scholarly journals ROS and TGFβ: from pancreatic tumour growth to metastasis

2021 ◽  
Vol 40 (1) ◽  
Author(s):  
Chao-Hui Chang ◽  
Siim Pauklin
Keyword(s):  
Tumour Growth ◽  
Cancer Metastasis ◽  
Transforming Growth Factor ◽  
Cancer Therapeutics ◽  
Transforming Growth Factor Β ◽  
Ductal Adenocarcinoma ◽  
Cellular Processes ◽  
Tumour Development ◽  
Pancreatic Tumour ◽  
Tgfβ Signalling

AbstractTransforming growth factor β (TGFβ) signalling pathway switches between anti-tumorigenic function at early stages of cancer formation and pro-tumorigenic effects at later stages promoting cancer metastasis. A similar contrasting role has been uncovered for reactive oxygen species (ROS) in pancreatic tumorigenesis. Down-regulation of ROS favours premalignant tumour development, while increasing ROS level in pancreatic ductal adenocarcinoma (PDAC) enhances metastasis. Given the functional resemblance, we propose that ROS-mediated processes converge with the spatial and temporal activation of TGFβ signalling and thereby differentially impact early tumour growth versus metastatic dissemination. TGFβ signalling and ROS could extensively orchestrate cellular processes and this concerted function can be utilized by cancer cells to facilitate their malignancy. In this article, we revisit the interplay of canonical and non-canonical TGFβ signalling with ROS throughout pancreatic tumorigenesis and metastasis. We also discuss recent insight that helps to understand their conflicting effects on different stages of tumour development. These considerations open new strategies in cancer therapeutics.

scholarly journals Downregulation of TRAIL-Receptor 1 Increases TGFβ Type II Receptor Expression and TGFβ Signalling Via MicroRNA-370-3p in Pancreatic Cancer Cells

Cancers ◽  
2018 ◽  
Vol 10 (11) ◽  
pp. 399 ◽  
Author(s):  
David Radke ◽  
Qi Ling ◽  
Robert Häsler ◽  
Gökhan Alp ◽  
Hendrik Ungefroren ◽  
...  
Keyword(s):  
Transient Expression ◽  
Transforming Growth Factor ◽  
Plasminogen Activator Inhibitor ◽  
Transforming Growth Factor Β ◽  
Receptor Expression ◽  
Ductal Adenocarcinoma ◽  
Type Ii ◽  
Plasminogen Activator Inhibitor 1 ◽  
Pancreatic Cancer Cells ◽  
Micro Rnas

The accumulation of perturbations in signalling pathways resulting in an apoptosis-insensitive phenotype is largely responsible for the desperate prognosis of patients with pancreatic ductal adenocarcinoma (PDAC). Accumulating evidence suggests that the death receptors TRAIL-R1 and TRAIL-R2 play important roles in PDAC biology by acting as either tumour suppressors through induction of cell death or tumour promoters through induction of pro-inflammatory signalling, invasion and metastasis. TRAIL-R2 can also associate with nuclear proteins and alter the maturation of micro RNAs (miRs). By genome-wide miR profiling and quantitative PCR analyses we now demonstrate that knockdown of TRAIL-R1 in PDAC cells decreased the level of mature miR-370 and led to an increased abundance of the type II receptor for transforming growth factor β (TGFβ). Transfection of cells with an artificial miR-370-3p decreased the levels of TGFβ-RII. We further show that transient expression of the miR-370 mimic decreased TGFβ1-induced expression of SERPINE1 encoding plasminogen activator-inhibitor 1 and partially relieved TGFβ1-induced growth inhibition. Moreover, stable TRAIL-R1 knockdown in Colo357 cells increased TGFβ1-induced SERPINE1 expression and this effect was partially reversed by transient expression of the miR-370 mimic. Finally, after transient knockdown of TRAIL-R1 in Panc1 cells there was a tendency towards enhanced activation of Smad2 and JNK1/2 signalling by exogenous TGFβ1. Taken together, our study reveals that TRAIL-R1 through regulation of miR-370 can decrease the sensitivity of PDAC cells to TGFβ and therefore represents a potential tumour suppressor in late-stage PDAC.

scholarly journals OTUD4 enhances TGFβ signalling through regulation of the TGFβ receptor complex

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Patrick William Jaynes ◽  
Prasanna Vasudevan Iyengar ◽  
Sarah Kit Leng Lui ◽  
Tuan Zea Tan ◽  
Natali Vasilevski ◽  
...  
Keyword(s):  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Negative Regulator ◽  
Deubiquitinating Enzyme ◽  
Tgfβ Receptor ◽  
Tgfβ Signalling ◽  
Systematic Control ◽  
General Regulation ◽  
Tgfβ Pathway ◽  
Transcriptional Target

