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

Abstract Fibrosis is a major pathway to organ injury and failure, accounting for more than one-third of deaths worldwide. Intestinal fibrosis causes irreversible and serious clinical complications, such as strictures and obstruction, secondary to a complex pathogenesis. Under the stimulation of profibrotic soluble factors, excessive activation of mesenchymal cells causes extracellular matrix deposition via canonical transforming growth factor-β/Smads signaling or other pathways (eg, epithelial-to-mesenchymal transition and endothelial-to-mesenchymal transition) in intestinal fibrogenesis. In recent studies, the importance of noncoding RNAs (ncRNAs) stands out in fibrotic diseases in that ncRNAs exhibit a remarkable variety of biological functions in modulating the aforementioned fibrogenic responses. In this review, we summarize the role of ncRNAs, including the emerging long ncRNAs and circular RNAs, in intestinal fibrogenesis. Notably, the translational potential of ncRNAs as diagnostic biomarkers and therapeutic targets in the management of intestinal fibrosis is discussed based on clinical trials from fibrotic diseases in other organs. The main points of this review include the following: • Characteristics of ncRNAs and mechanisms of intestinal fibrogenesis • Wide participation of ncRNAs (especially the emerging long ncRNAs and circular RNAs) in intestinal fibrosis, including transforming growth factor-β signaling, epithelial-to-mesenchymal transition/endothelial-to-mesenchymal transition, and extracellular matrix remodeling • Translational potential of ncRNAs in the diagnosis and treatment of intestinal fibrosis based on clinical trials from fibrotic diseases in other organs

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Acquired genetic and functional alterations associated with transforming growth factor β type I resistance in Hep3B human hepatocellular carcinoma cell line

Journal of Cellular and Molecular Medicine ◽

10.1111/j.1582-4934.2009.00769.x ◽

2009 ◽

Vol 13 (9b) ◽

pp. 3985-3992 ◽

Cited By ~ 2

Author(s):

Drazen B. Zimonjic ◽

Xiaoling Zhou ◽

Ju-Seog Lee ◽

Veronika Ullmannova-Benson ◽

Veenu Tripathi ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Growth Factor ◽

Transforming Growth Factor ◽

Carcinoma Cell ◽

Transforming Growth Factor Β ◽

Type I ◽

Hepatocellular Carcinoma Cell Line ◽

Human Hepatocellular Carcinoma Cell ◽

Hepatocellular Carcinoma Cell ◽

Type I Resistance

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Transforming Growth Factor β-Mediated Transcriptional Repression of c-myc Is Dependent on Direct Binding of Smad3 to a Novel Repressive Smad Binding Element

Molecular and Cellular Biology ◽

10.1128/mcb.24.6.2546-2559.2004 ◽

2004 ◽

Vol 24 (6) ◽

pp. 2546-2559 ◽

Cited By ~ 159

Author(s):

Joshua P. Frederick ◽

Nicole T. Liberati ◽

David S. Waddell ◽

Yigong Shi ◽

Xiao-Fan Wang

Keyword(s):

Growth Factor ◽

Transcriptional Repression ◽

Molecular Mechanisms ◽

Target Genes ◽

Transforming Growth Factor ◽

Transforming Growth Factor Β ◽

Cell Types ◽

Specific Cell ◽

Smad Proteins ◽

Smad Binding Element

ABSTRACT Smad proteins are the most well-characterized intracellular effectors of the transforming growth factor β (TGF-β) signal. The ability of the Smads to act as transcriptional activators via TGF-β-induced recruitment to Smad binding elements (SBE) within the promoters of TGF-β target genes has been firmly established. However, the elucidation of the molecular mechanisms involved in TGF-β-mediated transcriptional repression are only recently being uncovered. The proto-oncogene c-myc is repressed by TGF-β, and this repression is required for the manifestation of the TGF-β cytostatic program in specific cell types. We have shown that Smad3 is required for both TGF-β-induced repression of c-myc and subsequent growth arrest in keratinocytes. The transcriptional repression of c-myc is dependent on direct Smad3 binding to a novel Smad binding site, termed a repressive Smad binding element (RSBE), within the TGF-β inhibitory element (TIE) of the c-myc promoter. The c-myc TIE is a composite element, comprised of an overlapping RSBE and a consensus E2F site, that is capable of binding at least Smad3, Smad4, E2F-4, and p107. The RSBE is distinct from the previously defined SBE and may partially dictate, in conjunction with the promoter context of the overlapping E2F site, whether the Smad3-containing complex actively represses, as opposed to transactivates, the c-myc promoter.

