Expression Of SLC5A8 Research Articles

Machine learning and multi-omics characterization of SLC2A1 as a prognostic factor in hepatocellular carcinoma: SLC2A1 is a prognostic factor in HCC.

Hepatocellular carcinoma (HCC) is characterized by high incidence, significant mortality, and marked heterogeneity, making accurate molecular subtyping essential for effective treatment. Using multi-omics data from HCC patients, we applied diverse clustering algorithms to identify three HCC subtypes (HSs) with distinct prognostic characteristics. Among these, HS1 emerged as an immune-compromised subtype associated with the poorest prognosis. Additionally, we developed a novel, robust, and highly accurate machine learning-guided prognostic signature (MLPS) by integrating multiple machine learning algorithms and their combinations. Our study also identified SLC2A1, the core gene of MLPS, as being highly expressed during advanced stages of tumor progression. Knockdown experiments demonstrated that reducing SLC2A1 expression significantly suppressed the malignant behavior of HCC cells. Furthermore, SLC2A1 expression was linked to responsiveness to dasatinib and vincristine, suggesting potential therapeutic relevance. MLPS and SLC2A1 offer promising tools for individualized prognosis prediction and targeted therapy in HCC, providing new opportunities to improve patient outcomes.

Enhanced autophagy and cholesterol efflux in mouse mesenchymal stem cells infected with H37Rv compared to H37Ra.

Autophagy, metabolism, and associated signaling pathways play critical roles in bacterial survival within mammalian cells and influence the immunopathogenesis of infections. Mesenchymal stem cells (MSCs) are important host cells during Mycobacterium tuberculosis (Mtb) infection, yet how autophagy, metabolism, and related pathways are modulated in MSCs infected with the virulent H37Rv or the attenuated H37Ra strain of Mtb remains poorly understood. In this study, we utilized RNA-Seq screening, qRT-PCR, and Western Blotting to investigate the differences in these processes between H37Rv and H37Ra infections. Our results show that, at early time points (no more than 24h), infection with H37Rv significantly increased the expression of TlLR2, Prkaa2, and Prkaa2 phosphorylation in MSCs compared with H37Ra infection. Further analysis revealed that H37Rv infection induced a stronger autophagic response (evidenced by increased Atg9b and LC3II/LC3I) through the TLR2-AMP-AMPK pathway than H37Ra infection. Despite these differences in autophagy, there was no statistically significant difference in bacillary loads, suggesting that, in addition to autophagy, other factors such as apoptosis and immune-inflammatory responses may also regulate Mtb growth in MSCs. Additionally, the metabolic analysis showed that H37Rv infection led to increased expression of SLC2A3, PFKFB3, HK1, and ABCA1 in MSCs compared to H37Ra infection. These findings confirm that, during the early stages of infection, H37Rv induces enhanced autophagy, glucose metabolism, and cholesterol efflux through a more active TLR2-AMP-AMPK pathway than H37Ra. Therefore, MSCs may represent a novel target for the prevention and treatment of tuberculosis.

Solute carrier family 2 members (SLC2A) as potential targets for the treatment of head and neck squamous cell carcinoma patients

ObjectiveSolute carrier family 2 (SLC2A) members have drawn interest in cancer research due to their crucial function in glucose metabolism. To understand their role in Head and Neck Squamous Cell Carcinoma (HNSCC), we have comprehensively analyzed the gene expression of SLC2A family members in HNSCC patients. MethodRNAseq data of 520 HNSCC patients and 46 normals was downloaded from The Cancer Genome Atlas (TCGA) and analyzed using various statistical methods in R. ResultComparison of gene expression between normal and tumor samples showed significantly higher expression of SLC2A1, 4, 6, and 9 in tumor samples compared to normal. Further analysis revealed that both HPV(−)ve and HPV(+)ve samples showed significantly higher expression of SLC2A1 as compared to normal, though the difference was more pronounced in the case of HPV(−)ve. In contrast, SLC2A9 showed a highly significant difference between HPV(−)ve and normal but not between HPV(+)ve and normal. Furthermore, SLC2A genes showed significant variation among the basal (BA), classical (CL), and mesenchymal (MS) expression groups of HNSCC patients. SLC2A1 and 9 were significantly overexpressed in the BA group as compared to the other two groups, suggesting that these two genes can be utilized for the targeted therapy of HPV(−)ve HNSCC patients of the BA group. ConclusionOur results suggest that the biology of SLC2A family members is complex and, they may be playing different roles in different genomic backgrounds. More studies on SLC2A family members are needed to utilize them for targeted therapy or as diagnostic biomarkers.

Impact of expression of metabolic genes on patient (pts) outcomes in metastatic colorectal cancer (mCRC): Data from CALGB/SWOG 80405 (Alliance).

