Growth Factor Beta Signaling Pathway Research Articles

The Role of ARHGAP1 in Rho GTPase Inactivation during Metastasizing of Breast Cancer Cell Line MCF-7 after Treatment with Doxorubicin.

Breast cancer is the most prevalent cancer type in women worldwide. It proliferates rapidly and can metastasize into farther tissues at any stage due to the gradual invasiveness and motility of the tumor cells. These crucial properties are the outcome of the weakened intercellular adhesion, regulated by small guanosine triphosphatases (GTPases), which hydrolyze to the guanosine diphosphate (GDP)-bound conformation. We investigated the inactivating effect of ARHGAP1 on Rho GTPases involved signaling pathways after treatment with a high dose of doxorubicin. Label-free quantitative proteomic analysis of the proteome isolated from the MCF-7 breast cancer cell line, treated with 1 μM of doxorubicin, identified RAC1, CDC42, and RHOA GTPases that were inactivated by the ARHGAP1 protein. Upregulation of the GTPases involved in the transforming growth factor-beta (TGF-beta) signaling pathway initiated epithelial-mesenchymal transitions. These findings demonstrate a key role of the ARHGAP1 protein in the disruption of the cell adhesion and simultaneously allow for a better understanding of the molecular mechanism of the reduced cell adhesion leading to the subsequent metastasis. The conclusions of this study corroborate the hypothesis that chemotherapy with doxorubicin may increase the risk of metastases in drug-resistant breast cancer cells.

Prediction of diabetes mellitus after kidney transplantation using patient-specific induced pluripotent stem cells.

Multiple risk factors are involved in new-onset diabetes mellitus (DM) after organ transplantation; however, their ability to predict clinical prognosis remains unclear. Therefore, we investigated whether patient-specific induced pluripotent stem cells (iPSCs) could help predict DM development before performing kidney transplantation (KT). We first performed whole transcriptome and functional enrichment analyses of KT patient-derived iPSCs. Our results revealed that insulin resistance, type 2 DM, and transforming growth factor beta signaling pathways are associated between the groups of DM and non-DM. We next determined whether the genetic background was associated with development of iPSCs into pancreatic progenitor (PP) cells. The levels of differentiation-related key markers of PP cells were significantly lower in the DM group than in the non-DM group. Moreover, the results of tacrolimus toxicity screening showed a significant decrease in the number of PP cells of the DM group compared with the non-DM group, suggesting that these cells are more susceptible to tacrolimus toxicity. Taken together, these results indicate that PP cells of the DM group showed low developmental potency accompanied by a significantly different genetic background compared with the non-DM group. Thus, genetic analysis can be used to predict the risk of DM before KT.

NT-3 Combined with TGF-β Signaling Pathway Enhance the Repair of Spinal Cord Injury by Inhibiting Glial Scar Formation and Promoting Axonal Regeneration.

This study investigated the mechanism of neurotrophin-3 (NT-3) in promoting spinal cord injury repair through the transforming growth factor-beta (TGF-β) signaling pathway. A mouse model of spinal cord injury was established. Forty C57BL/6J mice were randomized into model, NT-3, NT-3 + TGF-β1 and NT-3 + LY364947 groups. The Basso-Beattie-Bresnahan (BBB) scores of the NT-3 and NT-3 + LY364947 groups were significantly higher than the model group. The BBB score of the NT-3 + TGF-β1 group was significantly lower than NT-3 group. Hematoxylin-eosin staining and transmission electron microscopy showed reduction in myelin sheath injury, more myelinated nerve fibers in the middle section of the catheter, and relatively higher density and more neatly arranged regenerated axons in the NT-3 and NT-3 + LY364947 groups compared with the model and NT-3 + TGF-β1 groups. Immunofluorescence, TUNEL and Western blot analysis showed that compared with model group, the NEUN expression increased, and the apoptosis and Col IV, LN, CSPG, tenascin-C, Sema 3A, EphB2 and Smad2/3 protein expression decreased significantly in the NT-3 and NT-3 + LY364947 groups; the condition was reversed in the NT-3 + TGF-β1 group compared with the NT-3 group. NT-3 combined with TGF-β signaling pathway promotes astrocyte differentiation, reduces axon regeneration inhibitory molecules, apoptosis and glial scar formation, promotes axon regeneration, and improves spinal cord injury.

