scholarly journals Transforming Growth Factor-β Activated Kinase 1 (Tak1) Is Activated in Hepatocellular Carcinoma, Mediates Tumor Progression, and Predicts Unfavorable Outcome

Cancers ◽  
2022 ◽  
Vol 14 (2) ◽  
pp. 430
Author(s):  
Dirk Andreas Ridder ◽  
Lana Louisa Urbansky ◽  
Hagen Roland Witzel ◽  
Mario Schindeldecker ◽  
Arndt Weinmann ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Molecular Mechanisms ◽  
Transforming Growth Factor ◽  
Cox Regression ◽  
Distant Metastases ◽  
Transforming Growth Factor Β ◽  
Cell Nuclei ◽  
Tumor Cell Migration ◽  
Independent Prognostic Marker ◽  
Huh7 Cells

Although knowledge on inflammatory signaling pathways driving cancer initiation and progression has been increasing, molecular mechanisms in hepatocarcinogenesis are still far from being completely understood. Hepatocyte-specific deletion of the MAPKKK Tak1 in mice recapitulates important steps of hepatocellular carcinoma (HCC) development, including the occurrence of cell death, steatohepatitis, dysplastic nodules, and HCCs. However, overactivation of Tak1 in mice upon deletion of its deubiquitinase Cyld also results in steatohepatitis and HCC development. To investigate Tak1 and Cyld in human HCCs, we created a tissue microarray to analyze their expression by immunohistochemistry in a large and well-characterized cohort of 871 HCCs of 561 patients. In the human liver and HCC, Tak1 is predominantly present as its isoform Tak1A and predominantly localizes to cell nuclei. Tak1 is upregulated in diethylnitrosamine-induced mouse HCCs as well as in human HCCs independent of etiology and is further induced in distant metastases. A high nuclear Tak1 expression is associated with short survival and vascular invasion. When we overexpressed Tak1A in Huh7 cells, we observed increased tumor cell migration, whereas overexpression of full-length Tak1 had no significant effect. A combined score of low Cyld and high Tak1 expression was an independent prognostic marker in a multivariate Cox regression model.

scholarly journals Key Enzymes in Pyrimidine Synthesis, CAD and CPS1, Predict Prognosis in Hepatocellular Carcinoma

Cancers ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 744
Author(s):  
Dirk Andreas Ridder ◽  
Mario Schindeldecker ◽  
Arndt Weinmann ◽  
Kristina Berndt ◽  
Lana Urbansky ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Overall Survival ◽  
Cox Regression ◽  
Distant Metastases ◽  
Carbamoyl Phosphate Synthetase ◽  
Carbamoyl Phosphate ◽  
Independent Prognostic Marker ◽  
Pyrimidine Synthesis ◽  
Short Overall Survival

Patients with hepatocellular carcinoma (HCC) have a highly variable clinical course. Therefore, there is an urgent need to identify new prognostic markers to determine prognosis and select specific therapies. Recently, it has been demonstrated that dysregulation of the urea cycle (UC) is a common phenomenon in multiple types of cancer. Upon UC dysregulation, nitrogen is diverted toward the multifunctional enzyme carbamoyl-phosphate synthetase 2, aspartate transcarbamoylase, and dihydroorotase (CAD), and increases pyrimidine synthesis. In this study, we investigated the role of CAD and carbamoyl-phosphate synthetase 1 (CPS1), a rate-limiting enzyme of the UC highly expressed in hepatocytes, in HCC. We created a tissue microarray to analyze expression of both enzymes by immunohistochemistry in a large and well-characterized overall cohort of 871 HCCs of 561 patients that underwent surgery. CAD was induced in recurrent HCCs, and high expression predicted shorter overall survival. CPS1 was downregulated in HCC and further reduced in recurrent tumors and distant metastases. Additionally, low CPS1 was associated with short overall survival. A combined score of both enzymes was an independent prognostic marker in a multivariate Cox regression model (HR = 1.37, 95% confidence interval 1.06–1.75, p = 0.014). Inhibition of pyrimidine synthesis may represent a novel therapeutic strategy for HCC.