224 Background: Metabolic pathways are reprogrammed during CRC development, leading to increased glycolysis, glutaminolysis, and fatty acid synthesis. Understanding the impact of metabolic reprogramming on treatment outcomes is paramount. Hence, we investigated whether the tumor gene expression of 4 selected major metabolic genes ( PKM, SLC2A1 , SLC16A1 , and CAV1 ) could affect treatment response in pts enrolled in the CALGB/SWOG 80405 trial. Methods: 433 mCRC pts treated with either bevacizumab (bev, n = 226) or cetuximab (cet, n = 207) in combination with first-line chemotherapy were analyzed. RNA was isolated from FFPE tumor samples and sequenced on the HiSeq 2500 (Illumina). Overall survival (OS) and progression-free survival (PFS) were compared between groups of pts categorized by tertiles of gene expression (high [H], medium [M] and low [L]). Logrank P -values provide a non-parametric unadjusted assessment of differences. Likelihood ratio tests (LRT) were computed from multivariate Cox proportional hazards models, adjusting for age, sex, ECOG, tumor side, number of metastatic sites, KRAS , CMS, and treatment. Results: PKM gene expression was associated with cet treatment outcomes with PKM- low tumors showing significantly longer PFS and OS (median PFS: 14.3 vs 9.8 vs 8.1 months, L vs M vs H, P < 0.0001, LRT P = 0.011; median OS: 45.9 vs 31.2 vs 20.9 months, P < 0.0001, LRT P = 0.12). Low SLC2A1 was also associated with longer OS in cet-treated pts (32.4 vs 35.8 vs 25.2 months, P = 0.02, LRT P < 0.0001). Similar results were observed in bev-treated pts where low SLC2A1 expressing tumors had longer OS (37.4 vs 26.1 vs 29 months, P = 0.037, LRT P = 0.069) and a non-significant trend for longer PFS (13.1 vs 11 vs 9.5 months, P = 0.076). CAV1 low gene expression was associated with longer OS in cet-treated pts (37.4 vs 34 vs 21.5 months, P = 0.0048, LRT P = 0.013), while no significant associations were found in bev-treated (interaction LRT P = 0.0009). No significant results were observed for SLC16A1 . Conclusions: The intratumoral expression of metabolic genes was prognostic and predictive in mCRC pts treated with first-line therapy. GLUT1 (encoded by SLC2A1 ) and PKM2 (encoded by PKM ) promote aerobic glycolysis of cancer cells, known as Warburg effect, supporting rapid cell proliferation and survival. CAV1 has been shown to be involved in mitochondrial bioenergetics and fatty acid metabolism and to play either a tumor suppressor or oncogenic role depending on the cancer type and stage. Lower expression of SLC2A1 and PKM was associated with improved survival and increased benefit from cet treatment in our cohort. Low CAV1 expression was also associated with increase survival suggesting a cancer-promoting role in mCRC. Our results suggest that targeting cancer cell metabolism through novel inhibitors of the aforementioned pathways may be a promising therapeutic strategy.

Predictive role of SLC1A5 in neuroblastoma prognosis and immunotherapy

BackgroundNeuroblastoma, a prevalent extracranial solid tumor in pediatric patients, demonstrates significant clinical heterogeneity, ranging from spontaneous regression to aggressive metastatic disease. Despite advances in treatment, high-risk neuroblastoma remains associated with poor survival. SLC1A5, a key glutamine transporter, plays a dual role in promoting tumor growth and immune modulation. However, its contributions to neuroblastoma biology remain largely unexplored.MethodsThis study utilized clinical neuroblastoma samples from 20 patients and 1310 cases from four public datasets to investigate SLC1A5 expression, biological function, and prognostic significance. Differential expression, Kaplan–Meier survival analysis, gene set enrichment analysis, and weighted correlation network analysis were conducted. Functional validation included qPCR, immunohistochemistry, Western blotting, and cell proliferation assays using the SLC1A5 inhibitor V-9302. A prognostic signature, SRPS, was constructed and validated using machine-learning approaches. Immune infiltration analysis was performed to evaluate the tumor immune microenvironment.ResultsSLC1A5 expression was significantly elevated in high-risk neuroblastoma and correlated with advanced stages and poor prognosis. GSEA revealed mTORC1 signaling enrichment in high SLC1A5 expression groups, validated by increased p-p70S6K levels in tumor samples and neuroblastoma cells. V-9302 treatment suppressed mTORC1 signaling and inhibited cell proliferation. Hub-genes were identified to form the SRPS model, which demonstrated superior prognostic performance compared to existing models. Immune infiltration analysis revealed a more immunosuppressive tumor microenvironment associated with high SLC1A5 expression. Additionally, SLC1A5 negatively regulated ST8SIA1, a gene crucial for GD2 biosynthesis, suggesting that SLC1A5 inhibition may enhance GD2-directed immunotherapies.ConclusionSLC1A5 plays a pivotal role in neuroblastoma by promoting tumor progression and shaping an immunosuppressive microenvironment. The SRPS model, incorporating SLC1A5-associated genes, offers robust prognostic utility. Targeting SLC1A5 through advanced drug delivery systems and combined metabolic-immunotherapeutic strategies may enhance treatment specificity and efficacy. These findings provide a foundation for novel therapeutic approaches to improve outcomes in high-risk neuroblastoma patients.

