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1.
Cancer Med ; 13(11): e7395, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38872370

RESUMO

BACKGROUND AND AIMS: Pancreatic cancer is one of the most lethal malignancies, partly due to resistance to conventional chemotherapy. The chemoresistance of malignant tumors is associated with epithelial-mesenchymal transition (EMT) and the stemness of cancer cells. The aim of this study is to investigate the availability and functional mechanisms of trefoil factor family 1 (TFF1), a tumor-suppressive protein in pancreatic carcinogenesis, to treat pancreatic cancer. METHODS: To investigate the role of endogenous TFF1 in human and mice, specimens of human pancreatic cancer and genetically engineered mouse model of pancreatic cancer (KPC/TFF1KO; Pdx1-Cre/LSL-KRASG12D/LSL-p53R172H/TFF1-/-) were analyzed by immunohistochemistry (IHC). To explore the efficacy of extracellular administration of TFF1, recombinant and chemically synthesized TFF1 were administered to pancreatic cancer cell lines, a xenograft mouse model and a transgenic mouse model. RESULTS: The deficiency of TFF1 was associated with increased EMT of cancer cells in mouse models of pancreatic cancer, KPC. The expression of TFF1 in cancer cells was associated with better survival rate of the patients who underwent chemotherapy, and loss of TFF1 deteriorated the benefit of gemcitabine in KPC mice. Extracellular administration of TFF1 inhibited gemcitabine-induced EMT, Wnt pathway activation and cancer stemness, eventually increased apoptosis of pancreatic cancer cells in vitro. In vivo, combined treatment of gemcitabine and subcutaneous administration of TFF1 arrested tumor growth in xenograft mouse model and resulted in the better survival of KPC mice by inhibiting EMT and cancer stemness. CONCLUSION: These results indicate that TFF1 can contribute to establishing a novel strategy to treat pancreatic cancer patients by enhancing chemosensitivity.


Assuntos
Resistencia a Medicamentos Antineoplásicos , Transição Epitelial-Mesenquimal , Células-Tronco Neoplásicas , Neoplasias Pancreáticas , Fator Trefoil-1 , Animais , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/genética , Fator Trefoil-1/metabolismo , Fator Trefoil-1/genética , Humanos , Camundongos , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/efeitos dos fármacos , Linhagem Celular Tumoral , Proteínas Supressoras de Tumor/metabolismo , Proteínas Supressoras de Tumor/genética , Ensaios Antitumorais Modelo de Xenoenxerto , Gencitabina , Camundongos Transgênicos , Feminino , Masculino , Proliferação de Células/efeitos dos fármacos , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacologia , Desoxicitidina/uso terapêutico , Apoptose/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos
2.
J Gastroenterol ; 59(7): 572-585, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38836911

RESUMO

BACKGROUND: Currently utilized serum tumor markers and fecal immunochemical tests do not have sufficient diagnostic power for colorectal cancer (CRC) due to their low sensitivities. To establish non-invasive urinary protein biomarkers for early CRC diagnosis, we performed stepwise analyses employing urine samples from CRCs and healthy controls (HCs). METHODS: Among 474 urine samples, 363 age- and sex-matched participants (188 HCs, 175 stage 0-III CRCs) were randomly divided into discovery (16 HCs, 16 CRCs), training (110 HCs, 110 CRCs), and validation (62 HCs, 49 CRCs) cohorts. RESULTS: Of the 23 urinary protein candidates comprehensively identified from mass spectrometry in the discovery cohort, urinary levels of dipeptidase 1 (uDPEP1) and Trefoil factor1 (uTFF1) were the two most significant diagnostic biomarkers for CRC in both training and validation cohorts using enzyme-linked immunosorbent assays. A urinary biomarker panel comprising uDPEP1 and uTFF1 significantly distinguished CRCs from HCs, showing area under the curves of 0.825-0.956 for stage 0-III CRC and 0.792-0.852 for stage 0/I CRC. uDPEP1 and uTFF1 also significantly distinguished colorectal adenoma (CRA) patients from HCs, with uDPEP1 and uTFF1 increasing significantly in the order of HCs, CRA patients, and CRC patients. Moreover, expression levels of DPEP1 and TFF1 were also significantly higher in the serum and tumor tissues of CRC, compared to HCs and normal tissues, respectively. CONCLUSIONS: This study established a promising and non-invasive urinary protein biomarker panel, which enables the early detection of CRC with high sensitivity.


Assuntos
Biomarcadores Tumorais , Neoplasias Colorretais , Dipeptidases , Detecção Precoce de Câncer , Fator Trefoil-1 , Humanos , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/urina , Biomarcadores Tumorais/urina , Biomarcadores Tumorais/sangue , Masculino , Detecção Precoce de Câncer/métodos , Feminino , Fator Trefoil-1/urina , Pessoa de Meia-Idade , Idoso , Dipeptidases/urina , Dipeptidases/sangue , Estudos de Casos e Controles , Estadiamento de Neoplasias , Ensaio de Imunoadsorção Enzimática , Adulto , Sensibilidade e Especificidade , Adenoma/diagnóstico , Adenoma/urina , Proteínas Ligadas por GPI
3.
Histol Histopathol ; 39(3): 357-365, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-37338164

