Factor Of T-cells Research Articles

A phase 1/2 study of FOG-001, a first-in-class direct β-catenin: TCF inhibitor, in patients with colorectal cancer (CRC) and other locally advanced or metastatic solid tumors.

TPS3169 Background: Activation of the Wnt/β-catenin pathway, often as truncal APC mutations, in 80–90% of CRCs and other solid tumors, is known to be a key driver of cancer progression and has been associated with immune exclusion and resistance to immunotherapy. Development of agents targeting this pathway at the key β-catenin: T-cell factor (TCF) node has eluded the pharmaceutical industry to date. FOG-001 is a Helicon peptide that competitively inhibits interaction between β-catenin and TCF transcription factors. Helicon peptides are hyperstabilized α-helices that can be tuned for picomolar binding affinities, robust cell penetration, broad tissue distribution, no immune recognition, and long in vivo half-lives. In studies in a wide range of patient-derived xenograft (PDX) CRC and HCC models, FOG-001 inhibited tumor growth and promoted tumor regression as monotherapy. Combinations with immune checkpoint inhibitors or standard-of-care therapies, including bevacizumab and 5-FU, showed strong additivity/synergy in PDX CRC models. Methods: This first-in-human, phase 1/2, multicenter, open-label, dose-escalation (part 1) and dose-expansion (part 2) study evaluates the safety/tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and anti-tumor effects of FOG-001 monotherapy and combined with other anti-cancer therapies in patients with microsatellite stable (MSS) CRC or advanced/metastatic solid tumors known to harbor a Wnt pathway-activating mutation (WPAM). Eligible patients must have received at least one prior systemic anti-cancer therapy and either progressed on, not responded to, or be unfit for available therapies. In Part 1, FOG-001 is administered intravenously every week, at escalating dose levels evaluated sequentially in a standard 3+3 design as monotherapy in patients with MSS CRC or any solid tumor with documented WPAM. PD effects are evaluated in a separate cohort of approximately six patients with MSS CRC. Combination cohorts will evaluate FOG-001 + FOLFOX/bevacizumab (1L MSS CRC), FOG-001 + nivolumab (3L MSS CRC or anti-PD-1/PD-L1-resistant CRC and solid tumors), and FOG-001 + trifluridine/tipiracil + bevacizumab (3L MSS CRC). Part 2 dose expansion will evaluate FOG-001 monotherapy in patients with MSS CRC and other solid WPAM+ tumors. Combination dose expansion will evaluate combinations initially studied in Part 1. Primary endpoints are safety/tolerability of FOG-001 alone or in combination. Secondary endpoints are PK, PD, recommended phase 2 dose and schedule, and preliminary anti-tumor activity (e.g., ctDNA changes, overall response rate, best objective response, duration of response, and progression-free survival). 156 patients are planned to be enrolled in Part 1, which is currently enrolling in the USA. Clinical trial information: NCT05919264 .

M6A hypermethylation of TCF-1 regulated by METTL16 promotes acute myeloid leukemia

BackgroundMethyltransferase 16 (METTL16) functions as an oncogene in various cancer, including leukemia. However, the role of METTL16 in acute myeloid leukemia (AML) is scarcely reported. The present study aimed to investigate the potential of METTL16 in AML.MethodsRT-qPCR was used to METTL16 expression in AML patients and healthy control. m6A levels was determined using m6A assay. Methylated RNA immunoprecipitation (MeRIP) assay applied for determining m6A hypermethylation of T cell factor 1 (TCF-1) transcripts in AML cells. Chimeric antigen receptor (CAR)-T-cell functions were analyzed using flow cytometry.ResultsMETTL16 is upregulated in AML patients. High levels of METTL16 were associated with poor prognosis of AML patients. Functionally, METTL16 deficiency promoted the persistence and tumor-killing ability of CAR-T cells. Moreover, METTL16 deficiency promoted the differentiation of CAR-T cells into TCF-1 precursor exhausted T cells (TPEX). METTL16 mediated the m6A modification of TCF-1 and inhibited its mRNA expression and stability. TCF-1 deficiency promoted the exhaustion and inhibited the self-renewal ability of T cells.ConclusionCollectively, METTL16 deficiency promoted the persistence of CAR-T cells and memory formation in AML. Therefore, targeting METTL16 may stimulate the anti-tumor immunity in AML.

TRPV4 Promotes Vascular Calcification by Directly Associating With and Activating β-Catenin.