SLC1A5 is a key regulator of glutamine metabolism and a prognostic marker for aggressive luminal breast cancer

Cancer cells exhibit altered metabolism, often relying on glutamine (Gln) for growth. Breast cancer (BC) is a heterogeneous disease with varying clinical outcomes. We investigated the role of the amino acid transporter SLC1A5 (ASCT2) and its association with BC subtypes and patient outcomes. In large BC cohorts, SLC1A5 mRNA (n = 9488) and SLC1A5 protein (n = 1274) levels were assessed and correlated their expression with clinicopathological features, molecular subtypes, and patient outcomes. In vitro SLC1A5 knockdown and inhibition studies in luminal BC cell lines (ZR-75-1 and HCC1500) were used to further explore the role of SLC1A5 in Gln metabolism. Statistical analysis was performed using chi-squared tests, ANOVA, Spearman’s correlation, Kaplan–Meier analysis, and Cox regression. SLC1A5 mRNA and SLC1A5 protein expression were strongly correlated in luminal B, HER2 + and triple-negative BC (TNBC). Both high SLC1A5 mRNA and SLC1A5 protein expression were associated with larger tumour size, higher grade, and positive axillary lymph node metastases (P < 0.01). Importantly, high SLC1A5 expression correlated with poor BC-specific survival specifically in the highly proliferative luminal subtype (P < 0.001). Furthermore, SLC1A5 knockdown by siRNA or GPNA inhibition significantly reduced cell proliferation and glutamine uptake in ZR-75-1 cells. Our findings suggest SLC1A5 plays a key role in the aggressive luminal BC subtype and represents a potential therapeutic target. Further research is needed to explore SLC1A5 function in luminal BC and its association with Gln metabolism pathways.

Mechanism Study of E2F8 Activation of SPC25-Mediated Glutamine Metabolism Promoting Immune Escape in Lung Adenocarcinoma.

Tumour cell immune infiltration is linked to spindle pole component 25 (SPC25). The purpose of this work was to examine the function and molecular mechanism of SPC25 in immune escape in lung adenocarcinoma (LUAD). SPC25 expression in LUAD was examined using The Cancer Genome Atlas (TCGA) database, and RT-qPCR was used to confirm the results. The study involved the use of CD8+ T lymphocytes for immunoinfiltration analysis of SPC25, Gene Set Enrichment Analysis (GSEA)analysis of signalling pathways enriched by SPC25, identification of putative regulatory molecules of SPC25, and confirmation through the use of dual-luciferase and ChIP tests. To evaluate LUAD cell capacity for immune escape, a co-culture technique was employed. Measurements of glutamine uptake, glutamate and α-ketoglutarate levels, NADPH/NADP and GSH/GSSG ratios, and SLC1A5 expression were used to assess the levels of glutamine metabolism. LUAD had increased SPC25 expression. In LUAD cells, immune escape was facilitated by SPC25 knockdown, whereas overexpression had the reverse effect. SPC25 enrichment in the glutamine metabolism pathway was shown by GSEA analysis. Through increased glutamine metabolism brought on by SPC25 overexpression, immune escape was improved in LUAD and could be mitigated by GPNA therapy. E2F8 was also shown to be the transcription factor associated with SPC25, and they showed a binding interaction. By inhibiting glutamine metabolism through SPC25, knocking down E2F8 prevented immune escape in LUAD cells. On the other hand, the suppression of immune escape in LUAD cells caused by E2F8 knockdown was overcome by overexpression of SPC25. In LUAD, E2F8 stimulates SPC25 expression to facilitate glutamine metabolism and encourage immune escape. Our research validates a novel immune escape pathway driven by SPC25 in LUAD cells, providing LUAD patients with potentially effective immunotherapeutic approaches.

SLC7A5 is required for cancer cell growth under arginine-limited conditions.

