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This study aimed to clarify the expression changes and clinical significance of regulatory T (Treg) cells and follicular regulatory T (TFR) cell subsets divided by glycoprotein A repetitions predominant protein (GARP) and T cell factor 1(TCF1) in peripheral blood of patients with chronic HBV infection. The peripheral blood of 26 chronic hepatitis B (CHB) patients, 27 inactive HBsAg carriers and 32 healthy controls were collected and GARP + percentages in Treg and TFR cells were analyzed by flow cytometry. In addition, Treg and TFR cell subsets sorted by CD62L and TCF1 were analyzed and compared. Correlation analyses were performed between Treg and TFR cell subpopulations and clinical parameters as well as cytokine concentrations, including IL-21, IL-10 and TGF-β1 in plasma. Circulating Treg and TFR levels were elevated in CHB patients. Moreover, GARP and TCF1 were up-regulated in circulating Treg and TFR cells of CHB patients. TCF1 + CD62L- Treg cells were increased while TCF1-CD62L + Treg cells were decreased in CHB patients. TCF1 + CD62L- and TCF1-CD62L- TFR cells were increased while TCF1 + CD62L + TFR cells were decreased in CHB patients. TCF1 + CD62L- Treg cells were positively correlated with HBV DNA, ALT and plasma IL-10, while TCF1 + CD62L + TFR cells were negatively correlated with HBV DNA, HBeAg, HBsAg, ALT, AST, T-BIL and positively correlated with plasma IL-21. Treg and TFR subsets sorted by TCF1, CD62L and GARP were changed in CHB patients. Changes in Treg and TFR functional subsets are associated with antiviral immunity in CHB patients.

Transcription factor 7-like 2 (TCF7L2) polymorphism plays an essential role in the occurrence and development of patients living with diabetes, but the current conclusions are inconsistent on the relationship between TCF7L2 polymorphism and the risk of diabetic nephropathy. This meta-analysis aims to explore the exact association between TCF7L2 rs7903146 locus polymorphism and susceptibility to diabetic nephropathy. PubMed, Embase, Web of Science, Cochrane Library, China National Knowledge Infrastructure (CNKI), and China Wanfang databases were searched for studies on the relationship between single nucleotide polymorphism at TCF7L2 rs7903146 locus and susceptibility to diabetic nephropathy until January 10, 2022. The data were analyzed by Stata 15.0 software. A total of 7 articles were included, covering 1443 patients with diabetic nephropathy and 2129 diabetic non-nephropathy patients. The results showed that allele C at TCF7L2 rs7903146 locus, compared to allele T, the pooled odds ratio (OR)=0.69 (95% CI: 0.56–0.85, p≤0.05). In the dominant gene inheritance model, recessive gene inheritance model, homozygous genetic model, and heterozygous genetic model, the pooled OR was 0.47 (95% CI: 0.36–0.61), 0.63 (95% CI: 0.54–0.73), 0.39 (95% CI: 0.29–0.51), and 0.59 (95% CI: 0.45–0.78), respectively, and the differences were statistically significant. In conclusion, TCF7L2 rs7903146 polymorphism is associated with susceptibility to diabetic nephropathy. Allele T and genotype TT can increase the risk of diabetic nephropathy.

Cholangiocarcinoma (CCA) is a type of highly malignant tumor originating from bile ducts. The prognosis of CCA is poor and the treatment options are limited. The biomarker study of CCA has made little progresses in recent years because of the difficulty to obtain CCA specimens. SOX9 is an important regulator of cholangiocyte proliferation and differentiation. We performed mRNA sequencing of CCA, retrieved TCGA data, and detected SOX9 expression in a large CCA cohort. With WNT3A stimulation, SOX9 expression and transcription was elevated by TCF7. Moreover, SOX9 was substantially up-regulated in CCA tissues and was identified as a prognostic biomarker of CCA. With mRNA sequencing and in vitro/vivo validation, we demonstrated that SOX9 enhanced the transcription and expression of FGF7 and FGFR2. FGF7 was significantly up-regulated in the bile and serum of CCA patients, and may promote CCA proliferation by activating FGFR2 in an autocrine pathway. co-expression of FGF7 and FGFR2 was a more sensitive marker for poor prognosis. SOX9-induced overexpression of FGF7 and FGFR2 was the key reason of SOX9-involved pemigatinib resistance. In conclusion, SOX9 and FGF7 were prognostic biomarkers of CCA. WNT3A-TCF7-SOX9 axis could induce pemigatinib resistance in two independent pathways: (1)SOX9 directly promotes FGFR2 transcription and expression; (2)SOX9 elevates FGF7 expression, which could be secreted from CCA cells and activates FGFR2 phosphorylation in an autocrine pathway.

Background Colorectal cancer (CRC) is one of the most common malignant tumours. The recurrence and metastasis of CRC seriously affect the survival rate of patients. Angiogenesis is an extremely important cause of tumour growth and metastasis. Circular RNAs (circRNAs) have been emerged as vital regulators for tumour progression. However, the regulatory role, clinical significance and underlying mechanisms still remain largely unknown. Methods High-throughput sequencing was used to analyse differential circRNAs expression in tumour and non-tumour tissues of CRC. In situ hybridization (ISH) and qRT-PCR were used to determine the level of circ3823 in CRC tissues and serum samples. Then, functional experiments in vitro and in vivo were performed to investigate the effects of circ3823 on tumour growth, metastasis and angiogenesis in CRC. Sanger sequencing, RNase R and Actinomycin D assay were used to verify the ring structure of circ3823. Mechanistically, dual luciferase reporter assay, fluorescent in situ hybridization (FISH), RNA immunoprecipitation (RIP) and RNA pull-down experiments were performed to confirm the underlying mechanisms of circ3823. Results Circ3823 was evidently highly expressed in CRC and high circ3823 expression predicted a worse prognosis of CRC patients. Receiver operating characteristic curves (ROCs) indicated that the expression of circ3823 in serum showed high sensitivity and specificity for detecting CRC which means circ3823 have the potential to be used as diagnostic biomarkers. Functional experiments in vitro and in vivo indicated that circ3823 promote CRC cell proliferation, metastasis and angiogenesis. Mechanism analysis showed that circ3823 act as a competing endogenous RNA of miR-30c-5p to relieve the repressive effect of miR-30c-5p on its target TCF7 which upregulates MYC and CCND1, and finally facilitates CRC progression. In addition, we found that N6-methyladenosine (m6A) modification exists on circ3823. And the m6A modification is involved in regulating the degradation of circ3823. Conclusions Our findings suggest that circ3823 promotes CRC growth, metastasis and angiogenesis through circ3823/miR-30c-5p/TCF7 axis and it may serve as a new diagnostic marker or target for treatment of CRC patients. In addition, m6A modification is involved in regulating the degradation of circ3823.