Abstract Systematic control of the transforming growth factor-β (TGFβ) pathway is essential to keep the amplitude and the intensity of downstream signalling at appropriate levels. Ubiquitination plays a crucial role in the general regulation of this pathway. Here we identify the deubiquitinating enzyme OTUD4 as a transcriptional target of the TGFβ pathway that functions through a positive feedback loop to enhance overall TGFβ activity. Interestingly we demonstrate that OTUD4 functions through both catalytically dependent and independent mechanisms to regulate TGFβ activity. Specifically, we find that OTUD4 enhances TGFβ signalling by promoting the membrane presence of TGFβ receptor I. Furthermore, we demonstrate that OTUD4 inactivates the TGFβ negative regulator SMURF2 suggesting that OTUD4 regulates multiple nodes of the TGFβ pathway to enhance TGFβ activity.

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 Acute Liver Injury after CCl4 Administration Is Independent of Smad7 Expression in Myeloid Cells

2019 ◽  
Vol 20 (22) ◽  
pp. 5528 ◽  
Author(s):  
Jessica Endig ◽  
Ludmilla Unrau ◽  
Paulina Sprezyna ◽  
Sebasting Rading ◽  
Meliha Karsak ◽  
...  
Keyword(s):  
Liver Injury ◽  
Transforming Growth Factor ◽  
Inflammatory Responses ◽  
Elevated Serum ◽  
Myeloid Cells ◽  
Transforming Growth Factor Β ◽  
Cellular Processes ◽  
Ccl4 Administration ◽  
Smad7 Expression ◽  
The Impact

Myeloid cells are essential for the initiation and termination of innate and adaptive immunity that create homeostasis in the liver. Smad7 is an inhibitor of the transforming growth factor β (TGF-β) signaling pathway, which regulates inflammatory cellular processes. Knockdown of Smad7 in hepatocytes has been shown to promote liver fibrosis, but little is known about the effects of Smad7 in myeloid cells during inflammatory responses in the liver. Using mice with a myeloid-specific knockdown of Smad7 (LysM-Cre Smad7fl/fl), we investigated the impact of Smad7 deficiency in myeloid cells on liver inflammation and regeneration using the well-established model of CCl4-mediated liver injury. Early (24/48 h) and late (7 d) time points were analyzed. We found that CCl4 induces severe liver injury, with elevated serum ALT levels, centrilobular and periportal necrosis, infiltrating myeloid cells and an increase of inflammatory cytokines in the liver. Furthermore, as expected, inflammation peaked at 24 h and subsided after 7 d. However, the knockdown of Smad7 in myeloid cells did not affect any of the investigated parameters in the CCl4-treated animals. In summary, our results suggest that the inhibition of TGF-β signaling via Smad7 expression in myeloid cells is dispensable for the induction and control of acute CCl4-induced liver injury.

scholarly journals Role of transforming growth factor-β in hematologic malignancies

Blood ◽  
2006 ◽  
Vol 107 (12) ◽  
pp. 4589-4596 ◽  
Author(s):  
Mei Dong ◽  
Gerard C. Blobe
Keyword(s):  
Growth Factor ◽  
Signaling Pathway ◽  
Transforming Growth Factor ◽  
Myeloproliferative Disorders ◽  
Transforming Growth Factor Β ◽  
Hematologic Malignancies ◽  
Negative Regulator ◽  
Cellular Processes ◽  
Signaling Field

AbstractThe transforming growth factor-β (TGF-β) signaling pathway is an essential regulator of cellular processes, including proliferation, differentiation, migration, and cell survival. During hematopoiesis, the TGF-β signaling pathway is a potent negative regulator of proliferation while stimulating differentiation and apoptosis when appropriate. In hematologic malignancies, including leukemias, myeloproliferative disorders, lymphomas, and multiple myeloma, resistance to these homeostatic effects of TGF-β develops. Mechanisms for this resistance include mutation or deletion of members of the TGF-β signaling pathway and disruption of the pathway by oncoproteins. These alterations define a tumor suppressor role for the TGF-β pathway in human hematologic malignancies. On the other hand, elevated levels of TGF-β can promote myelofibrosis and the pathogenesis of some hematologic malignancies through their effects on the stroma and immune system. Advances in the TGF-β signaling field should enable targeting of the TGF-β signaling pathway for the treatment of hematologic malignancies.

scholarly journals Uncoupling of ER-mitochondrial calcium communication by transforming growth factor-β

