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Canonical TGF-β Signaling. The TGF-β signaling pathway initiates with the binding of the TGF-β ligand to TGFβRII. Activated TGFβRII forms a complex with and phosphorylates TGFβRI. Upon phosphorylation by TGFβRI, R-Smads, Smad2, and Smad3, form a transcriptional complex with the co-Smad, Smad4. This complex then translocates into the nucleus, associates with DNA by cooperating with various cofactors, and regulates target gene expression. Smad6 and Smad7, the I-Smads, function as negative regulators of TGF-β/Smad signaling.
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Transforming growth factor β (TGF-β) signaling is a preeminent regulator of diverse cellular and physiological processes. Frequent dysregulation of TGF-β signaling has been implicated in cancer. In hepatocellular carcinoma (HCC), the most prevalent form of primary liver cancer, the autocrine and paracrine effects of TGF-β have parado...
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... Combining TGF-β inhibitors with existing therapies or developing targeted drug delivery systems could enhance treatment efficacy while minimizing side effects, providing alternatives for patients intolerant to conventional treatments. 45 Elucidating TGF-β-mediated pathways in fibroids may lead to the identification of novel biomarkers. Biomarkers indicative of TGF-β dysregulation or specific isoform expression levels could aid in early diagnosis, prognostication, and monitoring of fibroid progression, enabling timely interventions. ...
Fibroids, or uterine leiomyomas, represent a prevalent gynecological condition impacting women of reproductive age worldwide. Transforming Growth Factor-Beta (TGF-β) emerges as a critical mediator in the intricate landscape of fibroid development and progression. This abstract encapsulates a comprehensive review elucidating the multifaceted roles of TGF-β in the context of fibroid pathogenesis, encompassing molecular mechanisms and clinical implications. The TGF-β superfamily, comprising TGF-β isoforms (TGF-β1, TGF-β2, and TGF-β3), orchestrates diverse cellular responses governing cell proliferation, differentiation, and extracellular matrix remodeling. Dysregulated TGF-β signaling pathways contribute significantly to fibroid initiation and maintenance by promoting aberrant cellular proliferation, apoptosis resistance, and altered extracellular matrix composition within the uterine tissue. This paper consolidates current knowledge, highlighting the distinct contributions of TGF-β isoforms to fibroid pathophysiology. Enhanced TGF-β expression and downstream signaling dysregulation foster a microenvironment conducive to fibroid growth and progression. Insights into the pivotal role of TGF-β in fibroid pathogenesis open avenues for novel therapeutic modalities aimed at modulating TGF-β signaling cascades. Targeted strategies involving TGF-β inhibitors or modulation of downstream effectors hold promise for innovative treatments in fibroid management. In conclusion, this abstract provides a synopsis of the integral involvement of TGF-β in driving fibroid progression. Understanding the intricate molecular mechanisms underlying TGF-β signaling offers a foundation for novel therapeutic avenues and diagnostic advancements, fostering improved management strategies for this prevalent women's health concern. Continued research into TGF-β-mediated pathways is paramount for enhancing our understanding and clinical management of fibroids.
... 14 In cancers, the TGF-b pathway can be either tumor-suppressive or tumor-promoting, depending on the tumor type and stage. 15,16 In NPC, 24.3% of the TGF-b/Smad pathway genes are altered with inactive TGF-b signal and positive LMP1 status, 17 but the mechanisms remain unclear. CD109 belongs to a2-macroglobulin/C3, C4, and C5 family of thioester-containing proteins, which has been implicated in several kinds of cancers as an oncogene to drive tumor progression, such as glioblastoma, 18 lung adenocarcinoma, 19 and cervical squamous cell carcinoma. ...
In nasopharyngeal carcinoma (NPC), the TGF-β/Smad pathway genes are altered with inactive TGF-β signal, but the mechanisms remain unclear. RNA-sequencing results showed that FLOT2 negatively regulated the TGF-β signaling pathway via up-regulating CD109 expression. qRT-PCR, Western blot, ChIP, and dual-luciferase assays were used to identify whether STAT3 is the activating transcription factor of CD109. Co-IP, immunofluorescence staining assays were used to demonstrate the connection between FLOT2 and STAT3. In vitro and in vivo experiments were used to detect whether CD109 could rescue the functional changes of NPC cells resulting from FLOT2 alteration. IHC and Pearman correlation coefficients were used to assay the correlation between FLOT2 and CD109 expression in NPC tissues. Our results found that FLOT2 promotes the development of NPC by inhibiting TGF-β signaling pathway via stimulating the expression of CD109 by stabilizing STAT3, which provides a potential therapeutic strategy for NPC treatment.