Overexpression of ubiquitin-specific protease 28 (USP28) is found in hepatic carcinoma. It is unclear whether the deubiquitinase plays a role in hepatocarcinogenesis. Deregulation of the Wnt signaling pathway is frequently associated with liver cancer. Transcription factor 7-like 2 (TCF7L2) is an important downstream transcription factor of the Wnt/β-catenin signaling pathway, but the mechanisms by which TCF7L2 itself is regulated have not yet been revealed. Here, we report that USP28 promotes the activity of the Wnt signaling pathway through maintaining the stability of TCF7L2. We further show that FBXW7 is the E3 ubiquitin ligase for TCF7L2. By regulating the levels of TCF7L2, USP28 modulates the Wnt/β-catenin signaling in liver cancer and USP28 depletion or inhibition by a small molecule inhibitor leads to a halt of growth in liver cancer cells. These results suggest that USP28 could be a potential therapeutic target for liver cancer.

Background Hypertrophy of ligamentum flavum (HLF) is the mainly cause of lumbar spinal stenosis (LSS), but the precise mechanism of HLF formation has not been fully elucidated. Emerging evidence indicates that transcription factor 7 (TCF7) is the key downstream functional molecule of Wnt/β-catenin signaling, which participated in regulating multiple biological processes. However, the role and underlying mechanism of TCF7 in HLF is still unclear. Methods We used mRNAs sequencing analysis of human LF and subsequent confirmation with RT-qPCR, western blot and immunohistochemistry to identified the TCF7 in HLF tissues and cells. Then effect of TCF7 on HLF progression was investigated both in vitro and in vivo. Mechanically, chromatin immunoprecipitation, dual-luciferase reporter assays, and rescue experiments were used to validate the regulation of TCF7/SNAI2/miR-4306 feedback loop. Results Our results identified for first time that the TCF7 expression was obviously elevated in HLF tissues and cells compared with control, and also found that TCF7 expression had significant positive correlation with LF thickness and fibrosis score. Notably, TCF7 inhibition suppressed the hyper-proliferation and fibrosis phenotype of HLF cells in vitro and ameliorated progression of HLF in mice in vivo, whereas TCF7 overexpression promoted hyper-proliferation and fibrosis phenotype of HLF cells in vitro. Our data further revealed that TCF7 interacted with SNAI2 promoter to transactivated the SNAI2 expression, thereby promoting hyper-proliferation and fibrosis phenotype of HLF cells in vitro. Furthermore, miR-4036 negatively regulated by SNAI2 could negatively feedback regulate TCF7 expression by directly binding to TCF7 mRNA 3’-UTR, thus inhibiting the hyper-proliferation and fibrosis phenotype of HLF cells in vitro. Conclusions Our study demonstrated that TCF7 inhibition could suppress HLF formation by modulating TCF7/SNAI2/miR-4306 feedback loop, which might be considered as a novel potential therapeutic target for HLF.

T cell immune dysfunction is a prominent characteristic of chronic lymphocytic leukemia (CLL) and the main cause of failure for immunotherapy and multi-drug resistance. There remains a lack of specific biomarkers for evaluating T cell immune status with outcome for CLL patients. T cell factor 1 (TCF1, encoded by the TCF7 gene) can be used as a critical determinant of successful anti-tumor immunotherapy and a prognostic indicator in some solid tumors; however, the effects of TCF1 in CLL remain unclear. Here, we first analyzed the biological processes and functions of TCF1 and co-expressing genes using the GEO and STRING databases with the online tools Venny, Circos, and Database for Annotation, Visualization, and Integrated Discovery (DAVID). Then the expression and prognostic values of TCF1 and its partner gene B cell leukemia/lymphoma 11B (BCL11B) were explored for 505 CLL patients from 6 datasets and validated with 50 CLL patients from Henan cancer hospital (HNCH). TCF1 was downregulated in CLL patients, particularly in CD8+ T cells, which was significantly correlated with poor time-to-first treatment (TTFT) and overall survival (OS) as well as short restricted mean survival time (RMST). Function and pathway enrichment analysis revealed that TCF1 was positively correlated with BCL11B, which is involved in regulating the activation and differentiation of T cells in CLL patients. Intriguingly, BCL11B was highly consistent with TCF1 in its decreased expression and prediction of poor prognosis. More importantly, the combination of TCF1 and BCL11B could more accurately assess prognosis than either alone. Additionally, decreased TCF1 and BCL11B expression serves as an independent risk factor for rapid disease progression, coinciding with high-risk indicators, including unmutated IGHV, TP53 alteration, and advanced disease. Altogether, this study demonstrates that decreased TCF1 and BCL11B expression is significantly correlated with poor prognosis, which may be due to decreased TCF1+CD8+ T cells, impairing the effector CD8+ T cell differentiation regulated by TCF1/BCL11B.