scholarly journals Molecular mechanisms of circular RNAs, transforming growth factor‐ β , and long noncoding RNAs in hepatocellular carcinoma

2019 ◽  
Vol 8 (15) ◽  
pp. 6684-6699 ◽  
Author(s):  
Wenkang Shang ◽  
Gabriel Komla Adzika ◽  
Yujie Li ◽  
Qike Huang ◽  
Ningding Ding ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Growth Factor ◽  
Molecular Mechanisms ◽  
Transforming Growth Factor ◽  
Noncoding Rnas ◽  
Transforming Growth Factor Β ◽  
Long Noncoding Rnas ◽  
Circular Rnas

scholarly journals Role of Endoglin (CD105) in the Progression of Hepatocellular Carcinoma and Anti-Angiogenic Therapy

2018 ◽  
Vol 19 (12) ◽  
pp. 3887 ◽  
Author(s):  
Aldona Kasprzak ◽  
Agnieszka Adamek
Keyword(s):  
Hepatocellular Carcinoma ◽  
Molecular Mechanisms ◽  
Transforming Growth Factor ◽  
Primary Liver Cancer ◽  
Venous Blood ◽  
Transforming Growth Factor Β ◽  
Current Data ◽  
Solid Tumours ◽  
Angiogenic Therapy

The liver is perfused by both arterial and venous blood, with a resulting abnormal microenvironment selecting for more-aggressive malignancies. Hepatocellular carcinoma (HCC) is the most frequent primary liver cancer, the sixth most common cancer globally, and the third leading cause of cancer-related mortality worldwide. HCC is characterized by its hypervascularization. Improving the efficiency of anti-angiogenic treatment and mitigation of anti-angiogenic drug resistance are the top priorities in the development of non-surgical HCC therapies. Endoglin (CD105), a transmembrane glycoprotein, is one of the transforming growth factor β (TGF-β) co-receptors. Involvement of that protein in angiogenesis of solid tumours is well documented. Endoglin is a marker of activated endothelial cells (ECs), and is preferentially expressed in the angiogenic endothelium of solid tumours, including HCC. HCC is associated with changes in CD105-positive ECs within and around the tumour. The large spectrum of endoglin effects in the liver is cell-type- and HCC- stage-specific. High expression of endoglin in non-tumour tissue suggests that this microenvironment might play an especially important role in the progression of HCC. Evaluation of tissue expression, as well as serum concentrations of this glycoprotein in HCC, tends to confirm its role as an important biomarker in HCC diagnosis and prognosis. The role of endoglin in liver fibrosis and HCC progression also makes it an attractive therapeutic target. Despite these facts, the exact molecular mechanisms of endoglin functioning in hepatocarcinogenesis are still poorly understood. This review summarizes the current data concerning the role and signalling pathways of endoglin in hepatocellular carcinoma development and progression, and provides an overview of the strategies available for a specific targeting of CD105 in anti-angiogenic therapy in HCC.

scholarly journals Expression and function of Smad7 in autoimmune and inflammatory diseases

2021 ◽  
Author(s):  
Yiping Hu ◽  
Juan He ◽  
Lianhua He ◽  
Bihua Xu ◽  
Qingwen Wang
Keyword(s):  
Posttranscriptional Regulation ◽  
Molecular Mechanisms ◽  
Transforming Growth Factor ◽  
Inflammatory Diseases ◽  
Kidney Diseases ◽  
Critical Role ◽  
Transforming Growth Factor Β ◽  
Negative Regulator ◽  
Signaling Mechanism ◽  
And Function

AbstractTransforming growth factor-β (TGF-β) plays a critical role in the pathological processes of various diseases. However, the signaling mechanism of TGF-β in the pathological response remains largely unclear. In this review, we discuss advances in research of Smad7, a member of the I-Smads family and a negative regulator of TGF-β signaling, and mainly review the expression and its function in diseases. Smad7 inhibits the activation of the NF-κB and TGF-β signaling pathways and plays a pivotal role in the prevention and treatment of various diseases. Specifically, Smad7 can not only attenuate growth inhibition, fibrosis, apoptosis, inflammation, and inflammatory T cell differentiation, but also promotes epithelial cells migration or disease development. In this review, we aim to summarize the various biological functions of Smad7 in autoimmune diseases, inflammatory diseases, cancers, and kidney diseases, focusing on the molecular mechanisms of the transcriptional and posttranscriptional regulation of Smad7.