... The TGF-β and Hippo pathways have a physiological relevance in health and disease, as they regulate multiple homeostatic processes from development to adulthood. In the liver, a major crosstalk between TGF-β and Hippo pathways is critical for organ size control, regeneration, and hepatocarcinogenesis. TGF-β and Hippo pathways are tumor suppressors in hepatocytes, as both inhibit cell proliferation and maintain homeostasis, and are essential players in liver regeneration, although they may promote hepatocarcinogenesis when their signaling pathways become altered [1,2]. ...
... Alterations in these signaling pathways are associated with liver pathologies such as chronic liver diseases, fibrosis, and cancer [4,11,22]. In the context of cancer, TGF-β particularly has a dual role, acting as a tumor suppressor in early stages and as a tumor promoter in advanced stages [1]; although, this always depends on the cellular context. ...
... Liver cancer is one of the most common causes of cancer-related death worldwide. In this type of cancer, the tumor microenvironment may foster the tumor-promoting role of TGF-β in the late stages of cancer [1,22]. In 2008, a paper reported TGF-β-dependent temporal (early and late) gene expression signatures established in mouse hepatocytes that predict clinical outcomes in human cancer [26]. ...
The TGF-β and Hippo pathways are critical for liver size control, regeneration, and cancer progression. The transcriptional cofactor TAZ, also named WWTR1, is a downstream effector of Hippo pathway and plays a key role in the maintenance of liver physiological functions. However, the up-regulation of TAZ expression has been associated with liver cancer progression. Recent evidence shows crosstalk of TGF-β and Hippo pathways, since TGF-β modulates TAZ expression through different mechanisms in a cellular context-dependent manner but supposedly independent of SMADs. Here, we evaluate the molecular interplay between TGF-β pathway and TAZ expression and observe that TGF-β induces TAZ expression through SMAD canonical pathway in liver cancer HepG2 cells. Therefore, TAZ cofactor is a primary target of TGF-β/SMAD-signaling, one of the pathways altered in liver cancer.
... Several SASP components have been studied, considering their suppressive role in HCC development. More specifically, TGF-β1 has been demonstrated to act in an autocrine manner by inducing ROS generation and perpetuating senescent phenotype in HCC mice cells, thereby leading to a restriction in tumour growth by 75% [101,102]. ...
Hepatocellular carcinoma (HCC) represents a worryingly increasing cause of malignancy-related mortality, while Metabolic Associated Fatty Liver Disease (MAFLD) is going to become its most common cause in the next decade. Understanding the complex underlying pathophysiology of MAFLD-related HCC can provide opportunities for successful targeted therapies. Of particular interest in this sequela of hepatopathology is cellular senescence, a complex process characterised by cellular cycle arrest initiated by a variety of endogenous and exogenous cell stressors. A key biological process in establishing and maintaining senescence is oxidative stress, which is present in multiple cellular compartments of steatotic hepatocytes. Oxidative stress-induced cellular senescence can change hepatocyte function and metabolism, and alter, in a paracrine manner, the hepatic microenvironment, enabling disease progression from simple steatosis to inflammation and fibrosis, as well as HCC. The duration of senescence and the cell types it affects can tilt the scale from a tumour-protective self-restricting phenotype to the creator of an oncogenic hepatic milieu. A deeper understanding of the mechanism of the disease can guide the selection of the most appropriate senotherapeutic agent, as well as the optimal timing and cell type targeting for effectively combating HCC.
... As shown in Fig. 2D and E, Huh7, PLC/PRF/5, and Hep3B cells (termed as MALT1-low group) had significantly lower expression of MALT1 at both the mRNA and protein level than that in SNU449, Mahlavu, and Focus cells (MALT1-high group). Intriguingly, this finding pointed to a consensus across cell lines based on their differentiation status [36], the corollary being that Huh7, PLC/PRF/5, and Hep3B are defined as early stage well differentiated HCC cell lines characterized by epithelial-like features and very high expression of alpha-fetoprotein (AFP) mRNA expression (Fig. 2F). In contrast, SNU449, Mahlavu, and Focus cell lines are classified as late stage poorly differentiated HCC cell lines with mesenchymal-like characteristics with very low to non-detectable AFP expression (Fig. 2F) [24,37]. ...
Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer and the third leading cause of cancer-related deaths worldwide. Despite recent advances in treatment options, therapeutic management of HCC remains a challenge, emphasizing the importance of exploring novel targets. MALT1 paracaspase is a druggable signaling molecule whose dysregulation has been linked to hematological and solid tumors. However, the role of MALT1 in HCC remains poorly understood, leaving its molecular functions and oncogenic implications unclear. Here we provide evidence that MALT1 expression is elevated in human HCC tumors and cell lines, and that correlates with tumor grade and differentiation state, respectively. Our results indicate that ectopic expression of MALT1 confers increased cell proliferation, 2D clonogenic growth, and 3D spheroid formation in well differentiated HCC cell lines with relatively low MALT1 levels. In contrast, stable silencing of endogenous MALT1 through RNA interference attenuates these aggressive cancer cell phenotypes, as well as migration, invasion, and tumor-forming ability, in poorly differentiated HCC cell lines with higher paracaspase expression. Consistently, we find that pharmacological inhibition of MALT1 proteolytic activity with MI-2 recapitulates MALT1 depletion phenotypes. Finally, we show that MALT1 expression is positively correlated with NF-kB activation in human HCC tissues and cell lines, suggesting that its tumor promoting functions may involve functional interaction with the NF-kB signaling pathway. This work unveils new insights into the molecular implications of MALT1 in hepatocarcinogenesis and places this paracaspase as a potential marker and druggable liability in HCC.