Vascular calcification contributes to increased cardiovascular morbidity and mortality in patients with chronic kidney disease, diabetes, and atherosclerosis. Currently, there are no effective therapeutic strategies to prevent or reverse vascular calcification. TRPV4 (transient receptor potential channel V4), a key Ca2+-permeable channel, plays an important role in various diseases. However, the role and mechanism of TRPV4 in vascular calcification have not yet been elucidated. The effects of TRPV4 on vascular calcification were explored in vitro and in vivo. TRPV4 interactome assessment and molecular docking were performed to investigate the mechanism and specific therapeutic strategy for vascular calcification. TRPV4 was substantially upregulated in high inorganic phosphate-induced calcified vascular smooth muscle cells (SMCs) and calcified aortas from cholecalciferol (vitamin D3)-overloaded mice. TRPV4 overexpression increased the expression of the osteochondrogenic markers Runx2 (runt-related transcription factor 2), Msx2 (Msh homeobox 2), and Sox9 (SRY-box transcription factor 9) and exacerbated high inorganic phosphate-induced vascular SMC calcification in a Ca2+ influx-dependent manner. In contrast, TRPV4 deficiency or inactivation significantly inhibited vascular SMC calcification under high inorganic phosphate conditions. Moreover, compared with that in control littermates, SMC-specific TRPV4 deficiency in mice alleviated vitamin D3-induced and 5/6 nephrectomy-induced vascular calcification. Mechanistically, TRPV4 interacted with β-catenin and activated β-catenin/TCF (T-cell factor) transcriptional activity via Ca2+/ASK1 (apoptosis signal regulating kinase 1)/p38 signaling. β-Catenin knockdown abolished the effects of TRPV4 overexpression on vascular SMC calcification. TRPV4/β-catenin interaction is pivotal for maintaining TRPV4/Ca2+-induced ASK1/p38/β-catenin activation. Hesperidin, a natural product found in citrus fruits, effectively disrupted TRPV4/β-catenin interaction, thereby inhibiting ASK1/p38/β-catenin activity and preventing vascular calcification. Our study identified TRPV4 as a new pathogenic factor for vascular calcification that directly associates with and activates β-catenin. Blocking the TRPV4/β-catenin interaction through hesperidin suppressed the progression of vascular calcification and may be an effective precision strategy to address vascular calcification.

Correlation between changes in haemorheology and the HIF-1/EPO pathway in children with Mycoplasma pneumoniae pneumonia.

ObjectiveTo investigate the possible correlation between changes in haemorheology and the HIF-1/EPO pathway in children with Mycoplasma pneumoniae pneumonia (MPP) to provide new ideas for the early clinical identification of hypercoagulability and reduce the incidence of thrombosis.MethodsA total of 205 children with newly diagnosed MPP were selected from our department and divided into a general MPP group (100 patients) and a severe MPP group (105 patients) according to diagnostic criteria. In addition, 30 healthy children were selected as the control group. Routine blood and coagulation function data were collected, and the expression levels of T-cell factors, HIF-1α, EPO and haemorheology were detected.ResultsThe levels of D-dimer, FDP and fibrinogen in the MPP group were significantly greater than those in the control group and more obvious in the severe group than in the general group. Compared with those in the control group, the whole blood viscosity (low, medium, high tangential), plasma viscosity, whole blood low tangential reductive viscosity and erythrocyte aggregation index in the haemorheology of children in the MPP group were significantly greater, and the range of increase in the severe group was greater than those in the general group. The red blood cell (RBC) count and haematocrit (HCT) of children in the MPP group were significantly greater than those in the control group at admission and were more altered in the severe group than in the general group. Moreover, the serum expression levels of TNF-a, IFN-γ, IL-6, IL-8, IL-10, IL-17, HIF-1α and EPO in the MPP group were significantly greater than those in the healthy control group. With the exception of IFN-γ, the cytokines levels in the severe group were significantly greater than those in the general group. The expression level of HIF-1α was significantly correlated with the elevated levels of TNF-a, IL-6 and IL-8.ConclusionHypercoagulability occurs during the course of MPP in children, especially those with severe disease. The increase in blood viscosity may be an important reason for hypercoagulability, and highly inflammatory cytokines such as TNF-a, IL-6 and IL-8 in children may increase the RBC and HCT levels by activating the HIF-1α/EPO pathway, which may lead to changes in haemorheology and thus participate in the development of hypercoagulability.

Upregulated TCF1+ Treg Cells With Stronger Function in Systemic Lupus Erythematosus Through Activation of the Wnt-β-Catenin.

