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The master cytokine TGF-β mediates tissue fibrosis associated with inflammation and tissue injury. TGF-β induces fibroblast activation and differentiation into myofibroblasts that secrete extracellular matrix proteins. Canonical TGF-β signaling mobilizes Smad2 and Smad3 transcription factors that control fibrosis by promoting gene expression. However, the importance of TGF-β-Smad2/3 signaling in fibroblast-mediated cardiac fibrosis has not been directly evaluated in vivo. Here, we examined pressure overload-induced cardiac fibrosis in fibroblast- and myofibroblast-specific inducible Cre-expressing mouse lines with selective deletion of the TGF-β receptors Tgfbr1/2, Smad2, or Smad3. Fibroblast-specific deletion of Tgfbr1/2 or Smad3, but not Smad2, markedly reduced the pressure overload-induced fibrotic response as well as fibrosis mediated by a heart-specific, latency-resistant TGF-β mutant transgene. Interestingly, cardiac fibroblast-specific deletion of Tgfbr1/2, but not Smad2/3, attenuated the cardiac hypertrophic response to pressure overload stimulation. Mechanistically, loss of Smad2/3 from tissue-resident fibroblasts attenuated injury-induced cellular expansion within the heart and the expression of fibrosis-mediating genes. Deletion of Smad2/3 or Tgfbr1/2 from cardiac fibroblasts similarly inhibited the gene program for fibrosis and extracellular matrix remodeling, although deletion of Tgfbr1/2 uniquely altered expression of an array of regulatory genes involved in cardiomyocyte homeostasis and disease compensation. These findings implicate TGF-β-Smad2/3 signaling in activated tissue-resident cardiac fibroblasts as principal mediators of the fibrotic response.

Background Lung adenocarcinoma (LUAD) is the leading cause of death worldwide. However, the roles of long noncoding RNAs (lncRNAs) hijacked by super-enhancers (SEs), vital regulatory elements of the epigenome, remain elusive in the progression of LUAD metastasis. Methods SE-associated lncRNA microarrays were used to identify the dysregulated lncRNAs in LUAD. ChIP-seq, Hi-C data analysis, and luciferase reporter assays were utilized to confirm the hijacking of LINC01977 by SE. The functions and mechanisms of LINC01977 in LUAD were explored by a series of in vitro and in vivo assays. Results We found that LINC01977 , a cancer-testis lncRNA, was hijacked by SE, which promoted proliferation and invasion both in vitro and in vivo. LINC01977 interacted with SMAD3 to induce its nuclear transport, which facilitated the interaction between SMAD3 and CBP/P300, thereby regulating the downstream target gene ZEB1. Additionally, SMAD3 up-regulated LINC09177 transcription by simultaneously binding the promoter and SE, which was induced by the infiltration of M2-like tumor-associated macrophages (TAM2), subsequently activating the TGF-β/SMAD3 pathway. Moreover, LINC01977 expression was positively correlated with TAM2 infiltration and SMAD3 expression, especially in early-stage LUAD. Higher chromatin accessibility in the SE region of LINC01977 was observed with high expression of TGF-β. Early-stage LUAD patients with high LIN01977 expression had a shorter disease-free survival. Conclusions TAM2 infiltration induced a rich TGF-β microenvironment, activating SMAD3 to bind the promoter and the SE of LINC01977 , which up-regulated LINC01977 expression. LINC01977 also promoted malignancy via the canonical TGF-β/SMAD3 pathway. LINC01977 hijacked by SE could be a valuable therapeutic target, especially for the treatment of early-stage LUAD.

