Cryo-EM Reveals Integrin-Mediated TGF-ß Activation without Release from Latent TGF-ß.

Integrin αvß8 binds with exquisite specificity to latent transforming growth factor-ß (L-TGF-ß). This binding is essential for activating L-TGF-ß presented by a variety of cell types. Inhibiting αvß8-mediated TGF-ß activation blocks immunosuppressive regulatory T cell differentiation, which is a potential therapeutic strategy in cancer. Using cryo-electron microscopy, structure-guided mutagenesis, and cell-based assays, we reveal the binding interactions between the entire αvß8 ectodomain and its intact natural ligand, L-TGF-ß, as well as two different inhibitory antibody fragments to understand the structural underpinnings of αvß8 binding specificity and TGF-ß activation. Our studies reveal a mechanism of TGF-ß activation where mature TGF-ß signals within the confines of L-TGF-ß and the release and diffusion of TGF-ß are not required. The structural details of this mechanism provide a rational basis for therapeutic strategies to inhibit αvß8-mediated L-TGF-ß activation.

A Macrophage-Pericyte Axis Directs Tissue Restoration via Amphiregulin-Induced Transforming Growth Factor Beta Activation.

The epidermal growth factor receptor ligand Amphiregulin has a well-documented role in the restoration of tissue homeostasis after injury; however, the mechanism by which Amphiregulin contributes to wound repair remains unknown. Here we show that Amphiregulin functioned by releasing bioactive transforming growth factor beta (TGF-ß) from latent complexes via integrin-αV activation. Using acute injury models in two different tissues, we found that by inducing TGF-ß activation on mesenchymal stromal cells (pericytes), Amphiregulin induced their differentiation into myofibroblasts, thereby selectively contributing to the restoration of vascular barrier function within injured tissue. Furthermore, we identified macrophages as a critical source of Amphiregulin, revealing a direct effector mechanism by which these cells contribute to tissue restoration after acute injury. Combined, these observations expose a so far under-appreciated mechanism of how cells of the immune system selectively control the differentiation of tissue progenitor cells during tissue repair and inflammation.

Senataxin Mutation Reveals How R-Loops Promote Transcription by Blocking DNA Methylation at Gene Promoters.

R-loops are three-stranded nucleic acid structures found abundantly and yet often viewed as by-products of transcription. Studying cells from patients with a motor neuron disease (amyotrophic lateral sclerosis 4 [ALS4]) caused by a mutation in senataxin, we uncovered how R-loops promote transcription. In ALS4 patients, the senataxin mutation depletes R-loops with a consequent effect on gene expression. With fewer R-loops in ALS4 cells, the expression of BAMBI, a negative regulator of transforming growth factor ß (TGF-ß), is reduced; that then leads to the activation of the TGF-ß pathway. We uncovered that genome-wide R-loops influence promoter methylation of over 1,200 human genes. DNA methyl-transferase 1 favors binding to double-stranded DNA over R-loops. Thus, in forming R-loops, nascent RNA blocks DNA methylation and promotes further transcription. Hence, our results show that nucleic acid structures, in addition to sequences, influence the binding and activity of regulatory proteins.

A specialized integrin-binding motif enables proTGF-ß2 activation by integrin αVß6 but not αVß8.

Activation of latent transforming growth factor (TGF)-ß2 is incompletely understood. Unlike TGF-ß1 and ß3, the TGF-ß2 prodomain lacks a seven-residue RGDLXX (L/I) integrin-recognition motif and is thought not to be activated by integrins. Here, we report the surprising finding that TGF-ß2 contains a related but divergent 13-residue integrin-recognition motif (YTSGDQKTIKSTR) that specializes it for activation by integrin αVß6 but not αVß8. Both classes of motifs compete for the same binding site in αVß6. Multiple changes in the longer motif underlie its specificity. ProTGF-ß2 structures define interesting differences from proTGF-ß1 and the structural context for activation by αVß6. Some integrin-independent activation is also seen for proTGF-ß2 and even more so for proTGF-ß3. Our findings have important implications for therapeutics to αVß6 in clinical trials for fibrosis, in which inhibition of TGF-ß2 activation has not been anticipated.