RESUMO

BACKGROUND: Chronic rhinosinusitis with nasal polyps (CRSwNP) is a multifactorial inflammatory disease characterized by high prevalence and morbidity. However, its pathogenesis is still obscure. This work focuses on the effects of Eupatilin (EUP) on inflammation reaction and the epithelial-to-mesenchymal transition (EMT) process in CRSwNP. METHODS: In vivo and in vitro CRSwNP models were established based on BALB/c mice and human nasal epithelial cells (hNECs) to investigate the effects of EUP on EMT and inflammation in CRSwNP. Protein levels of TFF1, EMT-related factors (E-cadherin, N-cadherin, and Vimentin), and Wnt/ß-catenin signaling-related proteins (Wnt3α and ß-catenin) were assayed via western blotting. Pro-inflammatory factors (TNF-α, IL-6, and IL-8) were assessed via ELISA assay. RESULTS: EUP treatment significantly reduced the number of polyps, epithelial thickness, and mucosal thickness in CRSwNP mice. Besides, EUP treatment also suppressed inflammation reaction and EMT events in CRSwNP mice and SEB-challenged hNECs in a dose-dependent manner. Also, EUP treatment dose-dependently upregulated TFF1 expression and inhibited Wnt/ß-catenin activation in CRSwNP mice and SEB-challenged hNECs. In addition, TFF1 inhibition or Wnt/ß-catenin activation partially abated EUP-mediated protection against SEB-induced inflammation reaction and EMT events in hNECs. CONCLUSIONS: Taken together, our findings highlighted the inhibitory role of EUP on the inflammation and EMT processes in CRSwNP in vivo and in vitro via upregulating TFF1 and inhibiting the Wnt/ß-catenin signaling, suggesting EUP could be a promising therapeutic agent for CRSwNP.


Assuntos
Flavonoides , Pólipos Nasais , Rinite , Rinossinusite , Sinusite , Humanos , Animais , Camundongos , Pólipos Nasais/tratamento farmacológico , Pólipos Nasais/etiologia , Pólipos Nasais/metabolismo , Via de Sinalização Wnt , beta Catenina/metabolismo , Sinusite/tratamento farmacológico , Sinusite/complicações , Sinusite/metabolismo , Inflamação , Transição Epitelial-Mesenquimal/fisiologia , Doença Crônica , Rinite/tratamento farmacológico , Fator Trefoil-1/farmacologia
4.
Int J Mol Sci ; 24(16)2023 Aug 11.
Artigo em Inglês | MEDLINE | ID: mdl-37628863

RESUMO

Tff1 is a typical gastric peptide secreted together with the mucin, Muc5ac. Tff1-deficient (Tff1KO) mice are well known for their prominent gastric phenotype and represent a recognized model for antral tumorigenesis. Notably, intestinal abnormalities have also been reported in the past in these animals. Here, we have compared the expression of selected genes in Tff1KO mice and their corresponding wild-type littermates (RT-PCR analyses), focusing on different mucosal protection systems along the murine intestine. As hallmarks, genes were identified with maximum expression in the proximal colon and/or the duodenum: Agr2, Muc6/A4gnt/Tff2, Tff1, Fut2, Gkn2, Gkn3, Duox2/Lpo, Nox1. This is indicative of different protection systems such as Tff2/Muc6, Tff1-Fcgbp, gastrokines, fucosylation, and reactive oxygen species (ROS) in the proximal colon and/or duodenum. Few significant transcriptional changes were observed in the intestine of Tff1KO mice when compared with wild-type littermates, Clca1 (Gob5), Gkn1, Gkn2, Nox1, Tff2. We also analyzed the expression of Tff1, Tff2, and Tff3 in the pancreas, liver, and lung of Tff1KO and wild-type animals, indicating a cross-regulation of Tff gene expression. Furthermore, on the protein level, heteromeric Tff1-Fcgbp and various monomeric Tff1 forms were identified in the duodenum and a high-molecular-mass Tff2/Muc6 complex was identified in the proximal colon (FPLC, proteomics).


Assuntos
Intestinos , Animais , Camundongos , Duodeno , Colo , Animais Selvagens , Transporte Biológico , Fator Trefoil-1/genética
5.
Ann Clin Lab Sci ; 53(3): 427-437, 2023 May.
Artigo em Inglês | MEDLINE | ID: mdl-37437926

RESUMO

OBJECTIVE: As a retinal vaso-proliferative disorder, retinopathy of prematurity (ROP) is characterized by neovascularization and angiogenesis, causing irreversible retinal damage and even visual loss among premature infants. Trefoil factor 1 (TFF1) has been identified as a key regulator in mediating retinal angiogenesis in diabetic retinopathy. However, whether TFF1 can mediate the angiogenic process in ROP remains unknown. Here, we aimed to investigate the regulatory function of TFF1 and its underlying mechanisms in hypoxia-exposed human retinal vascular endothelial cells (HRVECs) in vitro. METHODS: HRVECs were exposed to hypoxia condition to establish the in vitro ROP models. HRVEC viability was validated using CCK-8 assay. The migratory and angiogenic capacities of HRVECs were assessed by wound healing and tube formation assays, respectively. RT-qPCR was performed to detect gene levels. Western blotting was used to measure the protein levels of TFF1 and Runt-related transcription factor 1 (RUNX1). The binding relationship between RUNX1 to TFF1 promoter was confirmed by chromatin immunoprecipitation and luciferase reporter assays. RESULTS: Hypoxia downregulated TFF1 expression and elevated RUNX1 expression in HRVECs. Moreover, hypoxic condition increased HRVEC viability and accelerated HRVEC migration and angiogenesis, which were antagonized by TFF1 elevation or RUNX1 knockdown. RUNX1 as a transcription factor bound to TFF1 promoter and transcriptionally repressed TFF1 expression in HRVECs. In rescue assays, overexpression of TFF1 counteracted the promotive effect of RUNX1 overexpression on the viability, migratory and angiogenic abilities of HRVECs under hypoxia. CONCLUSIONS: RUNX1 transcriptionally suppresses TFF1 expression to aggravate hypoxia-induced HRVEC dysfunction.