... The process of MALT1 upregulation involves the kinase activity of TGFBR1 which, in turn, triggers the phosphorylation of Smad2 and Smad3. The context-dependent and spatiotemporal regulation of gene expression by Smad2 and Smad3 molecules in TGF-β signaling has been well characterized [41,42]. Some genes are exclusively controlled by Smad2, while other genes are selectively regulated by Smad3 [43,44]. ...
TGF-β signaling mediates its biological effects by engaging canonical Smad proteins and crosstalking extensively with other signaling networks, including the NF-kB pathway. The paracaspase MALT1 is an intracellular signaling molecule essential for NF-kB activation downstream of several key cell surface receptors. Despite intensive research on TGF-β and NF-kB interactions, the significance of MALT1 in this context remains undecoded. Here we provide experimental evidence supporting that MALT1 functions to converge these pathways. Using A549 and Huh7 cancer cell line models, we report that TGF-β stimulation enhances MALT1 protein and transcript levels in a time- and dose-dependent manner. Systematic and selective perturbation of TGF-β signaling components identifies MALT1 as a downstream target of Smad3. Rescue experiments in SMAD3 knockout cells confirm that C-terminal phosphorylation of Smad3 is central to MALT1 induction. Corroborating these data, we document that the expression of SMAD3 and MALT1 genes are positively correlated in TCGA cohorts, and we trace the molecular basis of MALT1 elevation to promoter activation. Functional studies in parental as well as NF-kB p65 signaling reporter engineered cells conclusively reveal that MALT1 is paramount for TGF-β-stimulated nuclear translocation and transcriptional activation of NF-kB p65. Furthermore, we find that BCL10 is also implicated in TGF-β activation of NF-kB target genes, potentially coupling the TGF-β-MALT1-NF-kB signaling axis to the CARMA-BCL10-MALT1 (CBM) signalosome. The novel findings of this study indicate that MALT1 is a downstream target of the canonical TGF-β/Smad3 pathway and plays a critical role in modulating TGF-β and NF-kB crosstalk in cancer.
... We observed an important amelioration of liver fibrosis after vevorisertib and the vevorisertib + sorafenib combination treatment compared to control, which was confirmed by a shift in the matrix regulatory pathway leading to fibrosis resolution with a strong decrease in collagen accumulation. Another essential determinant of HCC progression and survival is cancer-associated inflammation, with TGFβ orchestrating a favorable microenvironment for tumor progression [23]. Here, we showed that expression TGFβ in liver tissue was downregulated by the vevorisertib + sorafenib combination. ...
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related mortality worldwide. The AKT pathway is often activated in HCC cases, and a longer exposure to tyrosine kinase inhibitors such as sorafenib may lead to over-activation of the AKT pathway, leading to HCC resistance. Here, we studied the efficacy of a new generation of allosteric AKT inhibitor, vevorisertib, alone or in combination with sorafenib. To identify specific adverse effects related to the background of cirrhosis, we used a diethylnitrosamine (DEN)-induced cirrhotic rat model. Vevorisertib was tested in vitro on Hep3B, HepG2, HuH7 and PLC/PRF cell lines. Rats were treated weekly with intra-peritoneal injections of DEN for 14 weeks to obtain cirrhosis with fully developed HCC. After that, rats were randomized into four groups (n = 7/group): control, sorafenib, vevorisertib and the combination of vevorisertib + sorafenib, and treated for 6 weeks. Tumor progression was followed by MRI. We demonstrated that the vevorisertib is a highly potent treatment, blocking the phosphorylation of AKT. The tumor progression in the rat liver was significantly reduced by treatment with vevorisertib + sorafenib (49.4%) compared to the control group (158.8%, p < 0.0001). Tumor size, tumor number and tumor cell proliferation were significantly reduced in both the vevorisertib group and vevorisertib + sorafenib groups compared to the control group. Sirius red staining showed an improvement in liver fibrosis by vevorisertib and the combination treatment. Moreover, vevorisertib + sorafenib treatment was associated with a normalization in the liver vasculature. Altogether, vevorisertib as a single agent and its combination with sorafenib exerted a strong suppression of tumor progression and improved liver fibrosis. Thus, results provide a rationale for testing vevorisertib in clinical settings and confirm the importance of targeting AKT in HCC.