Hic-5 regulates extracellular matrix-associated gene expression and cytokine secretion in cancer associated fibroblasts.

The focal adhesion protein, Hic-5 plays a key role in promoting extracellular matrix deposition and remodeling by cancer associated fibroblasts within the tumor stroma to promote breast tumor cell invasion. However, whether stromal matrix gene expression is regulated by Hic-5 is still unknown. Utilizing a constitutive Hic-5 knockout, Mouse Mammary Tumor Virus-Polyoma Middle T-Antigen spontaneous breast tumor mouse model, bulk RNAseq analysis was performed on cancer associated fibroblasts isolated from Hic-5 knockout mammary tumors. Functional network analysis highlighted a key role for Hic-5 in extracellular matrix organization, with both structural matrix genes, as well as matrix remodeling genes being differentially expressed in relation to Hic-5 expression. The subcellular distribution of the MRTF-A transcription factor and expression of a subset of MRTF-A responsive genes was also impacted by Hic-5 expression. Additionally, cytokine array analysis of conditioned media from the Hic-5 and Hic-5 knockout cancer associated fibroblasts revealed that Hic-5 is important for the secretion of several key factors that are associated with matrix remodeling, angiogenesis and immune evasion. Together, these data provide further evidence of a central role for Hic-5 expression in cancer associated fibroblasts in regulating the composition and organization of the tumor stroma microenvironment to promote breast tumor progression.

LRG1 loss effectively restrains glomerular TGF-ß signaling to attenuate diabetic kidney disease.

Transforming growth factor (TGF)-ß signaling is a well-established pathogenic mediator of diabetic kidney disease (DKD). However, owing to its pleiotropic actions, its systemic blockade is not therapeutically optimal. The expression of TGF-ß signaling regulators can substantially influence TGF-ß's effects in a cell- or context-specific manner. Among these, leucine-rich α2-glycoprotein 1 (LRG1) is significantly increased in glomerular endothelial cells (GECs) in DKD. As LRG1 is a secreted molecule that can exert autocrine and paracrine effects, we examined the effects of LRG1 loss in kidney cells in diabetic OVE26 mice by single-cell transcriptomic analysis. Gene expression analysis confirmed a predominant expression of Lrg1 in GECs, which further increased in diabetic kidneys. Loss of Lrg1 led to the reversal of angiogenic and TGF-ß-induced gene expression in GECs, which were associated with DKD attenuation. Notably, Lrg1 loss also mitigated the increased TGF-ß-mediated gene expression in both podocytes and mesangial cells in diabetic mice, indicating that GEC-derived LRG1 potentiates TGF-ß signaling in glomerular cells in an autocrine and paracrine manner. Indeed, a significant reduction in phospho-Smad proteins was observed in the glomerular cells of OVE26 mice with LRG1 loss. These results indicate that specific antagonisms of LRG1 may be an effective approach to curb the hyperactive glomerular TGF-ß signaling to attenuate DKD.

TGFB2-AS1 inhibits triple-negative breast cancer progression via interaction with SMARCA4 and regulating its targets TGFB2 and SOX2.

