scholarly journals Hepatocyte-specific TAK1 deficiency drives RIPK1 kinase-dependent inflammation to promote liver fibrosis and hepatocellular carcinoma

2020 ◽  
Vol 117 (25) ◽  
pp. 14231-14242 ◽  
Author(s):  
Shuixia Tan ◽  
Jing Zhao ◽  
Ziyu Sun ◽  
Shuangyi Cao ◽  
Kongyan Niu ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Death ◽  
Liver Fibrosis ◽  
Therapeutic Strategy ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Genetic Inactivation ◽  
Downstream Effectors ◽  
Compensatory Proliferation ◽  
Specific Deletion

Transforming growth factor β-activated kinase1 (TAK1) encoded by the gene MAP3K7 regulates multiple important downstream effectors involved in immune response, cell death, and carcinogenesis. Hepatocyte-specific deletion of TAK1 inTak1ΔHEPmice promotes liver fibrosis and hepatocellular carcinoma (HCC) formation. Here, we report that genetic inactivation of RIPK1 kinase using a kinase dead knockin D138N mutation inTak1ΔHEPmice inhibits the expression of liver tumor biomarkers, liver fibrosis, and HCC formation. Inhibition of RIPK1, however, has no or minimum effect on hepatocyte loss and compensatory proliferation, which are the recognized factors important for liver fibrosis and HCC development. Using single-cell RNA sequencing, we discovered that inhibition of RIPK1 strongly suppresses inflammation induced by hepatocyte-specific loss of TAK1. Activation of RIPK1 promotes the transcription of key proinflammatory cytokines, such as CCL2, and CCR2+macrophage infiltration. Our study demonstrates the role and mechanism of RIPK1 kinase in promoting inflammation, both cell-autonomously and cell-nonautonomously, in the development of liver fibrosis and HCC, independent of cell death, and compensatory proliferation. We suggest the possibility of inhibiting RIPK1 kinase as a therapeutic strategy for reducing liver fibrosis and HCC development by inhibiting inflammation.

scholarly journals Modulation of the TGF-β signaling pathway by long noncoding RNA in hepatocellular carcinoma

2020 ◽  
Vol 8 (1) ◽  
Author(s):  
Mengzhen Han ◽  
Zhibin Liao ◽  
Furong Liu ◽  
Xiaoping Chen ◽  
Bixiang Zhang
Keyword(s):  
Hepatocellular Carcinoma ◽  
Growth Factor ◽  
Noncoding Rna ◽  
Poor Prognosis ◽  
Therapeutic Strategy ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Cellular Processes ◽  
Therapy Targets ◽  
Non Coding Rnas

AbstractHepatocellular carcinoma (HCC) is a type of liver cancer with poor prognosis. There have been demonstrated to exist many possible mechanisms in HCC tumorigenesis, and recent investigations have provided some promising therapy targets. However, further mechanisms remain to be researched to improve the therapeutic strategy and diagnosis of HCC. Transforming growth factor-β (TGF-β) is a pleiotropic cytokine which plays critical roles in networks of different cellular processes, and TGF-β signaling has been found to participate in tumor initiation and development of HCC in recent years. Moreover, among the molecules and signaling pathways, researchers paid more attention to lncRNAs (long non-coding RNAs), but the connection between lncRNAs and TGF-βremain poorly understood. In this review, we conclude the malignant procedure which lncRNAs and TGF-β involved in, and summarize the mechanisms of lncRNAs and TGF-βin HCC initiation and development. Furthermore, the interaction between lncRNA and TGF-β are paid more attention, and the potential therapy targets are mentioned.

scholarly journals The noncoding MIR100HG RNA enhances the autocrine function of transforming growth factor β signaling

Oncogene ◽  
2021 ◽  
Author(s):  
Panagiotis Papoutsoglou ◽  
Dorival Mendes Rodrigues-Junior ◽  
Anita Morén ◽  
Andrew Bergman ◽  
Fredrik Pontén ◽  
...  
Keyword(s):  
Growth Factor ◽  
Target Genes ◽  
Rna Binding ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Tgfβ Signaling ◽  
Ribonucleoprotein Complexes ◽  
Expression Of Genes ◽  
Downstream Effectors ◽  
Human Carcinomas