Alteration of N6-methyladenosine (m6A) is closely linked to spanning biological processes including osteoporosis (OP) development. This research focuses on the function of methyltransferase like 14 (METTL14) in bone turnover and its interaction with T cell factor 1 (TCF1). A mouse model of OP was established by ovariectomy (OVX). The bone mass parameters were evaluated by micro-CT analysis. Mouse MC3T3-E1 cells and mouse bone marrow macrophages (BMMs) were induced for osteogenic or osteoclastic differentiation, respectively, for in vitro experiments. The osteogenesis or osteoclasis activity was analyzed by measuring the biomarkers such as OPG, ALP, NFATC1, CTSK, RANKL, and TRAP. RT-qPCR and IHC assays identified reduced METTL14 expression in bone tissues of osteoporotic patients and ovariectomized mice. Artificial METTL14 overexpression increased bone mass of mice and promoted osteogenesis whereas suppressed osteoclasis both in vivo and in vitro. METTL14 promoted TCF1 expression through m6A mRNA methylation, and TCF1 increased the osteogenic activity by elevating the protein level of RUNX2, a key molecule linked to bone formation. In rescue experiments, TCF1 restored the RUNX2 level and osteogenic activity of cells suppressed by METTL14 silencing. In summary, this research demonstrates that METTL14 plays a protective role against OP by promoting the TCF1/RUNX2 axis.

Immune checkpoint blockade is limited by resistance to treatment, with many patients not achieving durable antitumor responses. Self-renewing (T cell factor 1

The prognosis of patients with T-cell acute lymphoblastic leukemia (T-ALL) has been largely lacked behind than that of patients with B-cell ALL, especially in refractory or relapsed cases. Here, we describe a 4.7-year-old male child with TCF-SPI1-postitve T-ALL who developed refractoriness disease after a seven drugs-conventional therapy. Several studies have suggested the therapeutic potential of dasatinib in refractory T-ALL. Actually, dasatinib-included therapy dramatically reduces the leukemic burden and re-induces this patient into complete remission without systemic adverse events. Although this is a single exceptional case, the translational potential evidence of dasatinib in specific T-ALL subtype should not be under-estimated.

ObjectiveTo investigate the correlation between transcription factor 7-like 2 (TCF7L2) gene polymorphisms and gestational diabetes mellitus (GDM) risk in the central Chinese population.MethodsThis case–control study examined the association of seven TCF7L2 gene single-nucleotide polymorphisms (SNPs) (rs11196218, rs4506565, rs7895340, rs7901695, rs11196205, rs12243326, and rs290487) with GDM risk in the central Chinese population (843 GDM and 877 controls). The clinical information and blood samples were collected by trained interviewers and nurses. Genotyping of SNPs was conducted on the Sequenom MassARRAY platform. Statistical analyses including t-test, ANOVA, chi-square test, Fisher’s exact test, and logistic regression were performed.ResultsDifferences in age, pre-pregnant body mass index (BMI), and family history of type 2 diabetes mellitus (T2DM) between the case and control groups were significant (p < 0.05). Compared with the wild-type genotype, pregnant women with genotypes of rs4506565-AT (OR = 1.89, 95%CI: 1.18–3.02), rs7895340 GA (OR = 1.93, 95%CI: 1.06–3.54), rs7901695-TC (OR = 1.79, 95%CI: 1.11–2.88), and rs11196205-GC (OR = 2.15, 95%CI: 1.16–3.98) had a significantly higher risk of GDM, adjusted by age, pre-pregnant BMI, and family history of T2DM. Functional annotation showed that all these four SNPs fell in the functional elements of human pancreatic islets. Further cumulative effects analysis concluded that when participants carried all these four risk genotypes, the risk of GDM was 3.51 times (OR = 3.51, 95%CI: 1.38–8.90) than that of those without any risk genotypes.ConclusionsThe findings of this study suggested that rs4506565, rs7895340, rs7901695, and rs11196205 were the genetic susceptibility SNPs of GDM in the central Chinese population. Further studies are needed to validate our findings and clarify the underlying mechanisms.

lt;bgt;Background and Objective:lt;/bgt; The association of rs7903146 polymorphism of TCF7L2 gene with Type 2 diabetes mellitus found almost in all ethnic groups. Therefore, the current study focused on estimating this association in the Azerbaijan population for the 1st time.lt;bgt;Materials and Methods:lt;/bgt; A study was conducted on 110 patients with Type 2 diabetes mellitus and 115 healthy controls. The biochemical parameters were analyzed and calculated with an independent t-test and Fisher exact test. DNA extracted from the blood samples run in PCR. PCR was used to detect the presence of TCF7L2 rs7903146 C/T polymorphism and the products of the PCR were visualized in a 1.5% gel electrophoresis.lt;bgt;Results:lt;/bgt; According to the obtained data, T allele and TT genotype of rs7903146 polymorphism strongly correlated with the risk for Type 2 diabetes (odds ratio of 1.68 for T allele and p = 0.007, odds ratio of 3.9 for TT genotype, p = 0.0028). These results were adjusted by applying the recessive model (p = 0.003). Moreover, the biochemical parameters also show a significant difference in the fasting glucose level (p = 0.0001), fasting insulin (p = 0.0001), BMI (p = 0.0002) and age (p = 0.015) inpatient and control groups.lt;bgt;Conclusion:lt;/bgt; Based on the results, the TCF7L2 rs7903146 (CT) polymorphism is the genetic risk factor related to Type 2 diabetes in the Azerbaijan population.