Assuntos
Subunidade alfa 2 de Fator de Ligação ao Core , Células Endoteliais , Lactente , Recém-Nascido , Humanos , Fator Trefoil-1/genética , Regulação da Expressão Gênica , Hipóxia
6.
Cancer Epidemiol ; 83: 102333, 2023 04.
Artigo em Inglês | MEDLINE | ID: mdl-36758349

RESUMO

OBJECTIVE: Gastric carcinoma (GC) has received extensive attention due to its complex pathogenesis. Studies have shown that the expression of Trefoil factor 1 (TFF1) and Partner and localiser of BRCA2 (PALB2) genes promotes the occurrence of GC. Therefore, we investigated whether TFF1 and PALB2 gene polymorphisms are associated with GC risk in the Chinese Han population. METHODS: A total of 509 GC cases and 505 controls were recruited, and single nucleotide polymorphisms (SNPs) of TFF1 and PALB2 in these subjects were genotyped. The association between each candidate polymorphism and GC risk was assessed by calculating odds ratios (ORs) and 95% confidence intervals (CIs). The visualization of gene-gene interactions and functional enrichment analysis were then performed using Cytoscape software and the R package "cluster profile". RESULTS: The TFF1 rs2156310 polymorphism significantly reduced the predisposition to GC in people under 60 years of age (AA vs. AG - GG, OR = 0.58, 95% CI = 0.35-0.97, p = 0.036). The gender-stratified analysis found that PALB2 rs513313 was significantly associated with the risk of GC in males (CT vs. TT, OR = 1.51, 95% CI = 1.06-2.15, p = 0.022). Besides, PALB2 rs249954 significantly reduced the susceptibility to GC in females (AA vs GG, OR = 0.42, 95% CI = 0.19-0.94, p = 0.034). CONCLUSION: Our results revealed that TFF1 and PALB2 gene polymorphisms were correlated with the genetic susceptibility to GC, providing certain data support for researchers to further study the mechanism of GC.


Assuntos
Carcinoma , Neoplasias Gástricas , Masculino , Feminino , Humanos , Fator Trefoil-1/genética , População do Leste Asiático , Predisposição Genética para Doença , Genótipo , Polimorfismo de Nucleotídeo Único , Estudos de Casos e Controles , China , Proteína do Grupo de Complementação N da Anemia de Fanconi/genética
7.
Open Biol ; 12(12): 220278, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-36514982

RESUMO

Chronic Helicobacter pylori infection is the leading cause of intestinal-type adenocarcinoma, as prolonged Helicobacter colonization triggers chronic active gastritis, which may evolve into adenocarcinoma of the intestinal type. In this environment, cytokines play a significant role in determining the evolution of the infection. In combination with other factors (genetic, environmental and nutritional), the pro-inflammatory response may trigger pro-oncogenic mechanisms that lead to the silencing of tumour-suppressor genes, such as trefoil factor 1 (TFF1). The latter is known to play a protective role by maintaining the gastric mucosa integrity and retaining H. pylori in the mucus layer, preventing the progression of infection and, consequently, the development of gastric cancer (GC). Since TFF1 expression is reduced during chronic Helicobacter infection with a loss of gastric mucosa protection, we investigated the molecular pathways involved in this reduction. Specifically, we evaluated the effect of some pro-inflammatory cytokines on TFF1 regulation in GC and primary gastric cells by RT-qPCR and luciferase reporter assay analyses and the repressor role of the transcription factor C/EBPß, overexpressed in gastric-intestinal cancer. Our results show that, among several cytokines, IFNγ stimulates C/EBPß expression, which acts as a negative regulator of TFF1 by binding its promoter at three different sites.


Assuntos
Adenocarcinoma , Infecções por Helicobacter , Helicobacter pylori , Neoplasias Gástricas , Humanos , Infecções por Helicobacter/genética , Infecções por Helicobacter/metabolismo , Infecções por Helicobacter/patologia , Helicobacter pylori/metabolismo , Fator Trefoil-1/genética , Fator Trefoil-1/metabolismo , Fator Trefoil-1/farmacologia , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismo , Adenocarcinoma/genética , Citocinas/metabolismo
8.
Mol Biol Rep ; 49(10): 10127-10131, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-36057754

RESUMO

INTRODUCTION: Trefoil Factor 1 (TFF1) is a secretory peptide with gastrointestinal protective functions. Abnormal TFF1 expression is reported in some cancers and functional promoter polymorphism in TFF1 is believed to be associated with risk of gastric cancer. We evaluated rs3761376 in a sample of Iranian patients with colorectal cancer. METHODS: Peripheral blood samples were taken from pathology confirmed cases of colorectal cancer and healthy volunteers. Genotyping was carried out using Restriction Fragment Length Polymorphism (RFLP) PCR. Any association with clinicopathologic data was assessed by SPSS version 19. RESULTS: A total of 245 participants, including 122 patients with cancer and 123 non-cancer subjects were enrolled. Age, body mass index, and smoking habits were not significantly different between the two groups (P > 0.05). Distribution of TFF1 genotypes was not found to be associated with colorectal cancer. However, distant metastasis was more prevalent in carriers of the mutant allele. CONCLUSION: TFF1 rs3761376 was not associated with colorectal cancer but it may be involved in metastasis. Therefore, further investigation is warranted to determine this relationship.