A phase Ib/II study of GFH018 in combination with toripalimab in recurrent/metastatic nasopharyngeal carcinoma (R/M NPC).

6026 Background: The transformed growth factor beta (TGF-β) signaling pathway is dysregulated in carcinogenesis. In NPC patients, upregulation of TGF-β pathway is correlated with disease stage or phenotype due to Epstein-Barr virus (EBV) infection. GFH018, a novel TGF-βRI inhibitor, can inhibit tumor growth through inhibiting the activity of TGF-βRI kinase to block the signal transduction of TGF-β and modulate the tumor immune microenvironment. Preclinical studies showed that GFH018 in combination with PD-1/PD-L1 monoclonal antibody can significantly inhibit tumor growth synergistically. Here we report the preliminary results of combining GFH018 and Toripalimab treating R/M NPC patients (pts). Methods: This is a phase Ib/II study to evaluate the safety and efficacy of the combination of GFH018 and Toripalimab in pts with advanced solid tumors. Patients with RM NPC were enrolled to receive GFH018 80mg twice a day (BID) 14-day-on/14-day-off in combination with Toripalimab 3mg/kg every two weeks. Tumor assessment was performed every 8 weeks per Response Evaluation Criteria in Solid Tumor (RECIST) 1.1. Results: As of 31 Dec 2022, 32 pts with R/M NPC who had progressed on at least one prior line therapy were enrolled. Sixteen (50%) had received ≥3 lines of prior therapies, and 19 (59.4%) had previously received immune checkpoint inhibitors (ICIs) and platinum-based chemotherapies. The median duration of study drug exposure was 7 weeks. Twenty-five pts (78.1%) experienced treatment-related adverse events (TRAEs) of any grades, and 11 pts (34.4%) had ≥ Grade 3. The most common TRAEs (occurring in ≥ 3 pts) were anaemia (n = 6, 18.8%), hyponatraemia (n = 6, 18.8%), rash (n = 6, 18.8%), fatigue (n = 4, 12.5%), white blood cell count decreased (n = 4, 12.5%), aspartate aminotransferase increased (n = 3, 9.4%), back pain (n = 3, 9.4%), decreased appetite (n = 3, 9.4%), hypokalaemia (n = 3, 9.4%), and hypothyroidism (n = 3, 9.4%). As of 18 Jan 2023, among the 27 pts with post-baseline tumor assessments, 8 achieved partial response (PR), and 5 stable disease (SD); the overall response rate (ORR) was 29.6%, and disease control rate (DCR) was 48.1%. Six PR and 2 SD were observed among the 12 pts without prior treatment of ICIs; the ORR was 50%, and DCR was 66.7%. Four pts discontinued treatment without any post-baseline tumor assessments due to AEs or withdrawal of consent, and 1 patient is premature for tumor assessment. Conclusions: GFH018 combined Toripalimab was well tolerated and demonstrated preliminary efficacy in pts with R/M NPC. Specifically, in pts who had not previously received ICIs, promising antitumor activity was observed supporting further investigation to this group of pts. Clinical trial information: NCT04914286 .

Inhibition of TGF-β type I receptor by SB505124 down-regulates osteoblast differentiation and mineralization of human mesenchymal stem cells.

Numerous signaling pathways are well-known in osteoblastic differentiation of human bone marrow mesenchymal stem cells (hBMSCs), including transforming growth factor-beta (TGF-β) signaling pathway, which sends signals through specific type I and II serine/threonine kinase receptors. However, the key role of TGF-β signaling during bone formation and remodeling is yet to be studied. A TGF-β type I receptor inhibitor, SB505124, discovered through a screening of a small molecule library for their effect of osteoblast differentiation of hBMSCs. Alkaline phosphatase quantification and staining were tested as indicators of osteoblastic differentiation and Alizarin red staining was tested as an indicator of in vitro mineralization. Changes in gene expressions were assessed using qRT-PCR. SB505124 showed significant inhibition of the osteoblast differentiation of hBMSCs, as confirmed by reduced alkaline phosphatase, in vitro mineralization, and downregulation of osteoblast-associated gene expression. To further understand the molecular mechanisms involved in the inhibition of the TGF-β type I receptor, we assessed the effects on signature genes of several signaling pathways identified in the osteoblast differentiation of hBMSCs. SB505124 downregulated gene expression of many genes linked to osteoblast-related signaling pathways including TGF-β, insulin, focal adhesion, Notch, Vitamin D, interleukin (IL)-6, osteoblast signaling, and cytokines and inflammatory. We report TGF-β type I receptor inhibitor (SB505124) is a potent inhibitor of osteoblastic differentiation of hBMSCs that could be a valuable innovative therapeutic tool to cure bone disorders with increased bone formation, besides its potential use to treat patients with cancer and fibrosis.