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Cellular crosstalk mediated by platelet-derived growth factor BB and transforming growth factor β during hepatic injury activates hepatic stellate cells

Canadian Journal of Physiology and Pharmacology ◽

10.1139/cjpp-2017-0768 ◽

2018 ◽

Vol 96 (8) ◽

pp. 728-741 ◽

Cited By ~ 7

Author(s):

Sowmya Mekala ◽

SubbaRao V. Tulimilli ◽

Ramasatyaveni Geesala ◽

Kanakaraju Manupati ◽

Neha R. Dhoke ◽

...

Keyword(s):

Growth Factor ◽

Hepatic Stellate Cells ◽

Hepg2 Cells ◽

Molecular Mechanisms ◽

Transforming Growth Factor ◽

Stellate Cells ◽

Transforming Growth Factor Β ◽

Platelet Derived Growth Factor ◽

Hepatic Tissue

Apoptotic hepatocytes release factors that activate hepatic stellate cells (HSCs), thereby inducing hepatic fibrosis. In the present study, in vivo and in vitro injury models were established using acetaminophen, ethanol, carbon tetrachloride, or thioacetamide. Histology of hepatotoxicant-induced diseased hepatic tissue correlated with differential expression of fibrosis-related genes. A marked increase in co-staining of transforming growth factor β receptor type II (TGFRIIβ) – desmin or α-smooth muscle actin – platelet-derived growth factor receptor β (PDGFRβ), markers of activated HSCs, in liver sections of these hepatotoxicant-treated mice also depicted an increase in Annexin V – cytokeratin expressing hepatocytes. To understand the molecular mechanisms of disease pathology, in vitro experiments were designed using the conditioned medium (CM) of hepatotoxicant-treated HepG2 cells supplemented to HSCs. A significant increase in HSC proliferation, migration, and expression of fibrosis-related genes and protein was observed, thereby suggesting the characteristics of an activated phenotype. Treating HepG2 cells with hepatotoxicants resulted in a significant increase in mRNA expression of platelet-derived growth factor BB (PDGF-BB) and transforming growth factor β (TGFβ). CM supplemented to HSCs resulted in increased phosphorylation of PDGFRβ and TGFRIIβ along with its downstream effectors, extracellular signal-related kinase 1/2 and focal adhesion kinase. Neutralizing antibodies against PDGF-BB and TGFβ effectively perturbed the hepatotoxicant-treated HepG2 cell CM-induced activation of HSCs. This study suggests PDGF-BB and TGFβ as potential molecular targets for developing anti-fibrotic therapeutics.

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Knockdown of Long Noncoding RNA H19 Represses the Progress of Pulmonary Fibrosis through the Transforming Growth Factor β/Smad3 Pathway by Regulating MicroRNA 140

Molecular and Cellular Biology ◽

10.1128/mcb.00143-19 ◽

2019 ◽

Vol 39 (12) ◽

Cited By ~ 14

Author(s):

Xi Wang ◽

Zhe Cheng ◽

Lingling Dai ◽

Tianci Jiang ◽

Liuqun Jia ◽

...

Keyword(s):

Growth Factor ◽

Pulmonary Fibrosis ◽

Noncoding Rna ◽

Molecular Mechanisms ◽

Transforming Growth Factor ◽

Animal Experiments ◽

A549 Cells ◽

Transforming Growth Factor Β ◽

Tgf Β1

ABSTRACT Long noncoding RNAs (lncRNAs) are involved in various human diseases. Recently, H19 was reported to be upregulated in fibrotic rat lung and play a stimulative role in bleomycin (BLM)-induced pulmonary fibrosis in mice. However, its expression in human fibrotic lung tissues and mechanism of action remain unclear. Here, our observations showed that H19 expression was significantly upregulated and that of microRNA 140 (miR-140) was markedly reduced in pulmonary fibrotic tissues from idiopathic pulmonary fibrosis (IPF) patients and transforming growth factor β1 (TGF-β1)-induced HBE and A549 cells. Moreover, the expression of H19 was negatively correlated with the expression of miR-140 in IPF tissues. H19 knockdown attenuated TGF-β1-induced pulmonary fibrosis in vitro. Furthermore, animal experiments showed that H19 knockdown attenuated BLM-induced pulmonary fibrosis in mice. The study of molecular mechanisms showed that H19 functioned via reduction of miR-140 expression by binding to miR-140. The increase of miR-140 inhibited TGF-β1-induced pulmonary fibrosis, and H19 upregulation diminished the inhibitory effects of miR-140 on TGF-β1-induced pulmonary fibrosis, which was involved in the TGF-β/Smad3 pathway. Taken together, our findings showed that H19 knockdown attenuated pulmonary fibrosis via the regulatory network of lncRNA H19–miR-140–TGF-β/Smad3 signaling, and H19 and miR-140 might represent therapeutic targets and early diagnostic and prognostic biomarkers for patients with pulmonary fibrosis.

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

Biomarker Research ◽

10.1186/s40364-020-00252-x ◽

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.

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