2008 ◽  
Vol 295 (5) ◽  
pp. F1303-F1312 ◽  
Author(s):  
Pál Pacher ◽  
Kumar Sharma ◽  
György Csordás ◽  
Yanqing Zhu ◽  
György Hajnóczky
Keyword(s):  
Growth Factor ◽  
Transforming Growth Factor ◽  
Vascular Complications ◽  
Transforming Growth Factor Β ◽  
Sole Source ◽  
Atp Production ◽  
Permeabilized Cells ◽  
Cellular Processes ◽  
Diabetic Vascular Complications ◽  
Key Factor

Transforming growth factor-β (TGF-β) has been implicated as a key factor in mediating many cellular processes germane to disease pathogenesis, including diabetic vascular complications. TGF-β alters cytosolic [Ca2+] ([Ca2+]c) signals, which in some cases may result from the downregulation of the IP3 receptor Ca2+ channels (IP3R). Ca2+ released by IP3Rs is effectively transferred from endoplasmic reticulum (ER) to the mitochondria to stimulate ATP production and to allow feedback control of the Ca2+ mobilization. To assess the effect of TGF-β on the ER-mitochondrial Ca2+ transfer, we first studied the [Ca2+]c and mitochondrial matrix Ca2+ ([Ca2+]m) signals in single preglomerular afferent arteriolar smooth muscle cells (PGASMC). TGF-β pretreatment (24 h) decreased both the [Ca2+]c and [Ca2+]m responses evoked by angiotensin II or endothelin. Strikingly, the [Ca2+]m signal was more depressed than the [Ca2+]c signal and was delayed. In permeabilized cells, TGF-β pretreatment attenuated the rate but not the magnitude of the IP3-induced [Ca2+]c rise, yet caused massive depression of the [Ca2+]m responses. ER Ca2+ storage and mitochondrial uptake of added Ca2+ were not affected by TGF-β. Also, TGF-β had no effect on mitochondrial distribution and on the ER-mitochondrial contacts assessed by two-photon NAD(P)H imaging and electron microscopy. Downregulation of both IP3R1 and IP3R3 was found in TGF-β-treated PGASMC. Thus, TGF-β causes uncoupling of mitochondria from the ER Ca2+ release. The sole source of this would be suppression of the IP3R-mediated Ca2+ efflux, indicating that the ER-mitochondrial Ca2+ transfer depends on the maximal rate of Ca2+ release. The impaired ER-mitochondrial coupling may contribute to the vascular pathophysiology associated with TGF-β production.

scholarly journals Pattern analysis uncovers a chronic ethanol-induced disruption of the switch-like dynamics of C/EBP-β and C/EBP-α genome-wide binding during liver regeneration

2017 ◽  
Vol 49 (1) ◽  
pp. 11-26 ◽  
Author(s):  
Lakshmi Kuttippurathu ◽  
Biswanath Patra ◽  
Daniel Cook ◽  
Jan B. Hoek ◽  
Rajanikanth Vadigepalli
Keyword(s):  
Liver Regeneration ◽  
Regulatory Networks ◽  
Transforming Growth Factor ◽  
Dynamic Balance ◽  
Transforming Growth Factor Β ◽  
Ethanol Intake ◽  
Chronic Ethanol ◽  
Cellular Processes ◽  
Genome Wide ◽  
Chronic Ethanol Consumption

Chronic ethanol intake impairs liver regeneration through a system-wide alteration in the regulatory networks driving the response to injury. Our study focused on the initial phase of response to 2/3rd partial hepatectomy (PHx) to investigate how adaptation to chronic ethanol intake affects the genome-wide binding profiles of the transcription factors C/EBP-β and C/EBP-α. These factors participate in complementary and often opposing functions for maintaining cellular differentiation, regulating metabolism, and governing cell growth during liver regeneration. We analyzed ChIP-seq data with a comparative pattern count (COMPACT) analysis, which exhaustively enumerates temporal patterns of discretized binding profiles to identify dominant as well as subtle patterns that may not be apparent from conventional clustering analyses. We found that adaptation to chronic ethanol intake significantly alters the genome-wide binding profile of C/EBP-β and C/EBP-α before and following PHx. A subset of these ethanol-induced changes include C/EBP-β binding to promoters of genes involved in the profibrogenic transforming growth factor-β pathway, and both C/EBP-β and C/EBP-α binding to promoters of genes involved in the cell cycle, apoptosis, homeostasis, and metabolic processes. The shift in C/EBP binding loci, coupled with an ethanol-induced increase in C/EBP-β binding at 6 h post-resection, indicates that ethanol adaptation may change both the amount and nature of C/EBP binding postresection. Taken together, our results suggest that chronic ethanol consumption leads to a spatially and temporally reorganized activity at many genomic loci, resulting in a shift in the dynamic balance and coordination of cellular processes underlying regenerative response.

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