Identification and validation of key genes associated with atrial fibrillation in the elderly.

Atrial fibrillation (AF) is the most common cardiac arrhythmia and significantly increases the risk of stroke and heart failure (HF), contributing to a higher mortality rate. Increasing age is a major risk factor for AF; however, the mechanisms of how aging contributes to the occurrence and progression of AF remain unclear. This study conducted weighted gene co-expression network analysis (WGCNA) to identify key modules and hub genes and determine their potential associations with aging-related AF. WGCNA was performed using the AF dataset GSE2240 obtained from the Gene Expression Omnibus, which contained data from atrial myocardium in cardiac patients with permanent AF or sinus rhythm (SR). Hub genes were identified in clinical samples. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were also performed. Green and pink were the most critical modules associated with AF, from which nine hub genes, PTGDS, COLQ, ASTN2, VASH1, RCAN1, AMIGO2, RBP1, MFAP4, and ALDH1A1, were hypothesized to play key roles in the AF pathophysiology in elderly and seven of them have high diagnostic value. Functional enrichment analysis demonstrated that the green module was associated with the calcium, cyclic adenosine monophosphate (cAMP), and peroxisome proliferator-activated receptors (PPAR) signaling pathways, and the pink module may be associated with the transforming growth factor beta (TGF-β) signaling pathway in myocardial fibrosis. We identified nine genes that may play crucial roles in the pathophysiological mechanism of aging-related AF, among which six genes were associated with AF for the first time. This study provided novel insights into the impact of aging on the occurrence and progression of AF, and identified biomarkers and potential therapeutic targets for AF.

Abstract P2-11-18: Serum methylmalonic acid concentrations at breast cancer diagnosis are not associated with distant metastases

Abstract Introduction: Methylmalonic acid (MMA), a metabolite and by-product of propionate metabolism, promotes breast cancer (BC) progression in mice via the transforming growth factor-beta (TGFβ) signaling pathway (Gomes et al, Nature 2020). It is currently unknown if this effect also exists in patients with BC. Objectives: To investigate the association between baseline serum MMA concentrations in patients at BC diagnosis and development of distant metastases via a matched case-control study. Methods: We included 32 patients with early Luminal B-like BC (Lumb, median age 62.4y) and 52 patients with early triple-negative BC (TNBC, median age 50.5y) who developed distant metastases within 5 years. They were matched to an equal number of early BC patients with at least 5 years of follow-up (median age 62.2y for Lumb and 50.5y for TNBC) who did not develop distant metastases with at least 5 years of follow-up. Matching was performed based on age at diagnosis date (± 5y), tumor stage, and treatment received ((neo)adjuvant chemotherapy and radiotherapy, yes/no). Serum MMA concentrations were determined by liquid chromatography with tandem mass spectrometry (LC-MS-MS). Summary statistics, paired analyses, and multiple conditional logistic regression analyses were performed with and without adjusting for potential covariates (age, kidney function, and tumor stage). Results: Baseline serum MMA at BC diagnosis significantly correlated with age (rs=0.35, p=.005 in Lumb; rs=0.35, p=.0003 in TNBC), and negatively correlated with kidney function assessed by estimated glomerular filtration rate (eGFR, rs= -0.42, p=.0005 in Lumb; rs= -0.32, p=.0009 in TNBC). MMA concentrations at diagnosis were not associated with distant metastases in either subtype, after adjusting for kidney function, age, and tumor stage (all p>.05). Next, we categorized BC cases in the public TCGA (n=174 for Lumb; n=140 for TNBC), METABRIC (n=461 for Lumb; n=199 for TNBC), and GSE25066 (n=78 for Lumb; n=182 for TNBC) database according to their 5-year metastatic status, and analyzed the TGFβ signaling pathway activity of primary BC. Like MMA concentrations, a gene expression signature of TGFβ signaling was not associated with distant metastases in patients with BC. Conclusion: Baseline serum MMA concentrations and a gene signature for TGFβ signaling at BC diagnosis are not associated with distant metastases among patients with Lumb and TNBC subtypes. Citation Format: Qi Wu, Sigrid Hatse, Juan F. García, Patricia Altea-Manzano, Jaak Billen, Mélanie Planque, Anke Vandekeere, Yentl Lambrechts, François Richard, Annouschka Laenen, Kevin Punie, Patrick Neven, Ines Nevelsteen, Giuseppe Floris, Christine Desmedt, Ana Gomes, Sarah-Maria Fendt, Hans Wildiers. Serum methylmalonic acid concentrations at breast cancer diagnosis are not associated with distant metastases [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P2-11-18.