scholarly journals The Potential Association between the Risk of Post-Surgical Adhesion and the Activated Local Angiotensin II Type 1 Receptors: Need for Novel Treatment Strategies

2021 ◽  
pp. 1-8
Author(s):  
Mahmood Tavakkoli ◽  
Saeed Aali ◽  
Borzoo Khaledifar ◽  
Gordon A. Ferns ◽  
Majid Khazaei ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Molecular Mechanisms ◽  
Transforming Growth Factor ◽  
Therapeutic Potential ◽  
Angiotensin Receptor Blockers ◽  
Surgical Techniques ◽  
Treatment Strategies ◽  
Transforming Growth Factor Β

<b><i>Background:</i></b> Post-surgical adhesion bands (PSABs) are a common complication after abdominal or pelvic surgeries for different reasons like cancer treatment. Despite improvements in surgical techniques and the administration of drugs or the use of physical barriers, there has only been limited improvement in the frequency of postoperative adhesions. Complications of PSAB are pain, infertility, intestinal obstruction, and increased mortality. The most important molecular mechanisms for the development of PSAB are inflammatory response, oxidative stress, and overexpression of pro-fibrotic molecules such as transforming growth factor β. However, questions remain about the pathogenesis of this problem, for example, the causes for individual differences or why certain tissue sites are more prone to post-surgical adhesions. <b><i>Summary:</i></b> Addressing the pathological causes of PSAB, the potential role of local angiotensin II/angiotensin II type 1 receptors (AngII/AT1R), may help to prevent this problem. <b><i>Key Message:</i></b> The objective of this article was to explore the role of the AngII/AT1R axis potential to induce PSAB and the therapeutic potential of angiotensin receptor blockers in the prevention and treatment of PSAB.

scholarly journals The Role of Endoglin in Hepatocellular Carcinoma

2021 ◽  
Vol 22 (6) ◽  
pp. 3208
Author(s):  
Kuo-Shyang Jeng ◽  
I-Shyan Sheen ◽  
Shu-Sheng Lin ◽  
Chuen-Miin Leu ◽  
Chiung-Fang Chang
Keyword(s):  
Hepatocellular Carcinoma ◽  
Liver Diseases ◽  
Transforming Growth Factor ◽  
Antiangiogenic Therapy ◽  
Transforming Growth Factor Β ◽  
Postoperative Recurrence ◽  
Transmembrane Glycoprotein ◽  
Early Progression

Endoglin (CD105) is a type-1 integral transmembrane glycoprotein and coreceptor for transforming growth factor-β (TGF-β) ligands. The endoglin/TGF-β signaling pathway regulates hemostasis, cell proliferation/migration, extracellular matrix (ECM) synthesis and angiogenesis. Angiogenesis contributes to early progression, invasion, postoperative recurrence, and metastasis in hepatocellular carcinoma (HCC), one of the most widespread malignancies globally. Endoglin is overexpressed in newly formed HCC microvessels. It increases microvessel density in cirrhotic and regenerative HCC nodules. In addition, circulating endoglin is present in HCC patients, suggesting potential for use as a diagnostic or prognostic factor. HCC angiogenesis is dynamic and endoglin expression varies by stage. TRC105 (carotuximab) is an antibody against endoglin, and three of its clinical trials were related to liver diseases. A partial response was achieved when combining TRC105 with sorafenib. Although antiangiogenic therapy still carries some risks, combination therapy with endoglin inhibitors or other targeted therapies holds promise.

scholarly journals The Molecular Mechanism of Epithelial–Mesenchymal Transition for Breast Carcinogenesis