Tumor cells must optimize metabolite acquisition between synthesis and uptake from a microenvironment characterized by hypoxia, lactate accumulation, and depletion of many amino acids, including arginine. We performed a metabolism-focused functional screen using CRISPR-Cas9 to identify pathways and factors that enable tumor growth in an arginine-depleted environment. Our screen identified the SLC-family transporter SLC7A5 as required for growth, and we hypothesized that this protein functions as a high-affinity citrulline transporter. Using isotope tracing experiments, we show that citrulline uptake and metabolism into arginine are dependent upon expression of SLC7A5. Pharmacological inhibition of SLC7A5 blocks growth under low-arginine conditions across a diverse group of cancer cell lines. Loss of SLC7A5 reduces tumor growth and citrulline import in a mouse tumor model. We identify a conditionally essential role for SLC7A5 in arginine metabolism, and we propose that SLC7A5-targeting therapeutic strategies in cancer may be effective in the context of arginine limitation.

TAGLN-RhoA/ROCK2-SLC2A3-mediated Mechano-metabolic Axis Promotes Skin Fibrosis.

Skin fibrotic diseases are characterized by abnormal fibroblast function and excessive deposition of extracellular matrix. Our previous single-cell sequencing results identified an enriched fibroblast subcluster in skin fibrotic tissues that highly expresses the actin cross-linking cytoskeletal protein Transgelin (TAGLN), which bridges the mechanical environment of tissues and cellular metabolism. Therefore, we aimed to investigate the role of TAGLN in the pathogenesis of skin fibrosis. Transwell, wound healing, collagen gel contraction assay, immunofluorescence and RNA-seq analyses were used to validate and explore the potential mechanisms of the TAGLN-RhoA/ROCK2-SLC2A3-mediated mechano-metabolic axis in dermal fibrosis. The therapeutic efficacy of targeting TAGLN was validated using a bleomycin-induced mouse model of skin fibrosis. Functional assays revealed that downregulation of TAGLN inhibited motility and secretory function of fibroblasts, including invasion, migration, contraction, and collagen secretion. The glucose carrier SLC2A3 was identified as one of the downstream targets of TAGLN by RNA-sequencing analysis and further validation. We further demonstrated that TAGLN regulates the expression of SLC2A3 through the RhoA/ROCK2 pathway, a key pathway of mechanotransduction, thereby affecting glycolysis and motility of fibroblasts. This study reveals the existence of the TAGLN-RhoA/ROCK2-SLC2A3 mechano-metabolic axis in skin fibrotic diseases and provides a promising target for its clinical treatment.

Oral histidine affects gut microbiota and MAIT cells improving glycemic control in type 2 diabetes patients

ABSTRACT Amino acids, metabolized by host cells as well as commensal gut bacteria, have signaling effects on host metabolism. Oral supplementation of the essential amino acid histidine has been shown to exert metabolic benefits. To investigate whether dietary histidine aids glycemic control, we performed a case-controlled parallel clinical intervention study in participants with type 2 diabetes (T2D) and healthy controls. Participants received oral histidine for seven weeks. After 2 weeks of histidine supplementation, the microbiome was depleted by antibiotics to determine the microbial contribution to histidine metabolism. We assessed glycemic control, immunophenotyping of peripheral blood mononucelar cells (PBMC), DNA methylation of PBMCs and fecal gut microbiota composition. Histidine improves several markers of glycemic control, including postprandial glucose levels with a concordant increase in the proportion of MAIT cells after two weeks of histidine supplementation. The increase in MAIT cells was associated with changes in gut microbial pathways such as riboflavin biosynthesis and epigenetic changes in the amino acid transporter SLC7A5. Associations between the microbiome and MAIT cells were replicated in the MetaCardis cohort. We propose a conceptual framework for how oral histidine may affect MAIT cells via altered gut microbiota composition and SLC7A5 expression in MAIT cells directly and thereby influencing glycemic control. Future studies should focus on the role of flavin biosynthesis intermediates and SLC7A5 modulation in MAIT cells to modulate glycemic control.

High expression of SLC2A1 inhibits ferroptosis and promotes proliferation and invasion of lung adenocarcinoma cells

To examine how the glucose transporter SLC2A1 influences the proliferation and migration of lung adenocarcinoma (LUAD) and explore the underlying molecular mechanisms. We examined the differential expression of SLC2A1 between normal and LUAD tissues in the TCGA database and its prognostic implications. Immunohistochemistry was used to detect SLC2A1 protein levels in clinical samples of LUAD and adjacent tissues, and the association of SLC2A1 expression levels with clinicopathological features of the patients was analyzed. In PC9 cells with stable SLC2A1 overexpression or knockdown, the effects of SLC2A1 expression level on cell proliferation and migration were assessed using CCK-8 and Transwell assays, and the changes in expressions of ferroptosis- and autophagy-related proteins were measured; the occurrence of ferroptosis was confirmed using ROS and Fe2+ fluorescence staining. SLC2A1 expression was significantly higher in LUAD tumor tissues than in normal lung tissues (P<0.05) and was associated with worse pathological parameters and prognosis of the patients (P<0.05). In PC9 cells, SLC2A1 overexpression significantly promoted cell proliferation, invasion and migration, and SLC2A1 knockdown significanty increased cell death and inhibited cell invasion and proliferation. SLC2A1 knockdown caused obvious activation of cell ferroptosis, reduced GPX4 and xCT expressions, and increased intracellular levels of ROS and Fe2+. SLC2A1 knockdown also resulted in increased cell autophagy shown by increased LC3B expression, which could be reversed by treatement with 3-MA. High SLC2A1 expression is correlated with poor prognosis of patients with LUAD, and inhibiting SLC2A1 can induce ferroptosis and autophagy of LUAD cells, suggesting the potential of SLC2A1 as a target for LUAD diagnosis and treatment.