Sex-Inclined Piwi-Interacting RNAs in Serum Exosomes for Sex Determination in the Greater Amberjack (Seriola dumerili).

The greater amberjack (Seriola dumerili) is a gonochoristic fish with no sexual dimorphism in appearance, making sex identification difficult. Piwi-interacting RNAs (piRNAs) function in transposon silencing and gametogenesis and are involved in various physiological processes, including sex development and differentiation. Exosomal piRNAs can be indicators for the determination of sex and physiological status. In this study, four piRNAs were differentially expressed in both serum exosomes and gonads between male and female greater amberjack. Three piRNAs (piR-dre-32793, piR-dre-5797, and piR-dre-73318) were significantly up-regulated and piR-dre-332 was significantly down-regulated in serum exosomes and gonads of male fish, compared to female fish, consistent with the serum exosomal results. According to the relative expression of four marker piRNAs derived from the serum exosomes of greater amberjack, the highest relative expression of piR-dre-32793, piR-dre-5797, and piR-dre-73318 in seven female fish and that of piR-dre-332 in seven male fish can be used as the standard for sex determination. The method of sex identification can ascertain the sex of greater amberjack by blood collection from the living body, without sacrificing fish. The four piRNAs did not show sex-inclined expression in the hypothalamus, pituitary, heart, liver, intestine, and muscle tissue. A piRNA-target interaction network involving 32 piRNA-mRNA pairs was generated. Sex-related target genes were enriched in sex-related pathways, including oocyte meiosis, transforming growth factor-beta signaling pathway, progesterone-mediated oocyte maturation, and gonadotropin releasing hormone signaling pathway. These results provide a basis for sex determination in greater amberjack and improve our understanding of the mechanisms underlying sex development and differentiation in the species.

Endoplasmic reticulum stress promotes endometrial fibrosis through the TGF-β/SMAD pathway.

Intrauterine adhesion (IUA) is one of the main causes of female infertility. This study reveals that endoplasmic reticulum stress activation upregulates the TGF-β/SMAD pathway to induce epithelial-mesenchymal transition and promote endometrial fibrosis in an IUA model. IUA is a common gynecological disease and is a leading cause of female infertility. Mechanical or infectious damage to the endometrial basal layer can lead to endometrial fibrosis, which is the most common cause of IUA. Endoplasmic reticulum stress (ERS), the transforming growth factor beta signaling pathway (TGF-β/SMAD) and epithelial-mesenchymal transition (EMT) are important factors promoting endometrial fibrosis. The purpose of this study was to determine the up- and downstream regulatory relationships of the above three in the process of endometrial fibrosis. The rat IUA model was induced by double injury method and prophylactic injection of the ERS inhibitor 4-phenylbutyric acid (4-PBA) was given in vivo. The ERS activator tunicamycin and the TGF-β/SMAD pathway inhibitor A 83-01 were used in human endometrial epithelial cells (HEECs) in vitro. Masson's trichrome, Sirius red staining, immunohistochemistry, immunofluorescence and Western blot analyses were used to determine ERS, TGF-β/SMAD pathway, EMT and fibrosis markers in the uterine tissue and HEECs of the different treatment groups. In animal experiments, ERS and the TGF-β/SMAD pathway had been activated and EMT occurred in an in vivo model of IUA but was suppressed in animals treated with prophylactic 4-PBA. In in vitro experiments, tunicamycin-treated HEECs had increased the activation of ERS, the abundance of TGF-β/SMAD pathway and fibrosis markers while EMT occurred, but the TGF-β/SMAD pathway and EMT were significantly inhibited in the tunicamycin+A 83-01 group. Our data suggest that increased ERS can induce EMT and promote endometrial fibrosis through the TGF-β/SMAD pathway.