Assuntos
Neoplasias Colorretais , Polimorfismo de Nucleotídeo Único , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Humanos , Irã (Geográfico) , Peptídeos/genética , Peptídeos/metabolismo , Polimorfismo de Nucleotídeo Único/genética , Fator Trefoil-1/genética , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/metabolismo
9.
Pathol Res Pract ; 236: 153987, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-35749918

RESUMO

Precursor lesions that progress into colorectal cancer (CRC) could be largely classified into sessile serrated lesions (SSLs), traditional serrated adenoma (TSA), and tubular adenoma (TA). We aimed to determine whether high expression of trefoil factor 1 (TFF1) is closely associated with serrated lesions, particularly SSLs. The samples were divided into the first (12 SSLs, 5 TSAs, and 15 TAs) and second cohorts (15 SSLs, 9 TSAs, and 15 TAs). First, we investigated TFF1 expression in isolated gland samples using array-based and reverse-transcription PCR. Second, we performed immunohistochemical analysis of TFF1 expression in paraffin-embedded tissues obtained from SSL, TSA, TA, and hyperplastic polyp (HP) samples. In addition, we compared TFF1 mRNA levels between SSLs and HPs. TFF1 expression was significantly higher in SSLs than in TSA and TA in both cohorts. Additionally, immunohistochemical staining of TFF1 in the HP, SSL, TSA, and TA samples revealed significant differences in the immunohistochemical scores of TFF1 among the four types of lesions (higher expression in SSLs than in the other three lesions). Finally, there were significant differences in TFF1 mRNA expression levels between SSLs and HPs in paraffin-embedded tissues. However, there was considerable overlap in the immunohistochemical scores and expression levels of TFF1 transcripts between SSLs and HPs. The current findings may help elucidate the molecular mechanisms involved in serrated lesion development. In addition, we suggest that despite the limited practical application, upregulation of TFF1 transcripts may help differentiate SSLs from other lesions.


Assuntos
Adenoma , Pólipos do Colo , Neoplasias Colorretais , Neoplasias Gastrointestinais , Adenoma/patologia , Pólipos do Colo/genética , Pólipos do Colo/patologia , Neoplasias Colorretais/patologia , Humanos , RNA Mensageiro/genética , Fator Trefoil-1/genética
10.
Int J Mol Sci ; 23(10)2022 May 11.
Artigo em Inglês | MEDLINE | ID: mdl-35628183

RESUMO

In 2020, gastric cancer was the fourth leading cause of cancer deaths globally. About 90% of gastric cancers are sporadic and the vast majority are correlated with Helicobacter pylori infection; whereas familial clustering is observed in about 10% of cases. Gastric cancer is now considered to be a disease originating from dysregulated self-renewal of the gastric glands in the setting of an inflammatory environment. The human stomach contains two types of gastric units, which show bi-directional self-renewal from a complex variety of stem cells. This review focuses on recent progress concerning the characterization of the different stem cell populations and the mainly mesenchymal signals triggering their stepwise differentiation as well as the genesis of pre-cancerous lesions and carcinogenesis. Furthermore, a model is presented (Lectin-triggered Receptor Blocking Hypothesis) explaining the role of the lectin TFF1 as an antral tumor suppressor possibly regulating Lgr5+ antral stem cells in a paracrine or maybe autocrine fashion, with neighboring antral gland cells having a role as niche cells.


Assuntos
Infecções por Helicobacter , Helicobacter pylori , Neoplasias Gástricas , Epitélio/patologia , Mucosa Gástrica/patologia , Infecções por Helicobacter/patologia , Humanos , Lectinas , Neoplasias Gástricas/patologia , Fator Trefoil-1
11.
J Healthc Eng ; 2022: 7984591, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35392152