The role of T-cell factor 1 (TCF1) in human regulatory T cells (Treg) and its clinical significance in systemic lupus erythematosus (SLE) remain unclear. Through bioinformatics analysis and flow cytometry, the Tcf7 gene and TCF1 protein were found to be highly expressed in Treg cells. TCF1+ Treg cells exhibited increased expression of CTLA4 and LAG3 and higher IL-10 secretion than TCF1- Treg cells. Circulating TCF1+ Treg cells were elevated and displayed increased inhibitory markers in SLE patients. The Wnt-β-catenin pathway was activated in TCF1+ Treg cells in SLE patients. The addition of XAV939 impaired the function of TCF1+ Treg cells. Clinically, TCF1+ Treg cells were not only related to CRP, ESR and IL-2, but also could differentiate SLE patients from healthy controls, primary Sjögren's syndrome patients and rheumatoid arthritis patients. In conclusion, the increased TCF1+ Treg cells in SLE patients indicate a stronger suppressive function for the activated Wnt-β-catenin pathway and help screening and assisting in the diagnosis of SLE patients.

A novel PAK1/TCF1 regulatory axis promotes non-small cell lung cancer progression

BackgroundNon-small cell lung cancer (NSCLC) is the leading cause of cancer death, necessitating the identification of novel therapeutic targets. P21-activated kinases-1 (PAK1) plays a crucial role in oncogenesis, including NSCLC. Recent findings have elucidated T cell factor 1 (TCF1) as an anti-tumour factor, influencing T cell biology. However, the precise mechanism by which PAK1 promotes NSCLC progression via TCF1 regulation remains unclear.MethodsWe collected 23 pairs of NSCLC tissue samples and obtained NSCLC RNA sequencing data and corresponding clinicopathologic information from The Cancer Genome Atlas (TCGA). Quantitative reverse transcription polymerase chain reaction (qRT-PCR) and immunohistochemistry (IHC) assessed PAK1 and TCF1 expression in NSCLC tissues and cells. Gain and loss-of-function experiments evaluated PAK1 and TCF1 effects on cell proliferation, invasion, migration, and apoptosis in vitro. Mechanistically, western blot (WB) and immunoprecipitation analysis evaluated the interaction between PAK1 and TCF1 in NSCLC. Finally, we assessed the clinical prognostic, disease progression, and immunotherapy response of PAK1 and TCF1 and their correlation with immune cell infiltration, immune checkpoint inhibitors (PD1, PDL1).ResultsPAK1 expression was elevated in NSCLC tissues and cells, while TCF1 was significantly downregulated. PAK1 expression showed a significant inverse correlation with TCF1 mRNA in NSCLC. Silencing PAK1 (using shRNAs) and inhibiting PAK1 with the small molecule IPA-3 suppressed NSCLC cell malignancy in a dose-dependent manner, upregulating TCF1 expression, and vice versa. TCF1 amplification with the small molecule (TWS119) inhibited NSCLC cell proliferation, migration, and invasion in a dose-dependent manner without affecting PAK1 expression. Immunoprecipitation analysis confirmed PAK1 and TCF1 interaction in NSCLC. Joint survival analysis indicated that high PAK1 and low TCF1 expression were associated with unfavourable survival in patients with NSCLC. Lastly, the TCF1 was significantly correlated with immune cell infiltration [CD8+ T cell, and tumor infiltrating lymphocytes (TILs)], immune checkpoint inhibitors (PD1, PDL1), and can accurately predict the immunotherapeutic response.ConclusionThis study demonstrates, for the first time, that PAK1 negatively regulates TCF1, contributing to NSCLC pathogenesis. The PAK1/TCF1 regulatory axis emerges as a critical determinant of carcinogenesis and a promising therapeutic target for NSCLC.

Effect of β-catenin on hypoxia induced epithelial mesenchymal transition in HK-2cells by regulating Brachyury.

Effect of β-catenin on hypoxia induced epithelial mesenchymal transition in HK-2cells by regulating Brachyury.

Phase 1/2 study of FOG-001, a first-in-class direct β-catenin:TCF inhibitor, in patients with colorectal cancer, hepatocellular carcinoma, and other locally advanced or metastatic solid tumors.