Targeting the Transforming Growth Factor-beta Signaling Pathway in the Treatment of Gynecologic Cancer.

The transforming growth factor-beta (TGF-β) signaling pathway has been reported to be dysregulated in the pathogenesis of several malignancies, including gynecologic cancers. This provides proof of concept of its potential value as a therapeutic target and prognostic biomarker in cervical cancer. Here we provide an overview of the biological role and clinical impact of TGF-β inhibitors either as a single agent or as a combinatorial therapy in gynecological cancers, concentrating on phase I to phase II/III clinical trials. Aberrant TGF-β signaling may lead to carcinogenesis. Inhibition of TGF-β represents an interesting area of focus for the treatment of gynecological cancer. Several TGF-β inhibitors are potential anticancer agents and are undergoing clinical trials in cancer, including galunisertib, dalantercept, and vigil. There is a growing body of data showing the potential therapeutic impact of targeting the TGF-β pathway in different cancer types, although further studies are still warranted to explore the value of this strategy and finding the most appropriate patients who could most benefit from therapy.

Silencing of TMED5 inhibits proliferation, migration and invasion, and enhances apoptosis of hepatocellular carcinoma cells.

Transmembrane P24 trafficking protein 5 (TMED5) is highly expressed in cervical and bladder cancer cell lines. Moreover, TMED5 promotes nuclear autophagy and the malignant behavior of cervical cancer cells. However, the role of TMED5 in hepatocellular carcinoma (HCC) has not been extensively reported. To investigate the role of TMED5 in HCC cells. Bioinformatics was used to analyze the messenger-ribonucleic acid (mRNA) expression of TMED5 in HCC and its relationship with overall survival and disease-free interval of HCC patients. After TMED5 was decreased in SMMC-7721 and Hep3B cells, they were assayed for proliferation, cell cycle, apoptosis, migration, and invasion. The expression of TMED5 mRNA in HCC tissues was higher than in adjacent normal tissues, and the overall survival of HCC patients with high TMED5 transcription levels was worse. Moreover, the overexpression of TMED5 was associated with HCC progression. The downregulation of TMED5 suppressed cell proliferation, migration and invasion, and enhanced apoptosis. Therefore, TMED5 may be involved in the regulation of the cell cycle, the mammalian target of rapamycin signaling pathway, and the transforming growth factor beta (TGF-β) signaling pathway. The TMED5 has the potential to promote HCC progression. Therefore, lowering TMED5 levels could represent a potential strategy for the treatment of HCC.

KRAS mutation-induced EndMT of brain arteriovenous malformation is mediated through the TGF-β/BMP-SMAD4 pathway

ObjectiveSomatic KRAS mutations have been identified in the majority of brain arteriovenous malformations (bAVMs), and subsequent in vivo experiments have confirmed that KRAS mutation in endothelial cells (ECs) causes AVMs...

A micropeptide JunBP regulated by TGF-β promotes hepatocellular carcinoma metastasis

Transforming growth factor beta (TGF-β) signaling pathway plays important roles in hepatocellular carcinoma (HCC) progression. Long intergenic non-protein coding RNAs (lincRNAs) are important components of TGF-β signaling pathway and perform their functions through different mechanisms. Here, we found that LINC02551 was activated by TGF-β transcriptionally and identified a 174-amino-acid peptide, Jun binding micropeptide (JunBP), encoded by LINC02551 in HCC tissues and HCC cell lines. Functional study showed that JunBP promotes HCC metastasis through binding to c-Jun and subsequent promotion of its phosphorylated activation. Activated c-Jun has higher binding affinity to SMAD3, which in turn leads to more SMAD3 recruited to the promoter region of LINC02551. We find a positive feedback among them, and this mechanism provides a novel potential prognostic biomarker and therapeutic target in HCC.

Transforming growth factor beta (TGFβ) pathway is essential for hypoblast and epiblast development in ovine post-hatching embryos

The developmental failures occurring between blastocyst hatching and implantation in farm ungulates are a major cause of pregnancy losses. At the expanded blastocyst stage, three cell lineages emerge in the embryo: trophoblast, hypoblast and epiblast, the latter being the most vulnerable during post-hatching development. Transforming growth factor beta (TGFβ) signaling pathway is involved in hypoblast and epiblast development; however, previous in vitro functional studies are limited to the expanded blastocyst stage. In this study, we have analyzed the effect of TGFβ inhibition with 10, 20 or 40 μM SB431542 during ovine post-hatching developmental period using a recently developed culture system able to recapitulate major developmental landmarks. We have found a negative effect of TGFβ inhibition on hypoblast and epiblast development that could be partially reverted by Rho-associated protein kinase (ROCK) inhibitor Y-27632. Our findings provide new insights into the molecular networks regulating embryo development beyond the expanded blastocyst and could help to elucidate the causes of early pregnancy losses in farm ungulates.