Biomolecules ◽  
2019 ◽  
Vol 9 (9) ◽  
pp. 476 ◽  
Author(s):  
Chia-Jung Li ◽  
Pei-Yi Chu ◽  
Giou-Teng Yiang ◽  
Meng-Yu Wu
Keyword(s):  
Epithelial Cells ◽  
Tumor Progression ◽  
Signaling Pathways ◽  
Intracellular Signaling ◽  
Molecular Mechanisms ◽  
Transforming Growth Factor ◽  
Epithelial Mesenchymal Transition ◽  
Transforming Growth Factor Β ◽  
Inhibition Of Proliferation ◽  
Mesenchymal Transition

The transforming growth factor-β (TGF-β) signaling pathway plays multiple regulatory roles in the tumorigenesis and development of cancer. TGF-β can inhibit the growth and proliferation of epithelial cells and induce apoptosis, thereby playing a role in inhibiting breast cancer. Therefore, the loss of response in epithelial cells that leads to the inhibition of cell proliferation due to TGF-β is a landmark event in tumorigenesis. As tumors progress, TGF-β can promote tumor cell invasion, metastasis, and drug resistance. At present, the above-mentioned role of TGF-β is related to the interaction of multiple signaling pathways in the cell, which can attenuate or abolish the inhibition of proliferation and apoptosis-promoting effects of TGF-β and enhance its promotion of tumor progression. This article focuses on the molecular mechanisms through which TGF-β interacts with multiple intracellular signaling pathways in tumor progression and the effects of these interactions on tumorigenesis.

scholarly journals Gene expression profiling of bovine endometrium during the oestrous cycle: detection of molecular pathways involved in functional changes

2005 ◽  
Vol 34 (3) ◽  
pp. 889-908 ◽  
Author(s):  
S Bauersachs ◽  
S E Ulbrich ◽  
K Gross ◽  
S E M Schmidt ◽  
H H D Meyer ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Transforming Growth Factor ◽  
Cdna Array ◽  
Transforming Growth Factor Β ◽  
Early Embryo ◽  
Oestrous Cycle ◽  
Cdna Libraries ◽  
Functional Changes ◽  
Retinoic Acid Signalling ◽  
Subtracted Cdna Libraries

The endometrium plays a central role among the reproductive tissues in the context of early embryo–maternal communication and pregnancy. It undergoes typical changes during the sexual/oestrous cycle, which are regulated by the ovarian hormones progesterone and oestrogen. To identify the underlying molecular mechanisms we have performed the first holistic screen of transcriptome changes in bovine intercaruncular endometrium at two stages of the cycle – end of day 0 (late oestrus, low progesterone) and day 12 (dioestrus, high progesterone). A combination of subtracted cDNA libraries and cDNA array hybridisation revealed 133 genes showing at least a 2-fold change of their mRNA abundance, 65 with higher levels at oestrus and 68 at dioestrus. Interestingly, genes were identified which showed differential expression between different uterine sections as well. The most prominent example was the UTMP (uterine milk protein) mRNA, which was markedly upregulated in the cranial part of the ipsilateral uterine horn at oestrus. A Gene Ontology classification of the genes with known function characterised the oestrus time by elevated expression of genes, for example related to cell adhesion, cell motility and extracellular matrix and the dioestrus time by higher expression of mRNAs encoding for a variety of enzymes and transport proteins, in particular ion channels. Searching in pathway databases and literature data-mining revealed physiological processes and signalling cascades, e.g. the transforming growth factor-β signalling pathway and retinoic acid signalling, which are potentially involved in the regulation of changes of the endometrium during the oestrous cycle.

Abstract 126: High Efficiency Reprogramming of Fibroblasts Into Cardiomyocytes Requires Suppression of Pro-fibrotic Signaling

2015 ◽  
Vol 117 (suppl_1) ◽  
Author(s):  
Kunhua Song ◽  
Yuanbiao Zhao ◽  
Pilar Londono ◽  
Emily Sharpe ◽  
Joshua R Clair ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
High Efficiency ◽  
Transforming Growth Factor ◽  
Cardiac Fibroblasts ◽  
Rho Kinase ◽  
Transforming Growth Factor Β ◽  
Direct Reprogramming ◽  
Cardiac Gene Expression ◽  
Cardiac Gene ◽  
Kinetics Of