Background Dysregulation or abnormality of the programmed cell death (PCD) pathway is closely related to the occurrence and development of many tumors, including acute myeloid leukemia (AML). Studying the abnormal characteristics of PCD pathway-related molecular markers can provide a basis for prognosis prediction and targeted drug design in AML patients. Methods A total of 1394 genes representing 13 different PCD pathways were examined in AML patients and healthy donors. The upregulated genes were analyzed for their ability to predict overall survival (OS) individually, and these prognostic genes were subsequently combined to construct a PCD-related prognostic signature via an integrated approach consisting of 101 models based on ten machine learning algorithms. RNA transcriptome and clinical data from multiple AML cohorts (TCGA-AML, GSE106291, GSE146173 and Beat AML) were obtained to develop and validate the AML prognostic model. Results A total of 214 upregulated PCD-related genes were identified in AML patients, 39 of which were proven to be prognostic genes in the training cohort. On the basis of the average C-index and number of model genes identified from the machine learning combinations, a PCD index was developed and validated for predicting AML OS. A prognostic nomogram was then generated and validated on the basis of the PCD index, age and ELN risk stratification in the Beat AML cohort and the GSE146173 cohort, revealing satisfactory predictive power (AUC values ≥ 0.7). With different mutation patterns, a higher PCD index was associated with a worse OS. The PCD index was significantly related to higher scores for immunosuppressive cells and mature leukemia cell subtypes. As the gene most closely related to the PCD index, the expression of SMAD3 was further validated in vitro. AML cells harboring KMT2A rearrangements were more sensitive to the SMAD3 inhibitor SIS3, and the expression of the autophagy-related molecular marker LC3 was increased in KMT2A -rearranged cell lines after SIS3 monotherapy and combined treatment. Conclusion The PCD index and SMAD3 gene expression levels have potential prognostic value and can be used in targeted therapy for AML, and these findings can lead to the development of effective strategies for the combined treatment of high-risk AML patients.

The process of oncogene-induced senescence (OIS) and the conversion between OIS and malignant transformation during carcinogenesis is poorly understood. Here, we show that following overactivation of oncogene Ras in lung epithelial cells, high-level transforming growth factor β1 (TGF-β1)—activated SMAD3, but not SMAD2 or SMAD4, plays a determinant role in inducing cellular senescence independent of the p53/p16/p15 senescence pathways. Importantly, SMAD3 binds a potential tumor suppressor ATOH8 to form a transcriptional complex that directly represses a series of cell cycle—promoting genes and consequently causes senescence in lung epithelial cells. Interestingly, the prosenescent SMAD3 converts to being oncogenic and essentially facilitates oncogenic Ras-driven malignant transformation. Furthermore, depleting Atoh8 rapidly accelerates oncogenic Ras-driven lung tumorigenesis, and lung cancers driven by mutant Ras and Atoh8 loss, but not by mutant Ras only, are sensitive to treatment of a specific SMAD3 inhibitor. Moreover, hypermethylation of the ATOH8 gene can be found in approximately 12% of clinical lung cancer cases. Together, our findings demonstrate not only epithelial cellular senescence directed by a potential tumor suppressor—controlled transcriptional program but also an important interplay between the prosenescent and transforming effects of TGF-β/SMAD3, potentially laying a foundation for developing early detection and anticancer strategies.

In pancreatic ductal adenocarcinoma (PDAC), features of epithelial–mesenchymal transition (EMT) are often seen in tumor tissue, and such features correlate with poor prognosis. Solitary infiltration of tumor cells represents a morphological phenotype of EMT, and we previously reported that a high degree of solitary cell infiltration correlates with EMT-like features, including reduced E-cadherin and elevated vimentin levels. Using solitary cell infiltration to evaluate the degree of EMT, gene-expression profiling of 12 PDAC xenografts was performed, and SMAD3 was identified as an EMT-related gene. Immunohistochemistry using clinical specimens (n=113) showed that SMAD3 accumulated in the nuclei of tumor cells, but was not detected in most epithelial cells in the pancreatic duct. Moreover, SMAD3 upregulation correlated with malignant characteristics, such as higher tumor grade and lymph node metastasis, as well as with EMT-like features. SMAD4, which plays a key role in transforming growth factor-β (TGF-β) signaling, is inactivated in approximately half of PDAC cases. In this study, the nuclear accumulation of SMAD3 was immunohistochemically detected even in SMAD4-negative cases. SMAD3 knockdown resulted in upregulated E-cadherin, downregulated vimentin, and reduced cell motility in pancreatic cancer cells regardless of SMAD4 status. In addition, TGF-β-treatment resulted in EMT induction in cells carrying wild-type SMAD4, and EMT was suppressed by SMAD3 knockdown. Patients with upregulated SMAD3 and a high degree of solitary cell infiltration had shorter times to recurrence and shorter survival times after surgery, and multivariate analysis showed that both factors were independent prognostic factors linked to unfavorable outcomes. These findings suggest that SMAD3 in PDAC is involved in the promotion of malignant potential through EMT induction in tumor cells regardless of SMAD4 status and serves as a potential biomarker of poor prognosis.