RESUMO

Objective: To explore the diagnostic value of dynamic enhanced magnetic resonance imaging (MRI) combined with serum CA15-3, CYFRA21-1, and TFF1 for breast cancer. Methods: By means of a retrospective study, 60 breast cancer patients treated in our hospital from January 2018 to December 2020 were selected as the breast cancer group, 60 patients with benign breast lesions were selected as the benign group, and 60 healthy individuals who received physical examination in our hospital in the same period were selected as the control group. All study subjects received dynamic enhanced MRI scan and serological tests, their serum CA15-3 and CYFRA21-1 levels were measured with the electrochemiluminescence instrument and original auxiliary reagent, and the TFF1 level was measured with enzyme-linked immunosorbent assay (ELISA). The MRI performance variation in breast lesion patients was analyzed, the serum CA15-3, CYFRA21-1, and TFF1 levels of study subjects were compared among the three groups, and the efficacy of single diagnosis by dynamic enhanced MRI, CA15-3, CYFRA21-1, or TFF1 as well as combined diagnosis was explored by ROC curves. Results: Dynamic enhanced MRI showed that malignant lesion had obscure boundary, irregular margin, and heterogeneity after enhancement, and the time-signal intensity curve presented fast-in fast-out; the benign lesion had a clear boundary and smooth margin, 25 cases showed homogeneity after enhancement, and the time-signal intensity curve presented slow-in slow-out; the CA15-3, CYFRA21-1, and TFF1 levels were significantly different among the breast cancer group, benign group, and control group (33.81 ± 12.46 vs 19.02 ± 6.47 vs 9.55 ± 2.64, 4.08 ± 1.41 vs 1.96 ± 1.19 vs 0.99 ± 0.21, 1.39 ± 0.54 vs 1.04 ± 0.26 vs 0.89 ± 0.12, P < 0.05); 57 breast cancer patients were diagnosed by a combined examination, with a sensitivity of 95.0%, specificity of 83.3%, positive predictive value of 74.0%, negative predictive value of 97.1%, accuracy rate of 87.2%, and AUC (95%CI) = 0.892 (0.840-0.943), indicating a significantly higher diagnostic value of the combined examination than the single examination by CA15-3, CYFRA21-1, TFF1, or MRI. Conclusion: Combining dynamic enhanced MRI with serum CA15-3, CYFRA21-1, and TFF1 has good efficacy in diagnosing breast cancer, which can be applied in clinical diagnosis of breast cancer.


Assuntos
Neoplasias da Mama , Antígenos de Neoplasias , Biomarcadores Tumorais , Neoplasias da Mama/diagnóstico por imagem , Feminino , Humanos , Queratina-19 , Imageamento por Ressonância Magnética/métodos , Mucina-1 , Estudos Retrospectivos , Fator Trefoil-1
12.
Acta Biomed ; 93(1): e2022176, 2022 03 14.
Artigo em Inglês | MEDLINE | ID: mdl-35315403

RESUMO

BACKGROUND AND AIM: Epigenetic modifications exhibit promising evidence in etiology and prognosis of important diseases such as inflammatory bowel diseases (IBD). In addition to complex factors involved in IBD, a trend toward better prognosis have been reported in older ages of disease onset. Gastrointestinal mucous layer is one of the important components which is disturbed in the disease course. Integrity of this layer is maintained with an anti-inflammatory factor called trefoil factors (TFF). We investigated the methylation status of TFF1 gene in IBD patients alongside with correlation of its alteration level with age of disease onset. METHODS: We analyzed the promoter methylation status of TFF1 gene, using the real-time quantitative multiplex methylation specific PCR (QM-MSP). DNA was extracted from colorectal biopsies of 15 Crohn disease cases and 15 healthy controls. Correlation analysis was performed between unmethylated DNA level and age through Pearson correlation coefficient (PPC) test and simple linear regression models. RESULTS: … Our data didn't provide significant positive correlation of age and TFF1 hypomethylation in Crohn patients (r = .518, p = .058). CONCLUSIONS: In conclusion, our case-control study didn't show significant alteration in TFF1 methylation status in CD patients. (www.actabiomedica.it).


Assuntos
Doença de Crohn , Doenças Inflamatórias Intestinais , Estudos de Casos e Controles , Doença de Crohn/genética , Humanos , Peptídeos/genética , Fator Trefoil-1/genética , Fator Trefoil-2
13.
Lab Invest ; 102(8): 885-895, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35279702

RESUMO

Trefoil factor family 1 (TFF1) is one of three members of the trefoil factor family that are abundantly expressed in the gastrointestinal mucosal epithelium. Recent studies have shown that TFF1 acts as a tumor suppressor in gastric, pancreatic and hepatocellular carcinogenesis; however, little is known about its function in esophageal carcinogenesis, especially in esophageal adenocarcinoma (EAC). Barrett's epithelium is the metaplastic columnar epithelium of the esophagus and a known premalignant lesion of EAC. To investigate the role of TFF1 in EAC development, a mouse model of Barrett's epithelium was employed, and human specimens of EAC were assessed by immunohistochemistry (IHC) and methylation-specific PCR. Wild-type (WT) mice underwent gastrojejunostomy on the forestomach, resulting in the development of Barrett's epithelium-like (BE-like) epithelium adjacent to the anastomotic site. BE-like epithelium in these mice expressed TFF1, indicating the association of TFF1 with esophageal adenocarcinoma. TFF1-knockout (TFF1KO) mice underwent the same procedure as well, revealing that a deficiency in TFF1 resulted in the development of adenocarcinoma in the anastomotic site, presumably from BE-like epithelium. IHC of human samples revealed strong TFF1 expression in Barrett's epithelium, which was lost in some EACs, confirming the association between TFF1 and EAC development. Aberrant DNA hypermethylation in TFF1 promoter lesions was detected in TFF1-negative human EAC samples, further confirming not only the role of TFF1 in EAC but also the underlying mechanisms of TFF1 regulation. In addition, IHC revealed the nuclear translocation of ß-catenin in human and mouse EAC, suggesting that activation of the Wnt/ß-catenin pathway was induced by the loss of TFF1. In conclusion, these results indicate that TFF1 functions as a tumor suppressor to inhibit the development of esophageal carcinogenesis from Barrett's epithelium.