Clinical resistance to ABL tyrosine kinase inhibitor (TKI) imatinib remains a critical issue in the treatment of chronic myeloid leukemia (CML). Transcription factor 7 (TCF7) is one of the main Wnt/β‑catenin signaling mediators. Previous studies have shown that TCF7 is vital for tumor initiation, and targeting TCF7 can reduce drug resistance in many types of cancer. However, the role of TCF7 in CML imatinib‑resistant cells is unclear. In the present study, we analyzed the transcriptomic data from CML clinical samples in the Gene Expression Omnibus (GEO) and performed experimental verification in the CML imatinib‑resistant cell line K562/G01. We found that the expression of TCF7 was independent of BCR‑ABL1 activity. Silencing of TCF7 downregulated the expression levels of CTNNB1, CCND1, and ABCC2, and therefore inhibited proliferation, weakened colony formation, and increased the drug sensitivity of imatinib‑resistant cells. After analyzing the transcriptomic data of four groups (Scramble, TCF7_KD, Scramble+imatinib, and TCF7_KD+imatinib) using bioinformatics, we noted that Wnt/β‑catenin and ATP‑binding cassette (ABC) transporter signaling pathways were upregulated in imatinib‑resistant cells under conventional dose of imatinib, and TCF7 knockdown could neutralize this effect. Next, using ChIP‑qPCR, we demonstrated that TCF7 was recruited to the promoter region of ABCC2 and activated gene transcription. In summary, our results highlight that the upregulation of Wnt/β‑catenin and ABC transporter signaling pathways induced by imatinib treatment of resistant cells confers imatinib resistance, and reveal that targeting TCF7 to regulate the Wnt/β‑catenin/TCF7/ABC transporter signaling axis may represent an effective strategy for overcoming imatinib resistance.

MicroRNAs (miRNAs) are important regulators of gene expression in eukaryotes. Studies have shown that plant-derived miRNAs can be absorbed through diets and regulate gene expression in mammals. Although soybean-derived miRNAs have been reported, their biological functions are still unclear. In this study, we found that soybean-derived small RNAs (sRNAs) significantly inhibited the proliferation and stimulated the apoptosis of Caco-2 cells. Bioinformatics analysis indicated that the target gene set of soybean miRNAs was extensively enriched in cancer pathways. Besides, we obtained 8 target genes, including Transcription factor 7 (TCF7), associated with colon cancer through prediction. Further studies showed that gma-miR159a inhibited the proliferation of Caco-2 cells and played an important role in the inhibitory effect of sRNAs by inhibiting TCF7 protein, which are upregulated in colon cancer cells but not normal mucosal cells in culture. These findings provide a novel molecular mechanism of soybean-derived miRNAs for potential application in tumor prevention.

Artesunate (ART) is a clinically approved antimalarial drug and was revealed as a candidate of colorectal cancer chemopreventive agents in our drug screening system. Here, we aimed to understand the suppressive effects of ART on intestinal tumorigenesis. In vitro, ART reduced T-cell factor/lymphoid enhancer factor (TCF/LEF) promoter transcriptional activity. In vivo, ART inhibited intestinal polyp development. We found that ART reduces TCF1/TCF7 nuclear translocation by binding the Ras-related nuclear protein (RAN), suggesting that ART inhibits TCF/LEF transcriptional factor nuclear translocation by binding to RAN, thereby inhibiting Wnt signaling. Our results provide a novel mechanism through which artesunate inhibits intestinal tumorigenesis.

Fine particulate matter (PM2.5) is the primary air pollutant that is able to induce airway injury. Compelling evidence has shown the involvement of IL‐17A in lung injury, while its contribution to PM2.5‐induced lung injury remains largely unknown. Here, we probed into the possible role of IL‐17A in mouse models of PM2.5‐induced lung injury. Mice were instilled with PM2.5 to construct a lung injury model. Flow cytometry was carried out to isolate γδT and Th17 cells. ELISA was adopted to detect the expression of inflammatory factors in the supernatant of lavage fluid. Primary bronchial epithelial cells (mBECs) were extracted, and the expression of TGF signalling pathway‐, autophagy‐ and PI3K/Akt/mTOR signalling pathway‐related proteins in mBECs was detected by immunofluorescence assay and Western blot analysis. The mitochondrial function was also evaluated. PM2.5 aggravated the inflammatory response through enhancing the secretion of IL‐17A by γδT/Th17 cells. Meanwhile, PM2.5 activated the TGF signalling pathway and induced EMT progression in bronchial epithelial cells, thereby contributing to pulmonary fibrosis. Besides, PM2.5 suppressed autophagy of bronchial epithelial cells by up‐regulating IL‐17A, which in turn activated the PI3K/Akt/mTOR signalling pathway. Furthermore, IL‐17A impaired the energy metabolism of airway epithelial cells in the PM2.5‐induced models. This study suggested that PM2.5 could inhibit autophagy of bronchial epithelial cells and promote pulmonary inflammation and fibrosis by inducing the secretion of IL‐17A in γδT and Th17 cells and regulating the PI3K/Akt/mTOR signalling pathway.

In ascidian embryos, the earliest transcription from the zygotic genome begins between the 8-cell and 16-cell stages. Gata.a, a maternally expressed Gata transcription factor, activates target genes specifically in the animal hemisphere, whereas the complex of β-catenin and Tcf7 antagonizes the activity of Gata.a and activates target genes specifically in the vegetal hemisphere. Here, we show that genes zygotically expressed at the 16-cell stage have significantly more Gata motifs in their upstream regions. These genes included not only genes with animal hemisphere-specific expression but also genes with vegetal hemisphere-specific expression. On the basis of this finding, we performed knockdown experiments for Gata.a and reporter assays, and found that Gata.a is required for the expression of not only genes with animal hemisphere-specific expression, but also genes with vegetal hemisphere-specific expression. Our data indicated that weak Gata.a activity that cannot induce animal hemisphere-specific expression can allow β-catenin/Tcf7 targets to be expressed in the vegetal cells. Because genes zygotically expressed at the 32-cell stage also had significantly more Gata motifs in their upstream regions, Gata.a function may not be limited to the genes expressed specifically in the animal or vegetal hemispheres at the 16-cell stage, and Gata.a may play an important role in the earliest transcription of the zygotic genome.