Genetic overlap between breast cancer and sarcopenia: exploring the prognostic implications of SLC38A1 gene expression

BackgroundSarcopenia, an age-related syndrome characterized by a decline in muscle mass, not only affects patients’ quality of life but may also increase the risk of breast cancer recurrence and reduce survival rates. Therefore, investigating the genetic mechanisms shared between breast cancer and sarcopenia is significant for the prevention, diagnosis, and treatment of breast cancer.MethodsThis study downloaded gene expression datasets and clinical data related to breast cancer and skeletal muscle aging from the GEO database. Data preprocessing, integration, differential gene identification, functional enrichment analysis, and construction of protein-protein interaction networks were performed using R language. Subsequently, COX proportional hazards model analysis and survival analysis were conducted, and survival curves and nomograms were generated. The expression levels of genes in tissues were detected using qRT-PCR, and the Radiant DICOM viewer software was used to delineate the pectoralis major muscle area in CT images.ResultsWe identified 152 differentially expressed genes (P < .05) and 226 sarcopenia-related genes (r > .4) associated with skeletal muscle aging. The TCGA-BRCA dataset revealed 106 genes associated with breast cancer (P < .05, logFC = 1). Functional enrichment analysis indicated significant enrichment in cell proliferation and growth pathways. The PPI network identified critical molecules involved in muscle aging and tumor progression. After dimensionality reduction, a strong correlation was observed between the expression of the muscle aging-related gene set and the prognosis of breast cancer patients (P < .01). The expression of SLC38A1 identified through multivariate COX analysis was significantly associated with poor prognosis in breast cancer patients (P = .03). Incorporating SLC38A1 expression, the prognostic model precisely forecasted breast cancer survival (P < .01). External validation confirmed the higher expression of the SLC38A1 gene in breast cancer tissues compared to adjacent non-cancerous tissues (P < .01). The SLC38A1 index, calculated in combination with the patient’s age and BMI, can optimize the prognostic prediction model, providing a powerful tool for personalized treatment of breast cancer.ConclusionHigh SLC38A1 gene expression was significantly associated with poor prognosis in breast cancer patients. The combination of SLC38A1 expression and the pectoralis major muscle area provided an optimized prognostic prediction model, offering a potential tool for personalized breast cancer treatment.

Momordicine-I suppresses head and neck cancer growth by modulating key metabolic pathways

One of the hallmarks of cancer is metabolic reprogramming which controls cellular homeostasis and therapy resistance. Here, we investigated the effect of momordicine-I (M-I), a key bioactive compound from Momordica charantia (bitter melon), on metabolic pathways in human head and neck cancer (HNC) cells and a mouse HNC tumorigenicity model. We found that M-I treatment on HNC cells significantly reduced the expression of key glycolytic molecules, SLC2A1 (GLUT-1), HK1, PFKP, PDK3, PKM, and LDHA at the mRNA and protein levels. We further observed reduced lactate accumulation, suggesting glycolysis was perturbed in M-I treated HNC cells. Metabolomic analyses confirmed a marked reduction in glycolytic and TCA cycle metabolites in M-I-treated cells. M-I treatment significantly downregulated mRNA and protein expression of essential enzymes involved in de novo lipogenesis, including ACLY, ACC1, FASN, SREBP1, and SCD1. Using shotgun lipidomics, we found a significant increase in lysophosphatidylcholine and phosphatidylcholine loss in M-I treated cells. Subsequently, we observed dysregulation of mitochondrial membrane potential and significant reduction of mitochondrial oxygen consumption after M-I treatment. We further observed M-I treatment induced autophagy, activated AMPK and inhibited mTOR and Akt signaling pathways and leading to apoptosis. However, blocking autophagy did not rescue the M-I-mediated alterations in lipogenesis, suggesting an independent mechanism of action. M-I treated mouse HNC MOC2 cell tumors displayed reduced Hk1, Pdk3, Fasn, and Acly expression. In conclusion, our study revealed that M-I inhibits glycolysis, lipid metabolism, induces autophagy in HNC cells and reduces tumor volume in mice. Therefore, M-I-mediated metabolic reprogramming of HNC has the potential for important therapeutic implications.Graphical

Assessment of Changes in the Expression of Genes Involved in Insulin Signaling and Glucose Transport in Leukocytes of Women with Gestational Diabetes During Pregnancy and in the Postpartum Period.