Transforming growth factor‐beta (TGF‐β) functions as a potent proliferation inhibitor and apoptosis inducer in the early stages of breast cancer, yet promotes cancer aggressiveness in the advanced stages. The dual effect of TGF‐β on cancer development is known as TGF‐β paradox, and the remarkable functional conversion of TGF‐β is a pivotal and controversial phenomenon that has been widely investigated for decades. This phenomenon may be attributed to the cross talk between TGF‐β signaling and other pathways, including EGF receptor (EGFR) signaling during cancer progression. However, the underlying mechanism by which TGF‐β shifts its role from a tumor suppressor to a cancer promoter remains elusive. In this study, TGF‐β is positively correlated with EGFR expression in breast cancer tissues, and a functional linkage is observed between TGF‐β signaling and EGFR transactivation in breast cancer cell lines. TGF‐β promotes the migration and invasion abilities of breast cancer cells, along with the increase in EGFR expression. EGFR is also essential for TGF‐β‐induced enhancement of these abilities of breast cancer cells. Canonical Smad3 signaling and ERK/Sp1 signaling pathways mediate TGF‐β‐induced EGFR upregulation. Hence, our study provided insights into a novel mechanism by which TGF‐β supports breast cancer progression. Transforming growth factor (TGF)‐β promotes the migration and invasion abilities of breast cancer cells through the upregulation of EGFR expression. Canonical Smad3 signaling and ERK/Sp1 signaling pathways are required for the TGF‐β‐induced upregulation of EGFR and the enhancement of migration and invasion abilities of breast cancer cells. Hence, our findings provided insights into a novel mechanism by which TGF‐β favors breast cancer progression.

Introduction Epithelial-mesenchymal transition (EMT) plays a crucial role in diabetic kidney disease (DKD), particularly in the context of podocyte EMT. However, the regulatory networks controlling EMT activation in podocytes remain incompletely mapped. The FOS proto-oncogene (FOS) has emerged as a key player in EMT, yet its functional significance in DKD-podocytes remains poorly defined. Methods The predictive validity of FOS was confirmed through least absolute shrinkage and selection operator (LASSO) regression and multivariable logistic analysis in clinical data. A streptozotocin-induced DKD rat model was established, and podocyte cells (MPC5, HPC) treated with high glucose served as an in vitro model. The functional effect of FOS was explored using genetic interventions in vivo and in vitro. Results FOS expression is increased in patients with DKD, correlating with deterioration in renal function. LASSO and logistic analyses identified FOS as a robust predictor of DKD progression. FOS deficiency in vivo attenuated renal dysfunction and fibrosis. In podocytes, high glucose-primed FOS induced EMT and collagen accumulation, effects reversed by FOS knockdown. Crucially, FOS directly bound and activated Smad3, while Smad3 silencing abolished FOS-mediated injury. Conclusion This study demonstrates that the FOS/Smad3 axis is a critical contributor to coordinating EMT and fibrosis in diabetic renal podocytes, proposing a novel therapeutic target in DKD.