Colorectal cancer (CRC) is a severe risk to public health, and there is growing evidence that alternative splicing (AS) plays a crucial role in cancer. However, the AS biomarkers in CRC are seldom reported. In this study, we perform transcriptome analysis of colorectal samples for cancer-specific AS and transcriptomic alterations. We identify 1577 splice events in 885 genes, enriched in CRC-associated pathways and functions. In parallel, we find 10 splicing factors (SFs) with transcriptome variation or significant differential expression. Based on co-expression and binding motif, we construct an SF-AS regulatory network, revealing the association between cancer-specific AS and aberrant SF. Integrating The Cancer Genome Atlas and published sources, we observed that some recurrent AS is an indicator of poor prognosis. Through further experimental verification, we found that the AS of six genes showed significant differences between the tumor sample and the normal sample, and AS of TCF7, COL12A1, GK, and UBA1 can be used as new potential biomarkers in CRC. Our study provides an important analysis of CRC-associated AS, which could act as a starting point for future functional explorations, the development of biomarkers and AS-based target therapy.

Stevens-Johnson syndrome (SJS) and toxic epidermal necrosis (TEN) are rare but life-threatening severe cutaneous adverse reactions. Current studies have suggested that the pathobiology of drug-mediated SJS/TEN involves a dysregulation of cellular immunity with overwhelming activation of cytotoxic T lymphocytes. The canonical Wnt signaling pathway plays important roles in T cell development and activation, which may provide potential avenues for alleviating dysregulated immunity in SJS/TEN. In this study, we aimed to assess the implication of Wnt signaling in drug-reactive T cells in SJS/TEN. We showed downregulation of Wnt signaling components, including T cell factor 1 (TCF-1)/lymphoid enhancer binding factor 1 (LEF-1) transcription factors, in SJS/TEN patients, suggesting that canonical Wnt signaling is regulated during cytotoxic T cell responses in SJS/TEN. Further analyses demonstrated that engagement of the T cell receptor by antigen encounter and treatment of a prognostic marker of SJS/TEN, IL-15, in vitro led to the downregulation of LEF-1 and TCF-1 expression in CD8+ T cells. Enhancement of Wnt signaling by adding the Wnt activators attenuated ex vivo activation of drug-specific T cells from SJS/TEN patients, indicating a functional involvement of Wnt signaling in the pathomechanism of SJS/TEN. These findings provide additional insight into the immunopathogenesis and therapeutic intervention of this devastating condition.

Background Among candidate genes related to type 2 diabetes (T2DM), one of the strongest genes is Transcription factor 7 like 2 (TCF7L2), regarding the Genome-Wide Association Studies. We aimed to conduct a systematic review of the literature on the modification effect of TCF7L2 on the relation between glycemic parameters and lifestyle factors. Methods A systematic literature search was done for relevant publications using electronic databases, including PubMed, EMBASE, Scopus, and Web of Science, from January 1, 2000, to November 2, 2021. Results Thirty-eight studies (16 observational studies, six meal test trials, and 16 randomized controlled trials (RCTs)) were included. Most observational studies had been conducted on participants with non-diabetes showing that TCF7L2 modified the association between diet (fatty acids and fiber) and insulin resistance. In addition, findings from meal test trials showed that, compared to non-risk-allele carriers, consumption of meals with different percentages of total dietary fat in healthy risk-allele carriers increased glucose concentrations and impaired insulin sensitivity. However, ten RCTs, with intervention periods of less than ten weeks and more than one year, showed that TCF7L2 did not modify glycemic parameters in response to a dietary intervention involving different macronutrients. However, two weight loss dietary RCTs with more than 1-year duration showed that serum glucose and insulin levels decreased and insulin resistance improved in non-risk allele subjects with overweight/obesity. Regarding artichoke extract supplementation (ALE), two RCTs observed that ALE supplementation significantly decreased insulin concentration and improved insulin resistance in the TT genotype of the rs7903146 variant of TCF7L2. In addition, four studies suggested that physical activity levels and smoking status modified the association between TCF7L2 and glycemic parameters. However, three studies observed no effect of TCF7L2 on glycemic parameters in participants with different levels of physical activity and smoking status. Conclusion The modification effects of TCF7L2 on the relation between the lifestyle factors (diet, physical activity, and smoking status) and glycemic parameters were contradictory. PROSPERO registration number CRD42020196327

Type 2 diabetes mellitus (T2DM) is a prototypical complex disease with polygenic architecture playing an important role in determining susceptibility to develop the disease (and its complications) in subjects exposed to modifiable lifestyle factors. A current challenge is to quantify the degree of the individual's genetic risk using genetic risk scores (GRS) capturing the results of genome-wide association studies while incorporating possible ethnicity- or population-specific differences.This study included three groups of T2DM (T2DM-I, N = 1,032; T2DM-II, N = 353; and T2DM-III, N = 399) patients and 2,481 diabetes-free subjects. The status of the microvascular and macrovascular diabetes complications were known for the T2DM-I patients. Overall, 21 single nucleotide polymorphisms (SNPs) were analyzed, and selected subsets were used to determine the GRS (both weighted - wGRS and unweighted - uGRS) for T2DM risk predictions (6 SNPs) and for predicting the risks of complications (7 SNPs).The strongest T2DM markers (P 0.0001) were within the genes for TCF7L2 (transcription factor 7-like 2), FTO (fat mass and obesity associated protein) and ARAP1 (ankyrin repeat and PH domain 1). The T2DM-I subjects with uGRS values greater (Odds Ratio, 95 % Confidence Interval) than six had at least twice (2.00, 1.72-2.32) the risk of T2DM development (P 0.0001), and these results were confirmed in the independent groups (T2DM-II 1.82, 1.45-2.27; T2DM-III 2.63, 2.11-3.27). The wGRS (0.6) further improved (P 0.000001) the risk estimations for all three T2DM groups. The uGRS was also a significant predictor of neuropathy (P 0.0001), nephropathy (P 0.005) and leg ischemia (P 0.0005).If carefully selected and specified, GRS, both weighted and unweighted, could be significant predictors of T2DM development, as well as the diabetes complications development.