OR22-3 Uterine TGFβ Signaling Controls Endometrial Cell Homeostasis And Regeneration

Abstract The transforming growth factor beta (TGFβ) signaling pathway has critical roles in the transduction of paracrine and autocrine signals that control development, reproduction, and cancer. To study the tissue-specific contribution of TGFβ signaling in the endometrium, we developed mice with conditional deletion SMAD2 and SMAD3 in the endometrial epithelium (using Lactoferrin-cre, "Ltf-cre"). We identified that double conditional deletion of SMAD2 and SMAD3 in the endometrial epithelium resulted in endometrial hyperplasia by 12-weeks of age, with myometrial invasion, metastasis, and death by 6-9-months of age. Smad2/3-Ltf-cre mice also lost epithelial progesterone receptor expression in the endometrium by 12 weeks of age. To study the signaling mechanism that controlled the malignant transformation of the glandular epithelium in Smad2/3-Ltf-cre mice, we developed 3-dimensional (3D) endometrial organoid cultures from the uterine epithelial tissues of control and mutant mice. To test how suppression of TGFβ signaling affected endometrial regeneration, 3D endometrial organoids from WT or Smad2/3-Ltf-cre mice were grown in the presence or absence of the TGFβ receptor inhibitor, A83-01. Using these conditions, we identified that WT endometrial organoids cultured with the SB505124 inhibitor or from Smad2/3-Ltf-cre mice, developed abnormal morphology. Histological analysis of the endometrial organoids showed that organoids cultured with A83-01 or from Smad2/3-Ltf-cre mice, developed increased secretory-like cells with increased mucin-1 expression. RNA-sequencing of the endometrial organoids revealed that a large number of differentially expressed genes were conserved between the WT organoids cultured with A83-01 and those from Smad2/3-Ltf-cre mice. Gene ontology analysis of the differentially expressed genes indicated that pharmacological or genetic inhibition of TGFβ signaling, resulted in over-representation of gene families related to BMP/SMAD1/5 signaling and retinoic acid signaling, with decreased enrichment of WNT/β-catenin signaling. These studies indicate that TGFβ-mediated signals are critical to endometrial function and that perturbation of this balance results in endometrial cancer. Funding support NICHD grants R00-HD096057 (to DM) and R01-HD032067 (to MMM), and grants NGP10125 and 1016187 from the Burroughs Wellcome Fund (to DM). Presentation: Monday, June 13, 2022 11:30 a.m. - 11:45 a.m.

233 (PB-057) Poster - Serum methylmalonic acid concentrations at breast cancer diagnosis are not associated with distant metastases

Background: Methylmalonic acid (MMA), a metabolite and by-product of propionate metabolism, promotes breast cancer (BC) progression in mice via the transforming growth factor beta (TGFβ) signaling pathway (Gomes et al, Nature 2020). It is currently unknown if this effect also exists in patients with BC. This study is to investigate the association between baseline serum MMA concentrations in patients at BC diagnosis and the development of distant metastases via a matched case-control study.

Importance of TGFβ in Cancer and Nematode Infection and Their Interaction-Opinion.

Historically, there has been little interaction between parasitologists and oncologists, although some helminth infections predispose to the development of tumours. In addition, both parasites and tumours need to survive immune attack. Recent research suggests that both tumours and parasites suppress the immune response to increase their chances of survival. They both co-opt the transforming growth factor beta (TGFβ) signalling pathway to modulate the immune response to their benefit. In particular, there is concern that suppression of the immune response by nematodes and their products could enhance susceptibility to tumours in both natural and artificial infections.