AbstractActivation of the transforming growth factor β (TGFβ) pathway modulates the expression of genes involved in cell growth arrest, motility, and embryogenesis. An expression screen for long noncoding RNAs indicated that TGFβ induced mir-100-let-7a-2-mir-125b-1 cluster host gene (MIR100HG) expression in diverse cancer types, thus confirming an earlier demonstration of TGFβ-mediated transcriptional induction of MIR100HG in pancreatic adenocarcinoma. MIR100HG depletion attenuated TGFβ signaling, expression of TGFβ-target genes, and TGFβ-mediated cell cycle arrest. Moreover, MIR100HG silencing inhibited both normal and cancer cell motility and enhanced the cytotoxicity of cytostatic drugs. MIR100HG overexpression had an inverse impact on TGFβ signaling responses. Screening for downstream effectors of MIR100HG identified the ligand TGFβ1. MIR100HG and TGFB1 mRNA formed ribonucleoprotein complexes with the RNA-binding protein HuR, promoting TGFβ1 cytokine secretion. In addition, TGFβ regulated let-7a-2–3p, miR-125b-5p, and miR-125b-1–3p expression, all encoded by MIR100HG intron-3. Certain intron-3 miRNAs may be involved in TGFβ/SMAD-mediated responses (let-7a-2–3p) and others (miR-100, miR-125b) in resistance to cytotoxic drugs mediated by MIR100HG. In support of a model whereby TGFβ induces MIR100HG, which then enhances TGFβ1 secretion, analysis of human carcinomas showed that MIR100HG expression correlated with expression of TGFB1 and its downstream extracellular target TGFBI. Thus, MIR100HG controls the magnitude of TGFβ signaling via TGFβ1 autoinduction and secretion in carcinomas.

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.

Latency-associated Peptide Degradation Fragments Produced in Stellate Cells and Phagocytosed by Macrophages in Bile Duct-ligated Mouse Liver

2021 ◽  
pp. 002215542110536
Author(s):  
Ikuyo Inoue ◽  
Xian-Yang Qin ◽  
Takahiro Masaki ◽  
Yoshihiro Mezaki ◽  
Tomokazu Matsuura ◽  
...  
Keyword(s):  
Bile Duct ◽  
Liver Fibrosis ◽  
Hepatic Stellate Cells ◽  
Mouse Liver ◽  
Transforming Growth Factor ◽  
Degradation Products ◽  
Stellate Cells ◽  
Transforming Growth Factor Β ◽  
Early Stages ◽  
Cell Source

Transforming growth factor-β (TGF-β) activation is involved in various pathogeneses, such as fibrosis and malignancy. We previously showed that TGF-β was activated by serine protease plasma kallikrein-dependent digestion of latency-associated peptides (LAPs) and developed a method to detect LAP degradation products (LAP-DPs) in the liver and blood using specific monoclonal antibodies. Clinical studies have revealed that blood LAP-DPs are formed in the early stages of liver fibrosis. This study aimed to identify the cell source of LAP-DP formation during liver fibrosis. The N-terminals of LAP-DPs ending at residue Arg58 (R58) were stained in liver sections of a bile duct-ligated liver fibrosis model at 3 and 13 days. R58 LAP-DPs were detected in quiescent hepatic stellate cells at day 3 and in macrophages on day 13 after ligation of the bile duct. We then performed a detailed analysis of the axial localization of R58 signals in a single macrophage, visualized the cell membrane with the anti-CLEC4F antibody, and found R58 LAP-DPs surrounded by the membrane in phagocytosed debris that appeared to be dead cells. These findings suggest that in the early stages of liver fibrosis, TGF-β is activated on the membrane of stellate cells, and then the cells are phagocytosed after cell death: (J Histochem Cytochem XX:XXX–XXX, XXXX)

scholarly journals The lysosomal Rag-Ragulator complex licenses RIPK1– and caspase-8–mediated pyroptosis by Yersinia