T-cell longevity is undermined by antigen-driven differentiation programs that render cells prone to attrition through several mechanisms. CD8 Tcf-1 mRNA encoding TCF-1B and TCF-1E isoforms, along with GzmB expression were assessed in CD62L TCF-1B and TCF-1E were dynamically regulated during self-renewal, with progeny of recently activated naïve T cells more enriched for TCF-1B mRNA. Constitutive TCF-1B expression improved the survival of TCR-engineered CD8 Tcf-1 protects TCR-engineered CD8

Various studies have manifested that microRNAs (miRNAs) are involved in the modulation of the occurrence and development of osteosarcoma (OS). However, whether miR-22-3p is associated with OS growth remains unclear. In the study, the potential molecular mechanisms of miR-22-3p in OS was explored. It was affirmed that miR-22-3p was associated with distant metastasis and tumor size in OS patients, and reduced in OS tissues and cells while transcription factor 7-like 2 (TCF7L2) was elevated. Elevated miR-22-3p repressed OS cell progression, and the Wnt/β-catenin pathway, while elevated TCF7L2 was opposite. MiR-22-3p targeted TCF7L2 in OS. In functional rescue experiments, knockdown of miR-22-3p on OS progression and promotion of Wnt/β-catenin were reversed by simultaneous knockdown of TCF7L2. Transplantation experiments in nude mice showed that elevated miR-22-3p repressed OS tumor growth and decreased TCF7L2, Wnt and β-catenin. Shortly, this study suggest that miR-22-3p refrains the Wnt/β-catenin pathway by targeting TCF7L2 and thereby preventing OS deterioration. MiR-22-3p/TCF7L2 axis is supposed to be a candidate molecular target for future OS treatment.

In tumors, a subset of CD8(+) T cells expressing the transcription factor TCF-1 drives the response to immune checkpoint blockade. We examined the mechanisms that maintain these cells in an autochthonous model of lung adenocarcinoma. Longitudinal sampling and single-cell sequencing of tumor-antigen specific TCF-1(+) CD8(+) T cells revealed that whereas intratumoral TCF-1(+) CD8(+) T cells acquired dysfunctional features and decreased in number as tumors progressed, TCF-1(+) CD8(+) T cell frequency in the tumor draining LN (dLN) remained stable. Two discrete intratumoral TCF-1(+) CD8(+) T cell subsets developed over time – a proliferative SlamF6(+) subset and a non-cycling SlamF6- subset; blocking dLN egress decreased the frequency of intratumoral SlamF6+ TCF-1(+) CD8(+) T cells. Conventional type I dendritic cell (cDC1) in dLN decreased in number with tumor progression, and Flt3L+anti-CD40 treatment recovered SlamF6(+) T cell frequencies and decreased tumor burden. Thus, cDC1s in tumor dLN maintain a reservoir of TCF-1(+) CD8(+) T cells and their decrease contributes to failed anti-tumor immunity.

Immunological memory is a hallmark of adaptive immunity and facilitates an accelerated and enhanced immune response upon re-infection with the same pathogen

Spi-1 Proto-Oncogene (SPI1) fusion genes are recurrently found in T-cell acute lymphoblastic leukemia (T-ALL) cases but are insufficient to drive leukemogenesis. Here we show that SPI1 fusions in combination with activating NRAS mutations drive an immature T-ALL in vivo using a conditional bone marrow transplant mouse model. Addition of the oncogenic fusion to the NRAS mutation also results in a higher leukemic stem cell frequency. Mechanistically, genetic deletion of the β-catenin binding domain within Transcription factor 7 (TCF7)-SPI1 or use of a TCF/β-catenin interaction antagonist abolishes the oncogenic activity of the fusion. Targeting the TCF7-SPI1 fusion in vivo with a doxycycline-inducible knockdown results in increased differentiation. Moreover, both pharmacological and genetic inhibition lead to down-regulation of SPI1 targets. Together, our results reveal an example where TCF7-SPI1 leukemia is vulnerable to pharmacological targeting of the TCF/β-catenin interaction., SPI1 fusion genes in T-cell acute lymphoblastic leukemia (T-ALL) are commonly found with co-occurring NRAS mutations. Here, the authors show that the combination of these oncogenes is necessary to drive T-ALL in a murine model and that the oncogenic activity of the SPI1 fusion is dependent on β-catenin.

The ubiquitin-specific protease (USP) family is the largest group of cysteine proteases. Cancer genomic analysis identified frequent amplification of USP21 (22%) in human pancreatic ductal adenocarcinoma (PDAC). USP21 overexpression correlates with human PDAC progression, and enforced expression of USP21 accelerates murine PDAC tumor growth and drives PanIN to PDAC progression in immortalized human pancreatic ductal cells. Conversely, depletion of USP21 impairs PDAC tumor growth. Mechanistically, USP21 deubiquitinates and stabilizes the TCF/LEF transcription factor TCF7, which promotes cancer cell stemness. Our work identifies and validates USP21 as a PDAC oncogene, providing a potential druggable target for this intractable disease.