Triple-negative breast cancer (TNBC) is the most challenging breast cancer subtype for its high rates of relapse, great metastatic potential, and short overall survival. How cancer cells acquire metastatic potency through the conversion of noncancer stem-like cells into cancer cells with stem-cell properties is poorly understood. Here, we identified the long noncoding RNA (lncRNA) TGFB2-AS1 as an important regulator of the reversibility and plasticity of noncancer stem cell populations in TNBC. We revealed that TGFB2-AS1 impairs the breast cancer stem-like cell (BCSC) traits of TNBC cells in vitro and dramatically decreases tumorigenic frequency and lung metastasis in vivo. Mechanistically, TGFB2-AS1 interacts with SMARCA4, a core subunit of the SWI/SNF chromatin remodeling complex, and results in transcriptional repression of its target genes including TGFB2 and SOX2 in an in cis or in trans way, leading to inhibition of transforming growth factor ß (TGFß) signaling and BCSC characteristics. In line with this, TGFB2-AS1 overexpression in an orthotopic TNBC mouse model remarkably abrogates the enhancement of tumor growth and lung metastasis endowed by TGFß2. Furthermore, combined prognosis analysis of TGFB2-AS1 and TGFß2 in TNBC patients shows that high TGFB2-AS1 and low TGFß2 levels are correlated with better outcome. These findings demonstrate a key role of TGFB2-AS1 in inhibiting disease progression of TNBC based on switching the cancer cell fate of TNBC and also shed light on the treatment of TNBC patients.

Exploring the impact of the PNPLA3 I148M variant on primary human hepatic stellate cells using 3D extracellular matrix models.

BACKGROUND & AIMS: The PNPLA3 rs738409 C>G (encoding for I148M) variant is a risk locus for the fibrogenic progression of chronic liver diseases, a process driven by hepatic stellate cells (HSCs). We investigated how the PNPLA3 I148M variant affects HSC biology using transcriptomic data and validated findings in 3D-culture models. METHODS: RNA sequencing was performed on 2D-cultured primary human HSCs and liver biopsies of individuals with obesity, genotyped for the PNPLA3 I148M variant. Data were validated in wild-type (WT) or PNPLA3 I148M variant-carrying HSCs cultured on 3D extracellular matrix (ECM) scaffolds from human healthy and cirrhotic livers, with/without TGFB1 or cytosporone B (Csn-B) treatment. RESULTS: Transcriptomic analyses of liver biopsies and HSCs highlighted shared PNPLA3 I148M-driven dysregulated pathways related to mitochondrial function, antioxidant response, ECM remodelling and TGFB1 signalling. Analogous pathways were dysregulated in WT/PNPLA3-I148M HSCs cultured in 3D liver scaffolds. Mitochondrial dysfunction in PNPLA3-I148M cells was linked to respiratory chain complex IV insufficiency. Antioxidant capacity was lower in PNPLA3-I148M HSCs, while reactive oxygen species secretion was increased in PNPLA3-I148M HSCs and higher in bioengineered cirrhotic vs. healthy scaffolds. TGFB1 signalling followed the same trend. In PNPLA3-I148M cells, expression and activation of the endogenous TGFB1 inhibitor NR4A1 were decreased: treatment with the Csn-B agonist increased total NR4A1 in HSCs cultured in healthy but not in cirrhotic 3D scaffolds. NR4A1 regulation by TGFB1/Csn-B was linked to Akt signalling in PNPLA3-WT HSCs and to Erk signalling in PNPLA3-I148M HSCs. CONCLUSION: HSCs carrying the PNPLA3 I148M variant have impaired mitochondrial function, antioxidant responses, and increased TGFB1 signalling, which dampens antifibrotic NR4A1 activity. These features are exacerbated by cirrhotic ECM, highlighting the dual impact of the PNPLA3 I148M variant and the fibrotic microenvironment in progressive chronic liver diseases. IMPACT AND IMPLICATIONS: Hepatic stellate cells (HSCs) play a key role in the fibrogenic process associated with chronic liver disease. The PNPLA3 genetic mutation has been linked with increased risk of fibrogenesis, but its role in HSCs requires further investigation. Here, by using comparative transcriptomics and a novel 3D in vitro model, we demonstrate the impact of the PNPLA3 genetic mutation on primary human HSCs' behaviour, and we show that it affects the cell's mitochondrial function and antioxidant response, as well as the antifibrotic gene NR4A1. Our publicly available transcriptomic data, 3D platform and our findings on NR4A1 could facilitate the discovery of targets to develop more effective treatments for chronic liver diseases.