Not much is currently known about disturbances in insulin signaling and glucose transport in leukocytes of women with gestational diabetes mellitus (GDM) during and after pregnancy. In this study, the expression of insulin signaling (INSR, IRS1, IRS2 and PIK3R1)- and glucose transporter (SLC2A1, SLC2A3 and SLC2A4)-related genes in the leukocytes of 92 pregnant women was assayed using quantitative RT-PCR. The cohort consisted of 44 women without GDM (NGT group) and 48 with GDM (GDM group) at 24-28 weeks of gestation. GDM women were then tested again one year after childbirth (pGDM group: 14 women (29.2%) with abnormal glucose tolerance (AGT) and 34 women (70.8%) with normoglycemia). The GDM and NGT groups were closely matched for gestational age and parameters of obesity, such as pre-pregnancy body mass index (BMI), pregnancy weight, and gestational weight gain (GWG) (p > 0.05). Compared to the NGT group, the GDM and pGDM groups were hyperglycemic, but the GDM group featured a more highly insulin-resistant condition than the pGDM group, as reflected by higher fasting insulin (FI) levels and the values of the homeostasis model assessment for insulin resistance (HOMA-IR) (p < 0.05). In leukocytes from the GDM and pGDM groups, PIK3R1, SLC2A1, and SLC2A3 were upregulated and IRS1 was downregulated, with a larger magnitude in fold change (FC) values for PIK3R1 and IRS1 in the GDM group and for SLC2A1 and SLC2A3 in the pGDM group. The expression of SLC2A4 was unchanged in the GDM group but upregulated in the pGDM group, where it was inversely correlated with HOMA-IR (rho = -0.48; p = 0.007). Although the INSR and IRS2 levels did not significantly differ between the groups, the IRS2 transcript positively correlated with pregnancy weight, fasting plasma glucose, FI, and HOMA-IR in the GDM group. Our findings indicate that pronounced quantitative changes exist between the GDM and pGDM groups with respect to the expression of certain genes engaged in insulin signaling and glucose transport in leukocytes, with insulin resistance of a variable degree. These data also highlight the relationship of leukocyte SLC2A4 expression with insulin resistance in the postpartum period.

ATF4 promotes glutaminolysis and glycolysis in colorectal cancer by transcriptionally inducing SLC1A5.

Glutaminolysis and glycolysis promote the malignant progression of colorectal cancer. The role of activating transcription factor 4 (ATF4) in solute carrier family 1 member 5 (SLC1A5)-mediated glutaminolysis and glycolysis remains to be elucidated. SLC1A5 and ATF4 expression levels are detected in colorectal cancer tissues. ATF4 is knocked down or overexpressed to assess its role in cell viability, migration and invasion. SLC1A5 is knocked down to evaluate its role in cell viability, migration, invasion, and metastasis and the metabolism of glutamine and glucose. The regulatory effect of the transcription factor ATF4 on SLC1A5 transcription and expression is determined using a luciferase reporter assay and chromatin immunoprecipitation (ChIP) techniques. Upregulated ATF4 and SLC1A5 expressions are observed in tumor tissue, which is positively correlated with the tumor, node, and metastasis (TNM) stages. ATF4-overexpressing SW480 cells show the increased cell viability, migration and invasion. Conversely, ATF4 knockdown decreases the viability, migration and invasion of HCT-116 cells. SLC1A5 knockdown inhibits viability, migration, invasion, and metastasis and the metabolism of glutamine and glucose in HT-29 cells, as well as the expressions of two key glycolytic enzymes, hexokinase 2 (HK2) and pyruvate kinase M2 (PKM2). The luciferase activity of the SLC1A5 promoter is increased by ATF4 overexpression. SLC1A5 promoter enrichment is increased by anti-ATF4 antibody immunoprecipitation in ATF4-overexpressing colorectal cells, indicating that ATF4 targets SLC1A5 to promote glutamine and glucose metabolism in these cells. In summary, the ATF4/SLC1A5 axis plays a significant role in the progression of colorectal cancer by regulating glutamine metabolism and glycolysis.

KLF7 Promotes Hepatocellular Carcinoma Progression Through Regulating SLC1A5-Mediated Tryptophan Metabolism.