BACKGROUND Transcription factor 7 (TCF7) plays an essential role in Wnt signaling by interacting with s-catenin. Emerging evidence demonstrates that overexpression of TCF7 promotes progression or correlates with poor progression in several types of cancers, but the functions of TCF7 in gastric cancer (GC) have not been revealed. MATERIAL AND METHODS A total of 168 patients with GC who underwent radical surgeries were collected and regarded as the test cohort. The expression of TCF7 in the 168 patients was detected with immunohistochemistry. Moreover, the mRNA levels of TCF7 in 11 pairs of GC and adjacent tissues were detected with quantitative real-time PCR (qRT-PCR). The correlations between TCF7 and the clinicopathological factors were evaluated with the chi-square test, and the prognostic value of TCF7 in GC was investigated with univariate analysis and multivariate analysis. RESULTS The mRNA levels of TCF7 in GC tissues were significantly higher than in corresponding tumor adjacent tissues. The patients of low TCF7 expression and high TCF7 expression accounted for 76.79% (129/168) and 23.21% (39/168), respectively. In our experiments, TCF7 was significantly associated with positive lymphatic invasion (P=0.022) and metastasis (P

AimsOur previous study has demonstrated that β-catenin pathway was abnormally activated in nasopharyngeal carcinoma (NPC). The purposes of the present study are to investigate whether the alterations of LEF1 and TCF1 (TCF7) proteins, the important components of the canonical Wnt/β-catenin pathway, are associated with clinicopathological features and prognostic implications.MethodsWe collected 391 cases of NPC, 53 non-cancerous control nasopharyngeal mucosa and 28 pairs of NPC and their matched metastases, detected expression of LEF1 and TCF1 (TCF7) proteins in these tissues by immunohistochemistry. ResultsResults showed that there were significantly increased expression of both LEF1 and TCF1 (TCF7) proteins and coexpression of LEF1 and TCF1 (TCF7) in NPC than these in non-cancerous nasopharyngeal mucosa (all pConclusionsThe expression of LEF1 associated positively with TCF1 (TCF7) and clinical progression of NPC, and positive expression of LEF1 protein may act as valuable independent biomarker to predict poor prognosis for patients with NPC.

Numerous long noncoding RNAs (lncRNAs) are reported to be dysregulated in glioma. However, how lncRNA participates in the process of glioma development and progression still remains elusive. Here, we identified a novel lncRNA LOC728196 highly expressed in glioma tissues. LOC728196 high expression predicts low survival rate in patients. Our data proved that LOC728196 knockdown repressed cellular growth, migration and invasion in vitro. Silencing LOC728196 led to impaired growth of glioma in vivo. Mechanistic studies further demonstrated that LOC728196 acts as the sponge for miR-513c to upregulate TCF7 expression. We observed a reciprocal inhibition between LOC728196 and miR-513c. Rescue assay showed that either inhibition of miR-513c or TCF7 overexpression restored the abilities of proliferation, migration and invasion in LOC728196-silenced glioma cells. Taken together, our study provides a comprehensive investigation on the role of LOC728196 in glioma progression and contributes to understanding the vital role of competing endogenous RNA (ceRNA).

Despite substantial advances in treatment, clinical outcomes for oral squamous cell carcinoma (OSCC) remain unsatisfactory. Tumor-infiltrating lymphocytes (TILs) are an important prognostic factor for patients and are heterogeneous. Some studies have suggested that TCF1/TCF7We isolated OSCC cells and performed single-cell RNA sequencing (scRNA-seq). We used immunohistochemistry (IHC) to analyze the relationship between TLSs and prognosis. Multiplex immunohistochemistry (MIHC), flow cytometry (FCM) and spatial analysis were performed to verify the characteristics of TCF1/TCF7We found a strong association between TCF1/TCF7TCF1/TCF7

T cell factor 1 (TCF-1) is a transcription factor (TF) of the canonical Wnt signaling pathway that encoded by the Tcf7. The crucial role of TCF-1 in T cell development and memory formation has been widely recognized. Recent studies have demonstrated that exhausted CD8

Combination therapy with PD-1 blockade and IL-2 is highly effective during chronic lymphocytic choriomeningitis virus infection(1). Here we examine the underlying basis for this synergy. We show that PD-1 + IL-2 combination therapy, unlike PD-1 monotherapy, dramatically changes the differentiation program of the PD-1(+)TCF-1(+) stem-like CD8(+) T cells and results in the generation of transcriptionally and epigenetically distinct effector CD8(+) T cells that resemble highly functional effector CD8(+) T cells seen after an acute viral infection. The generation of these qualitatively superior CD8(+) T cells that mediate viral control underlies the synergy between PD-1 and IL-2. Our results show that the PD-1(+)TCF-1(+) stem-like CD8(+) T cells, also referred to as precursors of exhausted CD8(+) T cells, are not fate-locked into the exhaustion program and their differentiation trajectory can be changed by IL-2 signals. These virus-specific effector CD8(+) T cells emerging from the stem-like CD8(+) T cells after combination therapy expressed increased levels of the high affinity IL-2 trimeric (CD25, CD122, CD132) receptor. This was not seen after PD-1 blockade alone. Finally, we show that CD25 engagement with IL-2 plays an important role in the observed synergy between IL-2 cytokine and PD-1 blockade. Either blocking CD25 with an antibody or using a mutated version of IL-2 that does not bind CD25 but still binds CD122/CD132 almost completely abrogated the synergistic effects seen after PD-1 + IL-2 combination therapy. There is currently considerable interest in PD-1 + IL-2 combination therapy for patients with cancer(2,3) and our fundamental studies defining the underlying mechanisms of how IL-2 synergizes with PD-1 blockade should inform these human translational studies.