Tgfb1 deficiency impairs the self-renewal capacity of murine hematopoietic stem/progenitor cells in vivo.

Transforming growth factor ß1 (TGFB1) refers to a pleiotropic cytokine exerting contrasting roles in hematopoietic stem cells (HSCs) functions in vitro and in vivo. However, the understanding of hematopoiesis in vivo, when TGFB1 is constantly deactivated, is still unclear, mainly due to significant embryonic lethality and the emergence of a fatal inflammatory condition, which makes doing these investigations challenging. Our study aims to find the specific role of TGFB1 in regulating hematopoiesis in vivo. We engineered mice strains (Vav1 or Mx1 promoter-driven TGFB1 knockout) with conditional knockout of TGFB1 to study its role in hematopoiesis in vivo. In fetal and adult hematopoiesis, TGFB1 KO mice displayed deficiency and decreased self-renewal capacity of HSCs with myeloid-biased differentiation. The results were different from the regulating role of TGFB1 in vitro. Additionally, our results showed that TGFB1 deficiency from fetal hematopoiesis stage caused more severe defect of HSCs than in the adult stage. Mechanistically, our findings identified TGFB1-SOX9-FOS/JUNB/TWIST1 signal axis as an essential regulating pathway in HSCs homeostasis. Our study may provide a scientific basis for clinical HSC transplantation and expansion.

Progression of monoclonal gammopathy of undetermined significance to multiple myeloma is associated with enhanced translational quality control and overall loss of surface antigens.

BACKGROUND: Despite significant advancements in treatment strategies, multiple myeloma remains incurable. Additionally, there is a distinct lack of reliable biomarkers that can guide initial treatment decisions and help determine suitable replacement or adjuvant therapies when relapse ensues due to acquired drug resistance. METHODS: To define specific proteins and pathways involved in the progression of monoclonal gammopathy of undetermined significance (MGUS) to multiple myeloma (MM), we have applied super-SILAC quantitative proteomic analysis to CD138 + plasma cells from 9 individuals with MGUS and 37 with MM. RESULTS: Unsupervised hierarchical clustering defined three groups: MGUS, MM, and MM with an MGUS-like proteome profile (ML) that may represent a group that has recently transformed to MM. Statistical analysis identified 866 differentially expressed proteins between MM and MGUS, and 189 between MM and ML, 177 of which were common between MGUS and ML. Progression from MGUS to MM is accompanied by upregulated EIF2 signaling, DNA repair, and proteins involved in translational quality control, whereas integrin- and actin cytoskeletal signaling and cell surface markers are downregulated. CONCLUSION: Compared to the premalignant plasma cells in MGUS, malignant MM cells apparently have mobilized several pathways that collectively contribute to ensure translational fidelity and to avoid proteotoxic stress, especially in the ER. The overall reduced expression of immunoglobulins and surface antigens contribute to this and may additionally mediate evasion from recognition by the immune apparatus. Our analyses identified a range of novel biomarkers with potential prognostic and therapeutic value, which will undergo further evaluation to determine their clinical significance.

FBXO28 promotes cell proliferation, migration and invasion via upregulation of the TGF-beta1/SMAD2/3 signaling pathway in ovarian cancer.