Krüppel-like factor 7 is a transcriptional activator and acts as an oncogene in human cancers, including hepatocellular carcinoma (HCC). Tryptophan metabolism is important for HCC cell proliferation, metastasis, and invasion. It is unclear whether KLF7 could regulate Trp metabolism in HCC. In this study, we found that Trp metabolism was suppressed in HCC cells with KLF7 knockdown. The mRNA and protein levels of SLC1A5, SLC7A5, and TPH1, as well as the content of Trp and serotonin, were reduced after KLF7 knockdown, and were potentiated following KLF7 overexpression. Increasing the content of serotonin could restore the malignancy of tumour cells invitro and tumour growth invivo. Conversely, decreasing the content of serotonin suppressed HCC cell proliferation. The binding activity of KLF7 was on the promoter of SLC1A5, and KLF7 positively regulated the expression of SLC1A5. KLF7 contributed to the proliferation and migration of HCC cells by up-regulation of SLC1A5. Collectively, KLF7 promotes the progression of HCC through regulating Trp metabolism. The newly identified axis of KLF7/ SLC1A5 in HCC could represent a potential target for HCC therapy.

Identification of Ferroptosis-Related Gene in Age-Related Macular Degeneration Using Machine Learning.

Age-related macular degeneration (AMD) is a major cause of irreversible visual impairment, with dry AMD being the most prevalent form. Programmed cell death of retinal pigment epithelium (RPE) cells is a central mechanism in the pathogenesis of dry AMD. Ferroptosis, a recently identified form of programmed cell death, is characterized by iron accumulation-induced lipid peroxidation. This study aimed to investigate the involvement of ferroptosis in the progression of AMD. A total of 41 samples of AMD and 50 normal samples were obtained from the data set GSE29801 for differential gene expression analysis and functional enrichment. Differentially expressed genes (DEGs) were selected and intersected with genes from the ferroptosis database to obtain differentially expressed ferroptosis-associated genes (DEFGs). Machine learning algorithms were employed to screen diagnostic genes. The diagnostic genes were subjected to Gene Set Enrichment Analysis (GSEA). Expression differences of diagnostic genes were validated in in vivo and in vitro models. We identified 462 DEGs when comparing normal and AMD samples. The GO enrichment analysis indicated significant involvement in key biological processes like collagen-containing extracellular matrix composition, positive cell adhesion regulation, and extracellular matrix organization. Through the intersection with ferroptosis gene sets, we pinpointed 10 DEFGs. Leveraging machine learning algorithms, we pinpointed five ferroptosis feature diagnostic genes: VEGFA, SLC2A1, HAMP, HSPB1, and FADS2. The subsequent experiments validated the increased expression of SLC2A1 and FADS2 in the AMD ferroptosis model. The occurrence of ferroptosis could potentially contribute to the advancement of AMD. SLC2A1 and FADS2 have demonstrated promise as emerging diagnostic biomarkers and plausible therapeutic targets for AMD.

SLC2A3 promotes head and neck squamous cancer developing through negatively regulating CD8+ T cell in tumor microenvironment

Recent studies have identified SLC2A3 as being abnormally upregulated in multiple tumor types, correlating with poor survival and disrupted microenvironments. However, its prognostic significance in head and neck squamous cell carcinoma (HNSC) remains underexplored. In this study, SLC2A3 was screened as a potential risk gene influencing both immune and tumor components within the tumor microenvironment (TME) of 504 HNSC patients from the TCGA database. Immune infiltration analyses and clinical significance on SLC2A3 were conducted using ESTIMATE, CIBERSORT, ssGSEA, TIMER and clinical prognosis parameters. Additionally, the single-cell dataset is used to analyze the expression of SLC2A3 in various subpopulations. The magnetic activated cell sorting (MACS) is used to isolate CD8+ T cells from PBMCs or tumor tissues. Flow cytometry is used to identify purified and activated CD8+ T cells. GSEA and WB were used to investigate the molecular mechanism of SLC2A3 in CD8+ T cells. The co-culture system of CD8+ T cells and TU686 was used to investigate the effects of SLC2A3 on immune cells and tumor development. In this study, SLC2A3 was identified as a potential risk gene affecting both immune cells and tumor components within the TME of 504 HNSC patients derived from the TCGA database. We conducted immune infiltration analyses and assessed the clinical significance of SLC2A3 using various bioinformatics tools, including ESTIMATE, CIBERSORT, ssGSEA, and TIMER, along with clinical prognosis parameters. The single-cell RNA sequencing dataset was utilized to examine SLC2A3 expression across different cellular subpopulations. Magnetic activated cell sorting (MACS) was employed to isolate CD8+ T cells from peripheral blood mononuclear cells (PBMCs) or tumor tissues. Flow cytometry was implemented to confirm the purity and activation state of the isolated CD8+ T cells. GSEA and Western blot were applied to explore the molecular mechanisms underlying SLC2A3’s role in CD8+ T cells. Lastly, a co-culture system involving CD8+ T cells and TU686 tumor cells was established to study the impact of SLC2A3 on immune cell function and tumor progression. SLC2A3 emerges as an actively variable gene within the immune and stromal components of the TME, linked to aggravated immune infiltration and poor clinical outcomes. The upregulated expression of SLC2A3 is predominantly enriched in immune-related biological processes and linked to the suppression of CD8+ T cells, which are crucial for the survival of HNSC patients. Furthermore, SLC2A3 exhibits specific overexpression in CD8+ T cells and may potentially trigger ferroptosis. Knockdown of SLC2A3 led to a significant increase in the proliferation of CD8+ T cells compared to those without knockdown. In co-culture systems, CD8+ T cells with SLC2A3 knockdown demonstrated an enhanced ability to eliminate tumor cells compared to those without the knockdown. SLC2A3 is associated with changes in the TME and prognostic indicators. Moreover, high SLC2A3 expression in CD8+ T cells may drive cell death through ferroptosis, fostering tumor progression.