TPS322 Background: Wnt/B-catenin pathway activation, which is frequently present in most colorectal cancers and a variety of other solid tumors, is associated with poor prognosis and resistance to immunotherapy. FOG-001 is a Helicon peptide that competitively inhibits the interaction between β-catenin and the T-cell factor (TCF) family of transcription factors. Experiments in patient-derived-xenograft (PDX) models of colorectal cancer (CRC) and hepatocellular carcinoma (HCC) have demonstrated that FOG-001 can inhibit tumor growth and promote tumor regression when administered as monotherapy or in combination with immune checkpoint inhibitors or standard of care therapies, including bevacizumab and 5-FU. Methods: This first-in-human, Phase 1/2, multicenter, open-label, dose escalation (Part 1) and dose-expansion (Part 2) study evaluates the safety/tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and anti-tumor effects of FOG-001 as monotherapy and in combination with other anti-cancer therapies. Eligible patients must have received at least one prior systemic anti-cancer therapy and either progressed on, not responded to, or be unfit for available therapies. In Part 1, FOG-001 is administered intravenously, either weekly or every other week, at escalating dose levels evaluated sequentially in a standard 3+3 design as monotherapy in patients with: (1a) microsatellite stable (MSS) CRC or any solid tumor with a documented Wnt/b-catenin pathway activating mutation (WPAM) and (1c) HCC with WPAM. Part 1b will evaluate PD effects in cohorts of approximately six patients with MSS CRC. Upon selection of the preliminary recommended Phase 2 dose from Part 1a for weekly dosing, combination dose escalation (1d) evaluates the safety/tolerability, PK and anti-tumor effects of FOG-001 in CRC patients combined with FOLFOX+bevacizumab, anti-PD-1/PD-L1 (also includes other solid tumors with known WPAM), or trifluridine/tipiracil+bevacizumab. Part 2 dose expansion evaluates FOG-001 monotherapy in MSS CRC, HCC, and other solid tumors with documented WPAM. Combination dose expansion evaluates the combinations initially evaluated in Part 1d. Primary endpoints are safety/tolerability and preliminary anti-tumor effects (objective response rate). Secondary endpoints are PK, PD, and other anti-tumor responses (e.g., best objective response, duration of response, and progression free survival). Enrollment in Parts 1 and 2 is ongoing in the USA. Clinical trial information: NCT05919264 .

Anti-CTLA-4 generates greater memory response than anti-PD-1 via TCF-1

The effects of T cell differentiation arising from immune checkpoint inhibition targeting cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) and programmed cell death protein 1 (PD-1) on the immunological memory response remain unclear. Our investigation into the effects of anti-CTLA-4 and anti-PD-1 on memory T cell formation in mice reveals that memory T cells generated by anti-CTLA-4 exhibit greater expansion, cytokine production, and antitumor activity than those from anti-PD-1. Notably, anti-CTLA-4 preserves more T cell factor-1 (TCF-1)+ T cells during priming, while anti-PD-1 leads to more thymocyte selection-associated high mobility group box (TOX)+ T cells. Experiments using conditional Tcf7- or Tox-knockout mice highlight that TCF-1 is essential for the memory response generated by anti-CTLA-4, whereas TOX deletion alone in T cells has no effect on the response to anti-PD-1. Deepening our understanding of how checkpoint inhibition affects memory response is crucial for advancing our understanding of the enduring impacts of these immunotherapies on the immune system.

TCF1 dosage determines cell fate during T cell development.

Loss-of-function studies have shown that transcription factor T cell factor-1 (TCF1), encoded by the Tcf7 gene, is essential for T cell development in the thymus. We discovered that the Tcf7 expression level is regulated by E box DNA binding proteins, independent of Notch, and regulates αβ and γδ T cell development. Systematic interrogation of the five E protein binding elements (EPE1-5) in the Tcf7 enhancer region showed lineage-specific utilization. Specifically, loss-of-function analysis revealed that only EPE3 plays a critical role in supporting αβ T cell development, while EPE1, 3, and 5 regulate the γδ T cell maturation and functional cell fate decision. The importance of EPE3 in supporting both lineages may stem from its unique capacity to interact with the Tcf7 transcriptional start site. Together, these studies demonstrate that the precise dosage of TCF1 expression mediated by distinct EPEs generates a balanced output of T cells from the thymus.

A mutant BCL11B-N440K protein interferes with BCL11A function during T lymphocyte and neuronal development.