... This response appeared to be inhibitory, but not uniformly inverse to the actions of TGF-β in immortalized breast epithelial cells. Rexinoids are unequivocally linked to tumor-suppressing activity, whereas TGF-β has been proposed to behave in a dichotomous manner, depending on the state of malignant transformation of the cell [33]. While in the context of malignant transformation TGF-β may be a promoter of cell proliferation and invasion, in normal epithelium TGF-β signaling may convey tumor-suppressive effects by inducing cell cycle arrest, apoptosis, and cellular senescence and autophagy [34]. ...
Therapeutic targets in cancer cells defective for the tumor suppressor ARID1A are fundamentals of synthetic lethal strategies. However, whether modulating ARID1A function in premalignant breast epithelial cells could be exploited to reduce carcinogenic potential remains to be elucidated. In search of chromatin-modulating mechanisms activated by anti-proliferative agents in normal breast epithelial (HME-hTert) cells, we identified a distinct pattern of genome-wide H3K27 histone acetylation marks characteristic for the combined treatment by the cancer preventive rexinoid bexarotene (Bex) and carvedilol (Carv). Among these marks, several enhancers functionally linked to TGF-β signaling were enriched for ARID1A and Brg1, subunits within the SWI/SNF chromatin-remodeling complex. The recruitment of ARID1A and Brg1 was associated with the suppression of TGFBR2, KLF4, and FoxQ1, and the induction of BMP6, while the inverse pattern ensued upon the knock-down of ARID1A. Bex+Carv treatment resulted in fewer cells expressing N-cadherin and dictated a more epithelial phenotype. However, the silencing of ARID1A expression reversed the ability of Bex and Carv to limit epithelial–mesenchymal transition. The nuclear levels of SMAD4, a canonical mediator of TGF-β action, were more effectively suppressed by the combination than by TGF-β. In contrast, TGF-β treatment exceeded the ability of Bex+Carv to lower nuclear FoxQ1 levels and induced markedly higher E-cadherin positivity, indicating a target-selective antagonism of Bex+Carv to TGF-β action. In summary, the chromatin-wide redistribution of ARID1A by Bex and Carv treatment is instrumental in the suppression of genes mediating TGF-β signaling, and, thus, the morphologic reprogramming of normal breast epithelial cells. The concerted engagement of functionally linked targets using low toxicity clinical agents represents an attractive new approach for cancer interception.
The incidence of hepatocellular carcinoma (HCC) ranks first among primary liver cancers, and its mortality rate exhibits a consistent annual increase. The treatment of HCC has witnessed a significant surge in recent years, with the emergence of targeted immune therapy as an adjunct to early surgical resection. Adoptive cell therapy (ACT) using tumor-infiltrating lymphocytes (TIL) has shown promising results in other types of solid tumors. This article aims to provide a comprehensive overview of the intricate interactions between different types of TILs and their impact on HCC, elucidate strategies for targeting neoantigens through TILs, and address the challenges encountered in TIL therapies along with potential solutions. Furthermore, this article specifically examines the impact of oncogenic signaling pathways activation within the HCC tumor microenvironment on the infiltration dynamics of TILs. Additionally, a concise overview is provided regarding TIL preparation techniques and an update on clinical trials investigating TIL-based immunotherapy in solid tumors.
Hepatocellular carcinoma (HCC) is the most common type of liver cancer with a high death rate in the world. The molecular mechanisms related to the pathogenesis of HCC have not been precisely defined so far. Hence, this review aimed to address the potential cross‐talk between noncoding RNAs (ncRNAs) and programmed cell death in HCC. All related papers in the English language up to June 2023 were collected and screened. The searched keywords in scientific databases, including Scopus, PubMed, and Google Scholar, were HCC, ncRNAs, Epigenetic, Programmed cell death, Autophagy, Apoptosis, Ferroptosis, Chemoresistance, Tumor recurrence, Prognosis, and Prediction. According to the reports, ncRNAs, comprising long ncRNAs, microRNAs, circular RNAs, and small nucleolar RNAs can affect cell proliferation, migration, invasion, and metastasis, as well as cell death‐related processes, such as autophagy, ferroptosis, necroptosis, and apoptosis in HCC by regulating cancer‐associated genes and signaling pathways, for example, phosphoinositide 3‐kinase/Akt, extracellular signal‐regulated kinase/MAPK, and Wnt/β‐catenin signaling pathways. It seems that ncRNAs, as epigenetic regulators, can be utilized as biomarkers in diagnosis, prognosis, survival and recurrence rates prediction, chemoresistance, and evaluation of therapeutic response in HCC patients. However, more scientific evidence is suggested to be accomplished to confirm these results.