Science ◽  
2021 ◽  
Vol 372 (6549) ◽  
pp. eabg0269
Author(s):  
Zengzhang Zheng ◽  
Wanyan Deng ◽  
Yang Bai ◽  
Rui Miao ◽  
Shenglin Mei ◽  
...  
Keyword(s):  
Cell Death ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Host Cells ◽  
Caspase 8 ◽  
Death Domain ◽  
Interacting Protein ◽  
A Genome ◽  
Infection Inhibition ◽  
Guanosine Triphosphatase

Host cells initiate cell death programs to limit pathogen infection. Inhibition of transforming growth factor–β–activated kinase 1 (TAK1) by pathogenic Yersinia in macrophages triggers receptor-interacting serine-threonine protein kinase 1 (RIPK1)–dependent caspase-8 cleavage of gasdermin D (GSDMD) and inflammatory cell death (pyroptosis). A genome-wide CRISPR screen to uncover mediators of caspase-8–dependent pyroptosis identified an unexpected role of the lysosomal folliculin (FLCN)–folliculin-interacting protein 2 (FNIP2)–Rag-Ragulator supercomplex, which regulates metabolic signaling and the mechanistic target of rapamycin complex 1 (mTORC1). In response to Yersinia infection, Fas-associated death domain (FADD), RIPK1, and caspase-8 were recruited to Rag-Ragulator, causing RIPK1 phosphorylation and caspase-8 activation. Pyroptosis activation depended on Rag guanosine triphosphatase activity and lysosomal tethering of Rag-Ragulator but not mTORC1. Thus, the lysosomal metabolic regulator Rag-Ragulator instructs the inflammatory response to Yersinia.

scholarly journals The Activity of Differentiation Factors Induces Apoptosis in Polyomavirus Large T-Expressing Myoblasts

1998 ◽  
Vol 9 (6) ◽  
pp. 1449-1463 ◽  
Author(s):  
Gian Maria Fimia ◽  
Vanesa Gottifredi ◽  
Barbara Bellei ◽  
Maria Rosaria Ricciardi ◽  
Agostino Tafuri ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Death ◽  
Growth Factor ◽  
Cell Cycle Progression ◽  
Transforming Growth Factor ◽  
Myogenic Differentiation ◽  
Transforming Growth Factor Β ◽  
Large Tumor ◽  
Cycle Progression

It is commonly accepted that pathways that regulate proliferation/differentiation processes, if altered in their normal interplay, can lead to the induction of programmed cell death. In a previous work we reported that Polyoma virus Large Tumor antigen (PyLT) interferes with in vitro terminal differentiation of skeletal myoblasts by binding and inactivating the retinoblastoma antioncogene product. This inhibition occurs after the activation of some early steps of the myogenic program. In the present work we report that myoblasts expressing wild-type PyLT, when subjected to differentiation stimuli, undergo cell death and that this cell death can be defined as apoptosis. Apoptosis in PyLT-expressing myoblasts starts after growth factors removal, is promoted by cell confluence, and is temporally correlated with the expression of early markers of myogenic differentiation. The block of the initial events of myogenesis by transforming growth factor β or basic fibroblast growth factor prevents PyLT-induced apoptosis, while the acceleration of this process by the overexpression of the muscle-regulatory factor MyoD further increases cell death in this system. MyoD can induce PyLT-expressing myoblasts to accumulate RB, p21, and muscle- specific genes but is unable to induce G00arrest. Several markers of different phases of the cell cycle, such as cyclin A, cdk-2, and cdc-2, fail to be down-regulated, indicating the occurrence of cell cycle progression. It has been frequently suggested that apoptosis can result from an unbalanced cell cycle progression in the presence of a contrasting signal, such as growth factor deprivation. Our data involve differentiation pathways, as a further contrasting signal, in the generation of this conflict during myoblast cell apoptosis.

Sign in / Sign up

Export Citation Format

Share Document