BACKGROUND: Ovarian cancer is one of the most common gynecological malignancies due to the lack of early symptoms, early diagnosis and limited screening. Therefore, it is necessary to understand the molecular mechanism underlying the occurrence and progression of ovarian cancer and to identify a basic biomarker for the early diagnosis and clinical treatment of ovarian cancer. METHODS: The association between FBXO28 and ovarian cancer prognosis was analyzed using Kaplan‒Meier survival analysis. The difference in FBXO28 mRNA expression between normal ovarian tissues and ovarian tumor tissues was obtained from The Cancer Genome Atlas (TCGA), and Genotype-Tissue Expression (GTEx) cohorts. The expression levels of the FBXO28 protein in ovarian cancer tissues and normal ovarian tissues were measured via immunohistochemical staining. Western blotting was used to determine the level of FBXO28 expression in ovarian cancer cells. The CCK-8, the colony formation, Transwell migration and invasion assays were performed to evaluate cell proliferation and motility. RESULTS: We found that a higher expression level of FBXO28 was associated with poor prognosis in ovarian cancer patients. Analysis of the TCGA and GTEx cohorts showed that the FBXO28 mRNA level was lower in normal ovarian tissue samples than in ovarian cancer tissue samples. Compared with that in normal ovarian tissues or cell lines, the expression of FBXO28 was greater in ovarian tumor tissues or tumor cells. The upregulation of FBXO28 promoted the viability, proliferation, migration and invasion of ovarian cancer cells. Finally, we demonstrated that FBXO28 activated the TGF-beta1/Smad2/3 signaling pathway in ovarian cancer. CONCLUSIONS: In conclusion, FBXO28 enhanced oncogenic function via upregulation of the TGF-beta1/Smad2/3 signaling pathway in ovarian cancer.

Medical Management for Fracture Prevention in Children with Osteogenesis Imperfecta.

There are no licensed treatments for children with osteogenesis imperfecta. Children currently receive off-label treatment with bisphosphonates, without any consistent approach to dose, drug or route of administration. Meta-analyses suggest that anti-fracture efficacy of such interventions is equivocal. New therapies are undergoing clinical trials, and it is likely that one or more will receive marketing authorisation within the next three to five years. The long-term outcome from such interventions will need to be studied carefully well beyond the period over which the clinical trials are conducted, and a consistent approach to the collection of data in this regard will be needed as a major collaborative effort.

Advancing osteoarthritis therapy with GMOCS hydrogel-loaded BMSCs-exos.

This study investigated the mechanism of the extracellular matrix-mimicking hydrogel-mediated TGFB1/Nrf2 signaling pathway in osteoarthritis using bone marrow mesenchymal stem cell-derived exosomes (BMSCs-Exos). A GMOCS-Exos hydrogel was synthesized and evaluated for its impact on chondrocyte viability and neutrophil extracellular traps (NETs) formation. In an OA rat model, GMOCS-Exos promoted cartilage regeneration and inhibited NETs formation. Transcriptome sequencing identified TGFB1 as a key gene, with GMOCS-Exos activating Nrf2 signaling through TGFB1. Depletion of TGFB1 hindered the cartilage-protective effect of GMOCS-Exos. This study sheds light on a promising therapeutic strategy for osteoarthritis through GMOCS-Exos-mediated TGFB1/Nrf2 pathway modulation.

Inflow Tract Development.

The development of the inflow tract is undoubtedly one of the most complex remodeling events in the formation of the four-chambered heart. It involves the creation of two separate atrial chambers, the formation of an atrial/atrioventricular (AV) septal complex, the incorporation of the caval veins and coronary sinus into the right atrium, and the remodeling events that result in pulmonary venous return draining into the left atrium. In these processes, the atrioventricular mesenchymal complex, consisting of the major atrioventricular (AV) cushions, the mesenchymal cap on the primary atrial septum (pAS), and the dorsal mesenchymal protrusion (DMP), plays a crucial role.

Maternal exposure to dibutyl phthalate (DBP) impairs angiogenesis and AR signalling pathway through suppression of TGFB1I1 in hypospadias offspring.

Early exposure to dibutyl phthalate (DBP) can cause hypospadias in newborn foetuses. However, the underlying molecular mechanism is not well defined. Aberrant angiogenesis is associated with various dysplasias including urogenital deficits. In vivo and in vitro angiogenesis assays showed reduced angiogenesis in the hypospadias group and DBP exposed group. RNA-sequencing analysis of DBP-treated HUVECs revealed decreased expression of transforming growth factor beta 1-induced transcript 1 (TGFB1I1) and a significantly enriched angiogenesis-associated pathway. Further experiments revealed that decreased TGFB1I1 expression was associated with disrupted tube formation and migration, which resulted in decreased angiogenesis. Functional assays revealed that the overexpression of TGFB1I1 promoted tube formation and migration of HUVECs in the DBP-treated group. Moreover, we showed that the transcription factor AR was regulated by TGFB1I1 through inhibiting its translocation from the cytoplasm to the nucleus. Together, our results identified TGFB1I1 as a component of aberrant angiogenesis in hypospadias rats and its interaction with AR might be a potential target for hypospadias development.