RNA-seq reveals the role of miR-199a-3p in regulating inflammation of bovine mammary epithelial cells

MicroRNAs (miRNAs) are involved in the regulation of a variety of biological processes. However, the research on the regulatory role of bovine mammary epithelial cells (bMECs) is scarce. To date, there are no reports about the role of miR-199a-3p in bMECs. In this study, RNA sequencing (RNA-seq) technology was used to detect the transcriptomes of the miR-199a-3p overexpression and negative control (NC) groups of bMECs. Then, the screening and functional annotation of differentially expressed genes (DEGs) were conducted. The results showed that there were 140 DEGs (109 up-regulated and 31 down-regulated) in the miR-199a-3p overexpression group. The results of Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses indicated that the DEGs might regulate the immune and inflammatory responses via the phosphatidylinositol 3-kinase (PI3K)/AKT signaling pathway, transforming growth factor-beta (TGF-β) signaling pathway, and interleukin-17 (IL-17) signaling pathway, which revealed that miR-199a-3p might participate in regulating bMECs inflammation via affecting the expression of related genes and the above signaling pathways. This study may provide a new reference for potential therapeutic targets of cow mastitis.

MED1 Regulates BMP/TGF-β in Endothelium: Implication for Pulmonary Hypertension.

Dysregulated BMP (bone morphogenetic protein) or TGF-β (transforming growth factor beta) signaling pathways are imperative in idiopathic and familial pulmonary arterial hypertension (PAH) as well as experimental pulmonary hypertension (PH) in rodent models. MED1 (mediator complex subunit 1) is a key transcriptional co-activator and KLF4 (Krüppel-like factor 4) is a master transcription factor in endothelium. However, MED1 and KLF4 epigenetic and transcriptional regulations of the BMP/TGF-β axes in pulmonary endothelium and their dysregulations leading to PAH remain elusive. We investigate the MED1/KLF4 co-regulation of the BMP/TGF-β axes in endothelium by studying the epigenetic regulation of BMPR2 (BMP receptor type II), ETS-related gene (ERG), and TGFBR2 (TGF-β receptor 2) and their involvement in the PH. High-throughput screening involving data from RNA-seq, MED1 ChIP-seq, H3K27ac ChIP-seq, ATAC-seq, and high-throughput chromosome conformation capture together with in silico computations were used to explore the epigenetic and transcriptional regulation of BMPR2, ERG, and TGFBR2 by MED1 and KLF4. In vitro experiments with cultured pulmonary arterial endothelial cells (ECs) and bulk assays were used to validate results from these in silico analyses. Lung tissue from patients with idiopathic PAH, animals with experimental PH, and mice with endothelial ablation of MED1 (EC-MED1-/-) were used to study the PH-protective effect of MED1. Levels of MED1 were decreased in lung tissue or pulmonary arterial endothelial cells from idiopathic PAH patients and rodent PH models. Mechanistically, MED1 acted synergistically with KLF4 to transactivate BMPR2, ERG, and TGFBR2 via chromatin remodeling and enhancer-promoter interactions. EC-MED1-/- mice showed PH susceptibility. In contrast, MED1 overexpression mitigated the PH phenotype in rodents. A homeostatic regulation of BMPR2, ERG, and TGFBR2 in ECs by MED1 synergistic with KLF4 is essential for the normal function of the pulmonary endothelium. Dysregulation of MED1 and the resulting impairment of the BMP/TGF-β signaling is implicated in the disease progression of PAH in humans and PH in rodent models.

The role of zinc finger E-box-binding homeoboxin the prognosis of Glioblastoma: A review

Glioblastoma is one of the most malignant brain tumors that have a low survival rate compared to other cancers. The hallmark of tumor metastasis is controlled by a process called epithelial-mesenchymal transition (EMT). The EMT can also be affected by a protein called Zinc finger E-box-binding homeobox 1 encoded by the ZEB1 gene. Studies have found that this gene is expressed by the primary glioblastomas. This gene is localized in the invasion front of the tumor which also has fewer N-cadherin expression, another protein associated with the EMT process. The lower the N-cadherin expression, the less cell-cell connections and the greater the cell mobility, which means increased invasiveness. Therefore, redistributing the N-cadherin expression, such as by using the ROBO1, is a promising way to control the glioblastoma invasion. Coincidentally, the ROBO1 expression can be controlled by the expression of the ZEB1 gene. There is also a paralog of the ZEB1 gene, namely the ZEB2 gene which plays a role in Transforming growth factor beta (TGF-β) signaling pathways, which is positively correlated with aggressiveness of the cancers. In fact, studies have found that higher expression of the ZEB2 gene is correlated with lower survival rate of glioblastoma patients.