Genome Atlas database. Tumor HPV status and immune cell abundance scores were extracted from previous publications. Total 298 patients with appropriate information were analyzed. High GLUT1 expression was associated with old age, squamous cell carcinoma, high tumor stage, pelvic lymph node metastases, and low hysterectomy rate. HPV16 positivity itself was not associated with other factors, except low tumor grade. Multivariate survival analysis revealed that high GLUT1 expression (HR 2.57, p = 0.002) and HPV16 subtype (HR 0.56, p = 0.033) were independent prognostic factors for OS. In the subgroup analysis, poor prognostic impact of high GLUT1 expression was maintained in the HPV16-positive group (p < 0.001), but not in the HPV16-negative group (p = 0.495). Decreased immune cell abundance scores of B cells, CD8 T cells, and Th1 cells by high GLUT1 expression were observed only in the HPV16-positive group. Despite of heterogenous treatments, our results suggested that GLUT1 expression and HPV16 subtype may have an independent prognostic value in cervical cancer. Especially in the HPV16-positive group, GLUT1-mediated immunomodulation might be an important cause of treatment failure. Further proof-of-concept study is warranted to identify novel immunometabolic targets to overcome radioresistance.