Tobacco Smoke Condensate Induces Morphologic Changes in Human Papillomavirus-Positive Cervical Epithelial Cells Consistent with Epithelial to Mesenchymal Transition (EMT) with Activation of Receptor Tyrosine Kinases and Regulation of TGFB.

High-risk human papillomavirus (HR-HPV; HPV-16) and cigarette smoking are associated with cervical cancer (CC); however, the underlying mechanism(s) remain unclear. Additionally, the carcinogenic components of tobacco have been found in the cervical mucus of women smokers. Here, we determined the effects of cigarette smoke condensate (CSC; 3R4F) on human ectocervical cells (HPV-16 Ect/E6E7) exposed to CSC at various concentrations (10-6-100 µg/mL). We found CSC (10-3 or 10 µg/mL)-induced proliferation, enhanced migration, and histologic and electron microscopic changes consistent with EMT in ectocervical cells with a significant reduction in E-cadherin and an increase in the vimentin expression compared to controls at 72 h. There was increased phosphorylation of receptor tyrosine kinases (RTKs), including Eph receptors, FGFR, PDGFRA/B, and DDR2, with downstream Ras/MAPK/ERK1/2 activation and upregulation of common EMT-related genes, TGFB SNAI2, PDGFRB, and SMAD2. Our study demonstrated that CSC induces EMT in ectocervical cells with the upregulation of EMT-related genes, expression of protein biomarkers, and activation of RTKs that regulate TGFB expression, and other EMT-related genes. Understanding the molecular pathways and environmental factors that initiate EMT in ectocervical cells will help delineate molecular targets for intervention and define the role of EMT in the initiation and progression of cervical intraepithelial neoplasia and CC.

Control of the extracellular matrix by hypoxic lymphatic endothelial cells: Impact on the progression of lymphedema?

BACKGROUND: Initial lymphatic vessels do not have a continuous basement membrane. Therefore, the ability of lymphatic endothelial cells (LECs) to produce extracellular matrix (ECM) has received little attention. Untreated lymphedema is a chronic disease that progresses to massive fibrosclerosis in advanced stages. Expansion of the intercellular space and fibrosclerosis cause hypoxia, which also affects the LECs. RESULTS: We studied the expression of genes in human LECs in vitro by RNA sequencing, analyzed the effects of hypoxia (1% O2 ) vs. normoxia (21% O2 ), and focused on ECM genes. LECs express fibrillin-1 and many typical components of a basement membrane such as type IV, VIII, and XVIII collagen, laminin ß1, ß2, and α4, perlecan, and fibronectin. Under hypoxia, we found significant upregulation of expression of genes controlling hydroxylation of procollagen (PLOD2, P4HA1), and also cross-linking, bundling, and stabilization of collagen fibrils and fibers. Also striking was the highly significant downregulation of elastin expression, whereas fibulin-5, which controls the assembly of tropoelastin monomers, was upregulated under hypoxia. In the dermis from genital lymphedema, we observed significant PLOD2 expression in initial lymphatics. CONCLUSIONS: Overall, hypoxia results in the picture of a dysregulated ECM production of LECs, which might be partly responsible for the progression of fibrosclerosis in lymphedema.

Polymorphism of Transforming Growth Factor TGFB and Its Receptors TGFBRI, TGFBRII, TGFBRIIII Genes in Western Siberia Patients with Open-Angle Glaucoma.