Assuntos
Adenocarcinoma , Esôfago de Barrett , Neoplasias Esofágicas , Fator Trefoil-1 , Adenocarcinoma/etiologia , Adenocarcinoma/genética , Animais , Esôfago de Barrett/complicações , Esôfago de Barrett/genética , Carcinogênese , Metilação de DNA , Epitélio/metabolismo , Neoplasias Esofágicas/etiologia , Neoplasias Esofágicas/genética , Humanos , Camundongos , Regiões Promotoras Genéticas , Fator Trefoil-1/genética , Via de Sinalização Wnt , beta Catenina
14.
Biochem Genet ; 60(6): 2155-2170, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-35279761

RESUMO

Breast cancer (BC) is a common malignant tumor, and circular RNA-trefoil factor 1 (circ-TFF1; hsa_circ_0061825) has been found to be highly expressed in BC tissues and cells and is associated with the poor prognosis of BC patients. However, the interaction between circ-TFF1 and microRNA in BC has not been studied. Quantitative real-time PCR was used to detect the expression of circ-TFF1, miR-129-2-3p, and interleukin (IL)-1 receptor-associated kinase 1 (IRAK1). Through the detection of cell proliferation, migration, invasion, tube formation, and apoptosis, cell function was assessed. The expression levels of angiogenesis-related proteins were detected by western blot. The interaction between miR-129-2-3p and circ-TFF1 or IRAK1 was verified by dual-luciferase reporter assay and RNA immunoprecipitation assay. Xenotransplantation experiments were used to confirm the function of circ-TFF1 in vivo. Circ-TFF1 and IRAK1 were significantly high expressed in BC tissues and cells. Silencing of circ-TFF1 reduced the proliferation, migration, invasion and tube formation, while increased the apoptosis of MDA-MB-361 and SK-Br-3 cells. MiR-129-2-3p was a target of circ-TFF1. Silencing of circ-TFF1 inhibited the malignant behavior of BC cells by releasing miR-129-2-3p. In addition, IRAK1 was a target of miR-129-2-3p. Overexpression of IRAK1 partially restored the inhibitory effect of miR-129-2-3p on cell progression. Animal experiments confirmed the anti-tumor effect of circ-TFF1 knockdown in vivo. Circ-TFF1 regulated the expression of IRAK1 by sponging miR-129-2-3p, thereby, promoting the development of BC. These data provided a novel targeted therapy for BC.


Assuntos
MicroRNAs , Neoplasias , Animais , Fator Trefoil-1/genética , Regulação Neoplásica da Expressão Gênica , Movimento Celular/genética , MicroRNAs/genética , Proliferação de Células/genética , Neoplasias/genética , Linhagem Celular Tumoral
15.
Exp Eye Res ; 217: 108969, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-35114215

RESUMO

Diabetic retinopathy (DR) represents a major complication of diabetes, and molecular mechanisms related to vascular dysfunction, particularly endothelial dysfunction, in DR remains unclear. In the present work, we generated a DR animal model using mice and a cell model in mouse retinal microvascular endothelial cells (mRMECs) to examine the role of Trefoil factor family 1 (Tff1) in DR. Tff1 was poorly expressed in DR mice and high glucose (HG)-treated mRMECs. Overexpression of Tff1 significantly attenuated streptozotocin-induced retinal proliferation and angiogenesis in DR mice and reduced the secretion of inflammatory factors. In HG-treated mRMECs, overexpression of Tff1 remarkably reduced the proliferation and angiogenesis of mRMECs. In further experiments, we found that Tff1 was transcriptionally repressed by Runt-related transcription factor 1 (Runx1) directly, and Tff1 expression was indirectly modulated by Runx1 via the core-binding factor subunit beta (CBF-ß)/nuclear factor, erythroid 2/microRNA-423-5p axis and the CBF-ß/estrogen receptor 1 (ESR1) axis. Moreover, Tff1 could inhibit the activation of NF-κB signaling pathway, which in turn attenuated retinal endothelial cell proliferation and angiogenesis. It was thus proposed that Runx1/Tff1/NF-κB axis may be a potential target for the treatment strategy of DR, and further studies are needed.


Assuntos
Subunidade alfa 2 de Fator de Ligação ao Core , Diabetes Mellitus , Retinopatia Diabética , MicroRNAs , Fator Trefoil-1 , Animais , Subunidade alfa 2 de Fator de Ligação ao Core/metabolismo , Diabetes Mellitus/metabolismo , Retinopatia Diabética/metabolismo , Células Endoteliais/metabolismo , Camundongos , MicroRNAs/metabolismo , NF-kappa B/metabolismo , Neovascularização Patológica/metabolismo , Retina/metabolismo , Fator Trefoil-1/metabolismo
16.
Eur J Surg Oncol ; 48(1): 177-182, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34034940