Differential expression of the SLC34A2 gene in different histological subtypes of ovarian carcinomas

BACKGROUND: Patients with ovarian carcinoma demonstrate different sensitivity to chemotherapy; therefore, to increase the effectiveness of treatment, it is necessary to take into account the characteristics of each patient's tumor, including the histological subtype. AIM: To search for new molecular markers of ovarian cancer by analyzing the expression of candidate genes, including BAX, SLC34A2, MUC16, CD300A, and XKR8, in ovarian carcinomas of different histological subtypes. MATERIAL AND METHODS: Analysis of the expression of the BAX, SLC34A2, MUC16, CD300A, and XKR8 genes in 33 carcinomas taking into account their histological subtypes was performed using real-time polymerase chain reaction. Tumor samples from patients with ovarian carcinoma were obtained from the Blokhin National Medical Research Center of Oncology (Moscow) and the Republican Clinical Oncology Dispensary (Kazan) and divided into groups by histological subtypes: serous of high (n=16) and low (n=6) grade malignancy, endometrioid (n=8) and mucinous (n=3). Additional analysis was performed using microarray data from the Gene Expression Omnibus open database to determine the expression of selected candidate genes in ovarian carcinomas of different histological subtypes. The dataset included 4 normal ovary samples and 95 ovarian carcinoma samples of different histological subtypes: serous (n=41), endometrioid (n=37), and mucinous (n=13). Statistical analysis of the data was performed using Prism software. Nonparametric Dunn's test was used to compare gene expression in several patient groups. RESULTS: The expression level of the SLC34A2 gene was increased in low-grade serous carcinomas (p=0.0257) compared to mucinous carcinomas. Using bioinformatics analysis, we found increased expression of the SLC34A2 gene in serous (p=0.0023) and endometrioid ovarian carcinomas (p=0.0355) compared to normal ovarian tissues. CONCLUSION: The SLC34A2 gene can be considered as a potential molecular marker for differential diagnosis of ovarian cancer histological subtypes and a target for therapy of patients with low-grade serous ovarian carcinoma.

Dissecting the novel molecular interactions of solute carrier family 4 member 4 (SLC4A4) for prostate cancer (PCa) progression

Prostate cancer (PCa) is the most common malignancy diagnosed in men. The purpose of this study was to report the molecular pathways of Homo sapiens solute carrier family 4 member 4 (SLC4A4) in the progression of PCa. Here, we report our findings from clinical specimens of prostatic acinar adenocarcinoma collected from patients. We found that low-grade prostate cancers have higher SLC4A4 expression. We investigated the role of SLC4A4 and the signaling mechanism underlying its role in modulating the PCa progression. Firstly, we reported the SLC4A4/GSK-3β/β-catenin signaling axis, which regulates the clonogenic potential, invasiveness, and metastasis. In this, we found reduced phosphorylation of GSK at serine 21 of α and serine 9 of the β subunit in shSLC4A4 cells of PCa, which ultimately relieved the activity of GSK-3β. This activated GSK-3β phosphorylates β-catenin at Ser33/37 with a subsequently reduced β-catenin level in PCa cells. Our functional analysis revealed that SLC4A4 knockdown retards tumor growth and lowers invasion and migration potential. Secondly, we investigated the SLC4A4/RB axis, which acts to drive cell proliferation. SLC4A4 knockdown decreases the interaction between these molecules with hypophosphorylation of RB protein and cell cycle arrest. Likewise, transcriptome sequencing using the SLC4A4 knockdown in DU145 cells regulates differentiated expressed genes and multiple metabolic pathways. Our results suggest that SLC4A4 may serve as a potential therapeutic target for prostate cancer patients in the future.