Polymorphism of genes of transforming growth factor TGFB and its receptors (TGFBRI, TGFBRII, and TGFBRIIII) in patients with primary open-angle glaucoma was analyzed. The frequency of the TGFBRII CC genotype in patients is increased relative to the control group (OR=6.10, p=0.0028). Heterozygosity in this polymorphic position is reduced (OR=0.18, p=0.0052). As the effects of TGF-ß is mediated through its receptors, we analyzed complex of polymorphic variants of the studied loci in the genome of patients. Two protective complexes consisting only of receptor genes were identified: TGFBRI TT:TGFBRII CG (OR=0.10, p=0.02) and TGFBRII CG:TGFBRIII CG (OR=0.09, p=0.01). The study showed an association of TGFBRII polymorphism with primary open-angle glaucoma and the need to study functionally related genes in the development of the disease, which should contribute to its early diagnosis and prevention.

Hepatic stellate cell-released CXCL1 aggravates HCC malignant behaviors through the MIR4435-2HG/miR-506-3p/TGFB1 axis.

Hepatic stellate cell (HSC) activation is a critical event in the development of hepatic fibrosis and hepatocellular carcinoma (HCC). By the release of soluble cytokines, chemokines, and chemotaxis, HSCs affect HCC cell phenotypes through a complex tumor microenvironment. In this study, weighted gene co-expression network analysis (WGCNA) was used to identify the TGF-ß signaling pathway as a key signaling pathway in Hep3B cells cultured in HSC conditioned medium. MIR4435-2HG is a hub lncRNA associated with the TGF-ß signaling pathway and HSC activation. HSC-condition medium (CM) culture induced HCC cell malignant behaviors, which were partially reversed by MIR4435-2HG silencing. miR-506-3p directly bound to MIR4435-2HG and the 3'UTR of TGFB1. Similarly, overexpression of miR-506-3p also attenuated HSC-CM-induced malignant behavior of HCC cells. In HSC-CM cultured HCC cells, the effects of MIR4435-2HG knockdown on TGFB1 expression and HCC cell phenotypes were partially reversed by miR-506-3p inhibition. HSCs affected HCC cell phenotypes by releasing CXCL1. In an orthotopic xenotransplanted tumor model of HCC cells plus HSCs in mice, CXCR2 knockdown in HCC cells significantly inhibited tumorigenesis, which was partially reversed by MIR4435-2HG overexpression in HCC cells. In HCC tissue samples, the levels of CXCL1, TGF-ß1, and MIR4435-2HG were upregulated, while miR-506-3p expression was downregulated. In conclusion, HSC-released CXCL1 aggravated HCC cell malignant behaviors through the MIR4435-2HG/miR-506-3p/TGFB1 axis. In addition to CXCL1, the MIR4435-2HG/miR-506-3p/TGFB1 axis might also be the underlying target for HCC therapy.

Tumor suppressive activity of AHR in environmental arsenic-induced carcinogenesis.

The aryl hydrocarbon receptor (AHR) is a highly conserved pleiotropic transcription factor that senses environmental pollutants, microbial products, and endogenous ligands. The transcriptional targets of AHR include phase I and phase II detoxification enzymes, as well as numerous signaling molecules that affect a wide spectrum of biological and biochemical processes in a manner of cellular context-dependent. In this review, we systematically assess the latest discoveries of AHR in carcinogenesis with an emphasis on its tumor suppressor-like property that represses the expression of genes in oncogenic signaling pathways. Additionally, we outline recent progress in our studies on the interaction among AHR, TGFb and NRF2 in cellular responses to arsenic and malignant transformation. Our findings indicate that AHR antagonized TGFb and NRF2, suggesting that AHR could serve as a potential tumor suppressor in arsenic-induced carcinogenesis. Notably, while AHR can exhibit both oncogenic and tumor-suppressive properties in cancer development and the generation of the cancer stem-like cells (CSCs), the tumor suppressor-like effect of AHR warrants further extensive exploration for the prevention and clinical treatment of cancers.