RESUMO

BACKGROUND: Cancer cells in intraoperative peritoneal washings (PW) indicate increased peritoneal recurrence. Detection of CEA or CK20 genes indicates poor prognosis. We assessed long-term prognosis of patients with amplification of cancer-related genes in PW obtained intraoperatively during curative gastric cancer surgery. METHODS: PW was collected before and immediately after curative gastrectomy. CEA, CK20, TFF1, MUC2, and FABP1-mRNA were selected as marker genes for reverse transcription polymerase chain reaction. Peritoneal recurrence-free survival (PRFS) and overall survival (OS) after >7-year follow-up were examined using the Kaplan-Meier method. RESULTS: Of 138 patients who underwent gastrectomy with negative cytological findings at laparotomy, 80 patients showed negative cancer-related gene amplification in preoperative PW. Fifty-eight patients were excluded due to positive gene amplification, which suggested presence of preoperative peritoneal cancer cells. The 80 patients had mRNA amplification in PW after surgery. Amplification of multiple and single cancer-related marker genes was observed in 38 and 21 patients; 21 cases had marker-negative results. Five-year PRFS was 69.1%, 95.2%, and 100% in multi-marker-positive, single marker-positive, and marker-negative cases, respectively. Multi-marker-positive patients had significantly worse PRFS than the other groups (p < 0.05). Multivariate analysis in the Cox proportional hazards model identified multi-marker-positivity as an independent prognostic factor for PRFS (hazard ratio, 7.6; 95% confidence interval, 1.07-62.63; p = 0.046), and multi-marker-positive patients had significantly worse OS than other groups (p < 0.01). CONCLUSION: Multi-marker cancer-related gene amplification in PW is associated with worse prognosis in PRFS and OS even after a long follow-up; PRFS can be stratified by the number of genes amplified.


Assuntos
Carcinoma/cirurgia , Gastrectomia , Lavagem Peritoneal , Neoplasias Peritoneais/secundário , Neoplasias Gástricas/cirurgia , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígeno Carcinoembrionário/genética , Carcinoma/genética , Carcinoma/patologia , Carcinoma/secundário , Intervalo Livre de Doença , Proteínas de Ligação a Ácido Graxo/genética , Feminino , Humanos , Queratina-20/genética , Masculino , Pessoa de Meia-Idade , Mucina-2/genética , Prognóstico , Modelos de Riscos Proporcionais , RNA Mensageiro/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Neoplasias Gástricas/genética , Neoplasias Gástricas/patologia , Transcriptoma , Fator Trefoil-1/genética
17.
Biochem Genet ; 60(1): 315-335, 2022 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-34219206

RESUMO

Some circular RNAs (circRNAs) have been verified to act as essential regulators in the progression of breast cancer (BC). We aimed to investigate the role of circRNA trefoil factor 1 (circ-TFF1) in BC progression. The expression of circ-TFF1, microRNA-338-3p (miR-338-3p) and fibroblast growth factor receptor 1 (FGFR1) mRNA was measured by quantitative real-time polymerase chain reaction (qRT-PCR). Cell proliferation was evaluated by methylthiazolyldiphenyl-tetrazolium bromide (MTT), colony formation, and 5-Ethynyl-2'-deoxyuridine (EDU) assays. Cell apoptosis and invasion were assessed by flow cytometry and transwell assay, respectively. Cellular glycolysis, including glucose consumption, lactate production, and ATP/ADP ratio, was detected by commercial kits. All protein levels were measured by western blot assay. The relationship between miR-338-3p and circ-TFF1 or FGFR1 was predicted by online bioinformatics tool and verified by dual-luciferase reporter assay. Xenograft tumor model was established to verify the function of circ-TFF1 in vivo. Circ-TFF1 was overexpressed in BC tissues and cells. Circ-TFF1 knockdown inhibited cell proliferation, invasion and glycolysis and induced apoptosis in BC cells. Circ-TFF1 acted as a sponge of miR-338-3p, and the effects of circ-TFF1 knockdown on BC cell proliferation, apoptosis, invasion, and glycolysis were abolished by miR-338-3p inhibition. FGFR1 was confirmed to be a target gene of miR-338-3p, and miR-338-3p played a tumor-suppressive role in BC by targeting FGFR1. Moreover, circ-TFF1 regulated FGFR1 expression by targeting miR-338-3p. Additionally, circ-TFF1 knockdown hampered tumorigenesis in vivo. Circ-TFF1 knockdown suppressed BC progression by regulating miR-338-3p/FGFR1 axis, providing a promising therapeutic target for BC.


Assuntos
Neoplasias da Mama , MicroRNAs , Neoplasias da Mama/genética , Feminino , Humanos , MicroRNAs/genética , RNA Circular , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/genética , Fator Trefoil-1
18.
Bioengineered ; 13(1): 71-82, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34898361

RESUMO

The present study aimed to investigate the protective effects and molecular mechanisms of Dendrobium officinale polysaccharides on gastric mucosal injuries. Following one week of continuous intragastric administration, a gastric mucosal injury model was established using intragastric administration of anhydrous ethanol. The area of gastric ulcer was measured, the contents of interleukin- 6 (IL-6), epidermal growth factor receptor (EGFR), and thyroid transcription factor 1 (TFF-1) in serum were detected by enzyme linked immunosorbent assay (ELISA), and the expressions of EGFR, TFF-1, IL-6, Raf-2, MAP kinase kinase 1 (MEK1), MEK2, and ERK1 in the gastric tissue were determined utilizing qPCR, Western blotting and immunohistochemistry. Simultaneously, Dendrobium officinale polysaccharides and anhydrous ethanol were added to the gastric mucosal cells (GES1) cultured in vitro, and the protective effects of Dendrobium officinale polysaccharides on cell viability was detected using Cell Counting Kit (CCK)-8. The addition of Dendrobium officinale polysaccharides markedly improved the gastric epithelial defect, inflammatory cell infiltration, and redness and swelling stemmed from gastric mucosal injuries and greatly reduced the area of gastric ulcer. The inhibition rates of gastric ulcer were 48.12 ± 2.98, 42.95 ± 1.52, and 27.96 ± 2.05% in the high, medium, and low concentration Dendrobium officinale polysaccharide groups, respectively. Dendrobium officinale polysaccharides could increase the expressions of EGFR and TFF-1 and decrease the expressions of IL-6, Raf-2, MEK1, MEK2, and ERK1. Dendrobium officinale polysaccharides could reduce the level of inflammatory factors and protect gastric mucosa by inhibiting the expression of MAPK pathway genes and proteins.