The mammalian heart is composed of ~30% cardiomyocytes which have limited capacity to regenerate and ~70% non-cardiomyocytes including endothelial cells and cardiac fibroblasts. Direct reprogramming of fibroblasts into cardiomyocytes by forced expression of cardiomyogenic transcription factors, GMT (GATA4, Mef2C, Tbx5) or GHMT (GATA4, Hand2, Mef2C, Tbx5), has recently been demonstrated, suggesting a novel therapeutic strategy for cardiac repair. Despite extensive efforts, the efficiency of direct reprogramming of embryonic or adult fibroblasts into cardiomyocytes has yet to exceed 20%, or 0.1% respectively, leading many in the field to question the clinical translatability of this method. Here, we demonstrate that pro-fibrotic signaling events governed by transforming growth factor-β (TGF-β) and Rho kinase (ROCK) are concomitantly activated in GHMT-expressing fibroblasts, leading to potent suppression of cardiac reprogramming ( Figure 1 ). Remarkably, pharmacological inhibition of TGF-β, or ROCK leads to conversion of ≥ 60% of fibroblasts into highly functional cardiomyocytes, displaying global cardiac gene expression, spontaneous contractility, action potentials and calcium transients. Furthermore, inhibition of TGF-β, or ROCK dramatically enhances the kinetics of cardiac reprogramming, with spontaneously contracting cardiomyocytes emerging in less than two weeks, as opposed to 4 weeks with GHMT alone. These findings provide new insights into the molecular mechanisms underlying cardiac conversion of fibroblasts, and should enhance efforts to generate cardiomyocytes for clinical applications.

scholarly journals Identification of Hypoxia-Related Differentially Expressed Genes and Construction of the Clinical Prognostic Predictor in Hepatocellular Carcinoma by Bioinformatic Analysis

2021 ◽  
Vol 2021 ◽  
pp. 1-15
Author(s):  
Hao Guo ◽  
Jing Zhou ◽  
Yanjun Zhang ◽  
Zhi Wang ◽  
Likun Liu ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Regression Model ◽  
Molecular Mechanisms ◽  
Cox Regression ◽  
The Cancer Genome Atlas ◽  
Functional Enrichment ◽  
Differentially Expressed ◽  
Clinical Prognosis ◽  
Prognostic Predictor ◽  
Key Genes

Background. Hypoxia closely relates to malignant progression and appears to be prognostic for outcome in hepatocellular carcinoma (HCC). Our research is aimed at mining the hypoxic-related genes (HRGs) and constructing a prognostic predictor (PP) model on clinical prognosis in HCC patients. Methods. RNA-sequencing data about HRGs and clinical data of patients with HCC were obtained from The Cancer Genome Atlas (TCGA) database portal. Differentially expressed HRGs between HCC and para-carcinoma tissue samples were obtained by applying the Wilcox analysis in R statistical software. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes were used for gene functional enrichment analyses. Then, the patients who were asked to follow up for at least one month were enrolled in the following study. Cox proportional risk regression model was applied to obtain key HRGs which related to overall survival (OS) in HCC. PP was constructed and defined, and the accuracy of PP was validated by constructing the signature in a training set and validation set. Connectivity map (CMap) was used to find potential drugs, and gene set cancer analysis (GSCA) was also performed to explore the underlying molecular mechanisms. Results. Thirty-seven differentially expressed HRGs were obtained. It contained 28 upregulated and 9 downregulated genes. After the univariate Cox regression model analysis, we obtained 27 prognosis-related HRGs. Of these, 25 genes were risk factors for cancer, and 2 genes were protective factors. The PP was composed by 12 key genes (HDLBP, SAP30, PFKP, DPYSL4, SLC2A1, HMOX1, PGK1, ERO1A, LDHA, ENO2, SLC6A6, and TPI1). GSCA results showed the overall activity of these 12 key genes in 10 cancer-related pathways. Besides, CMap identified deferoxamine, crotamiton, talampicillin, and lycorine might have effects with HCC. Conclusions. This study firstly reported 12 prognostic HRGs and constructed the model of the PP. This comprehensive research of multiple databases helps us gain insight into the biological properties of HCC and provides deferoxamine, crotamiton, talampicillin, and lycorine as potential drugs to fight against HCC.

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