Idiopathic pulmonary fibrosis (IPF) is a fatal interstitial lung disease with limited therapeutic options. Tartrate-resistant acid phosphatase 5 (ACP5) performs a variety of functions. However, its role in IPF remains unclear. Here, we demonstrate that the levels of ACP5 are increased in IPF patient samples and mice with bleomycin (BLM)-induced pulmonary fibrosis. In particular, higher levels of ACP5 are present in the sera of IPF patients with a diffusing capacity of the lungs for carbonmonoxide (DLCO) less than 40% of the predicted value. Additionally, Acp5 deficiency protects mice from BLM-induced lung injury and fibrosis coupled with a significant reduction of fibroblast differentiation and proliferation. Mechanistic studies reveal that Acp5 is upregulated by transforming growth factor-β1 (TGF-β1) in a TGF-β receptor 1 (TGFβR1)/Smad family member 3 (Smad3)-dependent manner, after which Acp5 dephosphorylates p-β-catenin at serine 33 and threonine 41, inhibiting the degradation of β-catenin and subsequently enhancing β-catenin signaling in the nucleus, which promotes the differentiation, proliferation and migration of fibroblast. More importantly, the treatment of mice with Acp5 siRNA-loaded liposomes or Acp5 inhibitor reverses established lung fibrosis. In conclusions, Acp5 is involved in the initiation and progression of pulmonary fibrosis and strategies aimed at silencing or suppressing Acp5 could be considered as potential therapeutic approaches against pulmonary fibrosis. Idiopathic pulmonary fibrosis is a fatal lung disease with limited treatment options. Here the authors show that tartrate-resistant acid phosphatase 5 (Acp5) promotes lung fibrosis by enhancing beta-catenin signaling and that inhibition of Acp5 can reverse stablished pulmonary fibrosis.

Trimethylamine N-oxide (TMAO), a gut microbe-derived metabolite of dietary choline and other trimethylamine-containing nutrients, has been linked to increased cardiovascular disease risk. It is unknown whether TMAO plays a role in the development of cardiac hypertrophy. Transverse aortic constriction (TAC) was performed to induce cardiac hypertrophy in Sprague-Dawley (SD) rats. We observed that TMAO levels were significantly elevated in SD rats after 6 weeks of TAC, suggesting the potential role of TMAO in regulating cardiac hypertrophy. In cultured cardiomyocytes, TMAO treatment stimulated cardiac hypertrophy, as indicated by increased cell area of cardiomyocytes and expression of hypertrophic markers including atrial natriuretic peptide (ANP) and beta-myosin heavy chain (β-MHC). Additionally, TMAO treatment induced cardiac hypertrophy and cardiac fibrosis in SD rats. Reducing TMAO synthesis by antibiotics (Abs) attenuated TAC-induced cardiac hypertrophy and fibrosis. Furthermore, pharmacological inhibition of Smad3 by SIS3 significantly reduced the expression of ANP and β-MHC, and cardiomyocyte cell size in TMAO-treated group. These data for the first time demonstrate that gut microbe-derived metabolite TMAO induces cardiac hypertrophy and fibrosis involving Smad3 signaling, suggesting that inhibition of gut microbes or generation of TMAO may become a potential target for the prevention and treatment of cardiac hypertrophy.

Background/Aims: Endothelial-to-mesenchymal transition (EndMT) plays significant roles under various pathological conditions including cardiovascular diseases, fibrosis, and cancer. EndMT of endothelial progenitor cells (EPCs) contributes to neointimal hyperplasia following cell therapy Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is a long non-coding RNA (lncRNA) that promotes metastasis and cancer. MicroRNA-145 (miR-145) is a tumor suppressor that has been reported to inhibit SMAD3-mediated epithelial-to-mesenchymal transition (EMT) of cancer cells. In the present study, we investigated the role of MALAT1 and miR-145 in EndMT of human circulating EPCs induced by transforming growth factor beta1 (TGF-β1). Methods: Human circulating EPCs were isolated and characterized by fluorescence-activated cell sorting (FACS). Expression levels of EndMT markers were assessed by qRT-PCR and western blotting. Alpha-smooth muscle actin (α-SMA) expression was measured by cell immunofluorescence staining. The regulatory relationship between MALAT1 and miR-145 and its target genes, TGFBR2 (TGFβ receptortype II) and SMAD3 (mothers against decapentaplegic homolog 3) was analyzed using the luciferase reporter assay. Results: We found that EndMT of EPCs induced by TGF-β1 is accompanied by increased MALAT1 expression and decreased miR-145 expression, and MALAT1 and miR-145 directly bind and reciprocally repress each other in these cells. Dual-Luciferase Reporter assay indicated that miR-145 inhibits TGF-β1-induced EndMT by directly targeting TGFBR2 and SMAD3. Conclusions: MALAT1 modulates TGF-β1-induced EndMT of EPCs through regulation of TGFBR2 and SMAD3 via miR-145. Thus, the MALAT1-miR-145-TGFBR2/SMAD3 signaling pathway plays a key role in TGF-β1-induced EndMT.