Assuntos
Anti-Inflamatórios/administração & dosagem , Dendrobium/química , Etanol/efeitos adversos , Mucosa Gástrica/citologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Polissacarídeos/administração & dosagem , Úlcera Gástrica/tratamento farmacológico , Animais , Anti-Inflamatórios/farmacologia , Linhagem Celular , Sobrevivência Celular , Modelos Animais de Doenças , Mucosa Gástrica/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Genes erbB-1/efeitos dos fármacos , Humanos , Interleucina-6/metabolismo , Masculino , Extratos Vegetais , Polissacarídeos/farmacologia , Ratos , Úlcera Gástrica/induzido quimicamente , Úlcera Gástrica/metabolismo , Úlcera Gástrica/patologia , Fator Trefoil-1/efeitos dos fármacos , Fator Trefoil-1/metabolismo
19.
Biochem Biophys Res Commun ; 588: 75-82, 2022 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-34952473

RESUMO

Germline mutations to the breast cancer 2 (BRCA2) gene have been associated with hereditary breast cancer. In addition to estrogen uptake, BRCA2 expression increases in the S phase of the cell cycle and largely contributes to DNA damage repair associated with DNA replication. However, the role of BRCA2 in estrogen induction remains unclear. An expression plasmid was created to induce BRCA2 activation upon the addition of estradiol by introducing mutations to the binding sequences for the transcription factors USF1, E2F1, and NF-κB within the promoter region of BRCA2. Then, the estrogen receptor (ER) sites of the proteins that interact with BRCA2 upon the addition of estradiol were identified. Both proteins were bound by the helical domain of BRCA2 and activation function-2 of the ER, suggesting that this binding may regulate the transcriptional activity of pS2, a target gene of the estradiol-ER, by suppressing the binding of SRC-1, a coactivator required for activation of the transcription factor.


Assuntos
Proteína BRCA2/metabolismo , Estradiol/metabolismo , Receptor alfa de Estrogênio/metabolismo , Proteínas/genética , Transcrição Gênica , Fator Trefoil-1/genética , Proteína BRCA2/química , Regulação Neoplásica da Expressão Gênica , Humanos , Células MCF-7 , Coativador 1 de Receptor Nuclear/metabolismo , Regiões Promotoras Genéticas , Ligação Proteica , Domínios Proteicos , Proteínas/metabolismo , Fatores de Transcrição/metabolismo , Fator Trefoil-1/metabolismo
20.
Bioengineered ; 12(1): 5266-5278, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34424807

RESUMO

Long non-coding RNA (lncRNA) FOXD3 antisense RNA 1 (FOXD3-AS1) has been reported to participate in multiple processes that contribute toward the development of cancer. The present study aimed to explore the effect of lncRNA FOXD3-AS1 on anti-estrogen resistance in breast cancer (BC) cells. FOXD3-AS1 was found to be highly expressed in BC cell lines. Moreover, FOXD3-AS1 was highly expressed in estrogen receptor-negative (ER-) cells compared to the ER-positive (ER+) cells. FOXD3-AS1 overexpression in T47D and MCF-7 (ER+) cells enhanced the resistance of cells to tamoxifen (TMX), whereas FOX3-AS1 downregulation reduced the TMX resistance in MDA-MB-231 (ER-) cells. Similar results were reproduced in vivo that FOXD3-AS1 inhibition reduced the growth of xenograft tumors formed by MDA-MB-231 cells following TMX treatment whereas FOXD3-AS1 overexpression in T47D cells facilitated tumor growth. The bioinformatic analysis and luciferase assays indicated that FOXD3-AS1 sponged microRNA-363 (miR-363) to restore expression of trefoil factor 1 (TFF1) mRNA. Overexpression of miR-363 reduced T47D cell proliferation induced by FOXD3-AS1, whereas overexpression of TFF1 restored growth of MDA-MB-231 cells reduced after FOXD3-AS1 silencing. The phosphorylation of phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) was increased by FOXD3-AS1 but attenuated by miR-363. Inhibition of PI3K/Akt blocked the role of FOXD3-AS1 and reduced the TMX resistance in T47D and MCF-7 cells. Taken together, the present study suggested that FOXD3-AS1 sponges miR-363 to upregulate TFF1 expression, leading to PI3K/Akt signaling activation and anti-estrogen resistance in BC cells.


Assuntos
Neoplasias da Mama , MicroRNAs/genética , RNA Longo não Codificante/genética , Fator Trefoil-1/genética , Animais , Antineoplásicos Hormonais/farmacologia , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Antagonistas de Estrogênios/farmacologia , Feminino , Inativação Gênica , Humanos , Camundongos , Camundongos Nus , MicroRNAs/metabolismo , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , RNA Longo não Codificante/metabolismo , Transdução de Sinais , Tamoxifeno/farmacologia , Fator Trefoil-1/metabolismo
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