Hepatoblastoma (HB) is the most commonly seen pediatric liver malignancy. With frequent mutations in CTNNB1 gene that encodes β‐catenin, hepatoblastoma has been considered as a Wnt/β‐catenin‐activated malignant tumor. Altered glucose metabolism upon nutrient deprivation (glucose starvation) might also be a critical event in hepatoblastoma carcinogenesis. The present study provides a lncRNA NBR2/miR-22/TCF7 axis modulating proliferation, invasion, migration, and apoptosis of hepatoblastoma cells upon glucose starvation through Wnt and downstream TCF7 signaling pathways. The expression of NBR2 is significantly increased within hepatoblastoma tissue samples; moreover, under incubation with 0 mM glucose (glucose starvation), NBR2 expression is significantly upregulated. NBR2 silencing not only inhibited hepatoblastoma cell viability, invasion, and migration under normal culture condition but also promoted the cell apoptosis under glucose starvation. NBR2 silencing in hepatoblastoma cells also decreased TCF7 mRNA expression and TCF7 protein levels, as well as the protein levels of the cell cycle, glucose entrapment, and EMT markers. miR-22 is directly bound to both NBR2 and TCF7; lncRNA NBR2 counteracted miR-22-mediated repression on TCF7 via acting as a ceRNA. The effects of NBR2 silencing on TCF7 expression, hepatoblastoma cell phenotype, and cell cycle, glucose entrapment, and EMT markers were all significantly reversed by miR-22 inhibition. In conclusion, lncRNA NBR2 aggravates hepatoblastoma cell malignancy through competing with TCF7 for miR-22 binding, therefore counteracting miR-22-mediated repression on TCF7. LncRNA NBR2 might be a promising target to inhibit hepatoblastoma cell proliferation under glucose starvation.

T cell factor-1 (TCF-1) (encoded by the TCF7 gene) is a transcription factor that plays important role during the T cell development and differentiation for T cell to exercise its functions including producing memory T cells. Not only TCF-1 can modulate the T cell development but also exerts various effects on the differentiation and function of mature CD8

Mitochondrial fusion/fission dynamics plays a fundamental role in neuroprotection; however, there is still a severe lack of therapeutic targets for this biological process. Here, we found that the naturally derived small molecule echinacoside (ECH) significantly promotes mitochondrial fusion progression. ECH selectively binds to the previously uncharacterized casein kinase 2 (CK2) α′ subunit (CK2α′) as a direct cellular target, and genetic knockdown of CK2α′ abolishes ECH-mediated mitochondrial fusion. Mechanistically, ECH allosterically regulates CK2α′ conformation to recruit basic transcription factor 3 (BTF3) to form a binary protein complex. Then, the CK2α′/BTF3 complex facilitates β-catenin nuclear translocation to activate TCF/LEF transcription factors and stimulate transcription of the mitochondrial fusion gene Mfn2. Strikingly, in a mouse middle cerebral artery occlusion (MCAO) model, ECH administration was found to significantly improve cerebral injuries and behavioral deficits by enhancing Mfn2 expression in wild-type but not CK2α′+/− mice. Taken together, our findings reveal, for the first time, that CK2 is essential for promoting mitochondrial fusion in a Wnt/β-catenin-dependent manner and suggest that pharmacologically targeting CK2 is a promising therapeutic strategy for ischemic stroke.

Background Combined inhibition of BRAF/MEK is an established therapy for melanoma. In addition to its canonical mode of action, effects of BRAF/MEK inhibitors on antitumor immune responses are emerging. Thus, we investigated the effect of these on adaptive immune responses. Patients, methods and results Sequential tumor biopsies obtained before and during BRAF/MEK inhibitor treatment of four (n = 4) melanoma patients were analyzed. Multiplexed immunofluorescence staining of tumor tissue revealed an increased infiltration of CD4+ and CD8+ T cells upon therapy. Determination of the T-cell receptor repertoire usage demonstrated a therapy induced increase in T-cell clonotype richness and diversity. Application of the Grouping of Lymphocyte Interactions by Paratope Hotspots algorithm revealed a pre-existing immune response against melanoma differentiation and cancer testis antigens that expanded preferentially upon therapy. Indeed, most of the T-cell clonotypes found under BRAF/MEK inhibition were already present in lower numbers before therapy. This expansion appears to be facilitated by induction of T-bet and TCF7 in T cells, two transcription factors required for self-renewal and persistence of CD8+ memory T cells. Conclusions Our results suggest that BRAF/MEK inhibition in melanoma patients allows an increased expansion of pre-existing melanoma-specific T cells by induction of T-bet and TCF7 in these.

OBJECTIVE To determine the frequency and association of single nucleotide polymorphism of transcription cell factor7-like2 rs7903146 (C>T) in metabolic syndrome patients with and without acute coronary syndrome. METHODS The cross-sectional comparative study was conducted at the University of Health Sciences, Lahore, Pakistan, from July to December 2017. Patients of metabolic syndrome with and without acute coronary syndrome were selected from Sheikh Zayed Hospital, Lahore, and the Punjab Institute of Cardiology, Lahore. Healthy subjects were enrolled to act as controls. A fasting blood sample of 8ml was taken for deoxyribonucleic acid extraction and estimation of biochemical parameters. Single nucleotide polymorphism of transcription cell factor7-like2 rs7903146 C>T was determined using restriction fragment length polymorphism. SPSS 22 was used for data analysis. RESULTS Of the 500 subjects, 200(40%) were group A patients without acute coronary syndrome, 100(20%) were in group B with acute coronary syndrome and 200(40%) were group C controls. Overall, 385(77%) were males and 115(23%) were females. The frequency of CC variant in group A was 35(17.5%) and in group C 22(11%), while CT was 32(16%) and 65(32.5%), and TT was 133(66.5%) and 113(56.5%), respectively. There was significant association of TT genotype with increased risk of metabolic syndrome (p=0.031), and CC genotype had no association (p=0.121). There was no significant difference of genotype frequency between groups A and B (p=0.246), but TT variant was significantly higher in group A compared to group B (p=0.009). CONCLUSIONS TT genotype of transcription cell factor7-like2 rs7903146 C>T was found to be associated with increased risk of metabolic syndrome in patients without acute coronary syndrome compared to those with acute coronary syndrome and healthy controls.

Recent advances have re-defined a role for T cell factor 1 (Tcf1) that goes beyond T cell development and T memory formation and encompasses new functions in the regulation of T cell biology. Here, we discuss the multi-faceted and context-dependent role of Tcf1 in peripheral T cells, particularly during disease-induced inflammatory states such as autoimmunity, cancer, and chronic infections. Understanding how Tcf1 fine-tunes peripheral T cell biology holds the potential to tailor improved immune-targeted therapies.