Genetic studies in mice have shown that the zinc finger transcription factor BCL11B has an essential role in regulating early T cell development and neurogenesis. A de novo heterozygous missense BCL11B variant, BCL11BN441K, was isolated from a patient with T cell deficiency and neurological disorders. Here, we show that mice harboring the corresponding Bcl11bN440K mutation show the emergence of natural killer (NK)/group 1 innate lymphoid cell (ILC1)-like NKp46+ cells in the thymus and reduction in TBR1+ neurons in the neocortex, which are observed with loss of Bcl11a but not Bcl11b. Thus, the mutant BCL11B-N440K protein interferes with BCL11A function upon heterodimerization. Mechanistically, the Bcl11bN440K mutation dampens the interaction of BCL11B with T cell factor 1 (TCF1) in thymocytes, resulting in weakened antagonism against TCF1 activity that supports the differentiation of NK/ILC1-like cells. Collectively, our results shed new light on the function of BCL11A in suppressing non-T lymphoid developmental potential and uncover the pathogenic mechanism by which BCL11B-N440K interferes with partner BCL11 family proteins.

Compound #41 Targets Acute Myelogenous Leukemia by Inhibiting the Wnt/β-catenin Signaling Pathway.

Aberrant activation of the Wnt/β-catenin signaling pathway contributes to the pathogenesis of acute myelogenous leukemia (AML). Thus, targeting this pathway offers a promising therapeutic strategy against AML. Here, we synthesized a novel dipeptide-type inhibitor of the Wnt/β-catenin signaling pathway, compound #41, and explored its anti-tumor effects on AML cells. We evaluated the inhibitory effect of compound #41 on T cell factor (TCF)/β-catenin transcriptional activity using a luciferase (Luc) reporter assay. The anti-tumor effects were assessed on KG1a and MV4;11 human AML cells using RT-qPCR, western blotting, and WST-8, cell cycle, and apoptosis assays. Differentially expressed genes were analyzed by RNA-sequencing (RNA-seq). Additionally, we investigated the in vivo effects of compound #41 using KG1a-Luc/GFP cells in an orthotopic mouse model. The Luc reporter assay showed that compound #41 decreased the TCF/β-catenin transcriptional activity. Compound #41 blocked the cell cycle progression, inhibited cell proliferation, and induced apoptosis in AML cells. Treatment with compound #41 down-regulated the expression of β-catenin, Survivin, and β-catenin-specific target genes, as demonstrated by RNA-seq. In vivo analysis showed that compound #41 blocked the expansion of KG1a-Luc/GFP cells in the bone marrow and prolonged the overall survival of KG1a-Luc/GFP-transplanted mice. Compound #41 suppressed the Wnt/β-catenin signaling pathway by reducing CTNNB1 levels and induced apoptosis in AML cells. Furthermore, compound #41 inhibited the proliferation of KG1a-Luc/GFP cells in the bone marrow and extended the overall survival of mice. Thus, compound #41 is an attractive Wnt/β-catenin signaling pathway inhibitor of AML.

Transcription factor TCF1 binds to RORγt and orchestrates a regulatory network that determines homeostatic Th17 cell state

Transcription factor TCF1 binds to RORγt and orchestrates a regulatory network that determines homeostatic Th17 cell state

FoxO1/Rictor axis induces a non-genetic adaptation to Ibrutinib via Akt activation in chronic lymphocytic leukemia.

BTK inhibitor therapy induces peripheral blood lymphocytosis in chronic lymphocytic leukemia (CLL) lasting for several months. It remains unclear whether non-genetic adaptation mechanisms exist, allowing CLL cells' survival during BTK inhibitor-induced lymphocytosis and/or playing a role in therapy resistance. We show that in approximately 70 % of CLL cases, ibrutinib treatment in vivo increases Akt activity above pre-therapy levels within several weeks, leading to compensatory CLL cell survival and a more prominent lymphocytosis on therapy. Ibrutinib-induced Akt phosphorylation (pAktS473) is caused by the upregulation of FoxO1 transcription factor, which induces expression of Rictor, an assembly protein for mTORC2 protein complex that directly phosphorylates Akt at serine 473 (S473). Knock-out or inhibition of FoxO1 or Rictor led to a dramatic decrease in Akt phosphorylation and growth disadvantage for malignant B cells in the presence of ibrutinib (or PI3K inhibitor idelalisib) in vitro and in vivo. FoxO1/Rictor/pAktS473 axis represents an early non-genetic adaptation to BCR inhibitor therapy not requiring PI3Kδ or BTK kinase activity. We further demonstrate that FoxO1 can be targeted therapeutically, and its inhibition induces CLL cells' apoptosis alone or in combination with BTK inhibitors (ibrutinib, acalabrutinib, pirtobrutinib) and blocks their proliferation triggered by T-cell factors (CD40L, IL-4, and IL-21).

Inhibitory Fcγ receptor deletion enhances CD8 T cell stemness increasing anti-PD-1 therapy responsiveness against glioblastoma

BackgroundCertain cancers present challenges for treatment because they are resistant to immune checkpoint blockade (ICB), attributed to low tumor mutational burden and the absence of T cell-inflamed features. Among these,...

Impact of soluble BCMA and non–T-cell factors on refractoriness to BCMA targeting T-cell engagers in multiple myeloma

Impact of soluble BCMA and non–T-cell factors on refractoriness to BCMA targeting T-cell engagers in multiple myeloma

Cholecystokinin regulates atrial natriuretic peptide secretion through activation of NOX4–Sirt1–LEF1 signaling in beating rat hypoxic atria

Cholecystokinin regulates atrial natriuretic peptide secretion through activation of NOX4–Sirt1–LEF1 signaling in beating rat hypoxic atria

ICAT-Mediated Crosstalk Between Cervical Cancer Cells and Macrophages Promotes M2-Like Macrophage Polarization to Reinforce Tumor Malignant Behaviors.

Inhibitor of β-catenin and T-cell factor (ICAT) is a classical inhibitor of the Wnt signaling pathway. Nonetheless, our previous work found that ICAT is overexpressed in cervical cancer (CC), resulting in the augmentation of migration and invasion capabilities of CC cells. It remains unclear what molecular mechanism underlies this phenomenon. The interaction between cancer cells and the tumor microenvironment (TME) promotes the outgrowth and metastasis of tumors. Tumor-associated macrophages (TAMs) are a major constituent of the TME and have a significant impact on the advancement of CC. Consequently, our inquiry pertains to the potential of ICAT to facilitate tumor development through its modulation of the cervical TME. In this study, we first verified that ICAT regulated the secretion of cytokines interleukin-10 (IL-10) and transforming growth factor-β (TGF-β) in CC cells, leading to M2-like macrophage polarization and enhancement of the migration and invasion of CC cells. Furthermore, the system of co-culturing human umbilical vein endothelial cells (HUVECs) with macrophages revealed that depending on the CC cells' overexpression or inhibition of ICAT, the vascular tube formation by HUVECs can be either increased or decreased. Overall, our study indicates that ICAT stimulates M2-like polarization of TAMs via upregulating IL-10 and TGF-β, which results in increased neovascularization, tumor metastasis, and immunosuppression in CC. In upcoming times, inhibiting crosstalk between CC cells and TAMs may be a possible strategy for CC therapy.

TCF4 as a potential prognostic biomarker and an anticancer target in gastric cancer.

Lymphoid enhancer-binding factor 1 (LEF1)/T cell factor (TCF) family members are key transcription factors in malignant tumors. In this study, the role of T cell factor 4 (TCF4) in the progression of gastric cancer (GC) cell migration and invasion was investigated. Fifty-five pairs of GC tissues and adjacent non-tumor tissues were collected for evaluating the expression of LEF1/TCF family members, which were also evaluated by the Gene Expression Profiling Interactive Analysis (GEPIA) database, an online analysis platform based on The Cancer Genome Atlas and Genotype-Tissue Expression databases. Through GEPIA online analysis and our experimental specimens, we found that TCF4 messenger RNA (mRNA) expression was significantly upregulated in GC tissues compared with normal non-tumor tissues. The findings from protein-protein interaction (PPI) analysis suggested that myocyte enhancer factor 2C (MEF2C) may function as a regulatory gene for TCF4 and play a role in the progression of GC. A significant increase in TCF4 mRNA expression was observed in the GC cell lines. Silencing of TCF4 led to significant inhibition of the proliferation, migration, and invasion of the MGC-803 and SGC-7901 cells. TdT-mediated dUTP nick end labeling (TUNEL)-positive staining cells were significantly increased after transfection with TCF4 small interfering (si)-RNA into GC cells. In addition, patients with GC with high TCF4 expression were associated with poor T stage, pathologic stages, histologic grade, overall survival, and recurrence-free survival, indicating that TCF4 may be a potential prognostic marker of GC. TCF4 potentially exerts a carcinogenic role in the progression of GC. TCF4 may serve as a prognostic indicator and therapeutic target for GC.

T cell factor 1 (TCF-1) defines T cell differentiation in colorectal cancer

T cell factor 1 (TCF-1) defines T cell differentiation in colorectal cancer