Transforming growth factor‐β (TGF‐β) is the key player in tissue fibrosis. However, antifibrotic therapy targeting this multifunctional protein may interfere with other physiological processes to ...cause side effects. Thus, precise therapeutic targets need to be identified by further understanding the underlying mechanisms of TGF‐β1 signalling during fibrogenesis. Equilibrium of Smad signalling is crucial for TGF‐β‐mediated renal fibrosis, where Smad3 is pathogenic but Smad2 and Smad7 are protective. The activation of TGF‐β1/Smad signalling triggers extracellular matrix deposition, and local myofibroblast generation and activation. Mechanistic studies have shown that TGF‐β/Smad3 transits the microRNA profile from antifibrotic to profibrotic and therefore promotes renal fibrosis via regulating non‐coding RNAs at transcriptional levels. More importantly, disease‐specific Smad3‐dependent long non‐coding RNAs have been recently uncovered from mouse kidney disease models and may represent novel precision therapeutic targets for chronic kidney disease. In this review, mechanisms of TGF‐β‐driven renal fibrosis via non‐coding RNAs and their translational capacities will be discussed in detail.
TGF‐β1/Smad3 signaling promotes renal fibrosis via transcriptional regulation. TGF‐β1 triggers the development and progression of renal fibrosis in the injured kidney by regulating the expression levels of both pro‐fibrotic and anti‐fibrotic genes at transcriptional level via Smad3 activation.
Transforming growth factor-β (TGF-β) signaling triggers diverse biological actions in inflammatory diseases. In tissue fibrosis, it acts as a key pathogenic regulator for promoting immunoregulation ...via controlling the activation, proliferation, and apoptosis of immunocytes. In cancer, it plays a critical role in tumor microenvironment (TME) for accelerating invasion, metastasis, angiogenesis, and immunosuppression. Increasing evidence suggest a pleiotropic nature of TGF-β signaling as a critical pathway for generating fibrotic TME, which contains numerous cancer-associated fibroblasts (CAFs), extracellular matrix proteins, and remodeling enzymes. Its pathogenic roles and working mechanisms in tumorigenesis are still largely unclear. Importantly, recent studies successfully demonstrated the clinical implications of fibrotic TME in cancer. This review systematically summarized the latest updates and discoveries of TGF-β signaling in the fibrotic TME.
Transforming growth factor-β/Smad3 signaling plays an important role in diabetic nephropathy, but its underlying working mechanism remains largely unexplored. The current study uncovered the ...pathogenic role and underlying mechanism of a novel Smad3-dependent long noncoding RNA (lncRNA) (LRNA9884) in type 2 diabetic nephropathy (T2DN). We found that LRNA9884 was significantly upregulated in the diabetic kidney of
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mice at the age of 8 weeks preceding the onset of microalbuminuria and was associated with the progression of diabetic renal injury. LRNA9884 was induced by advanced glycation end products and tightly regulated by Smad3, and its levels were significantly blunted in
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mice and cells lacking Smad3. More importantly, kidney-specific silencing of LRNA9884 effectively attenuated diabetic kidney injury in
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mice, as shown by the reduction of histological injury, albuminuria excretion, and serum creatinine. Mechanistically, we identified that LRNA9884 promoted renal inflammation-driven T2DN by triggering MCP-1 production at the transcriptional level, and its direct binding significantly enhanced the promoter activity of MCP-1. Thus, LRNA9884 is a novel Smad3-dependent lncRNA that is highly expressed in
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mice associated with T2DN development. Targeting of LRNA9884 effectively blocked MCP-1-dependent renal inflammation, therefore suppressing the progressive diabetic renal injury in
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mice. This study reveals that LRNA9884 may be a novel and precision therapeutic target for T2DN in the future.
Unresolved inflammation can lead to tissue fibrosis and impaired organ function. Macrophage–myofibroblast transition (MMT) is one newly identified mechanism by which ongoing chronic inflammation ...causes progressive fibrosis in different forms of kidney disease. However, the mechanisms underlying MMT are still largely unknown. Here, we discovered a brain-specific homeobox/POU domain protein Pou4f1 (Brn3a) as a specific regulator of MMT. Interestingly, we found that Pou4f1 is highly expressed by macrophages undergoing MMT in sites of fibrosis in human and experimental kidney disease, identified by coexpression of the myofibroblast marker, α-SMA. Unexpectedly, Pou4f1 expression peaked in the early stage in renal fibrogenesis in vivo and during MMT of bone marrow-derived macrophages (BMDMs) in vitro. Mechanistically, chromatin immunoprecipitation (ChIP) assay identified that Pou4f1 is a Smad3 target and the key downstream regulator of MMT, while microarray analysis defined a Pou4f1-dependent fibrogenic gene network for promoting TGF-β1/Smad3-driven MMT in BMDMs at the transcriptional level. More importantly, using two mouse models of progressive renal interstitial fibrosis featuring the MMT process, we demonstrated that adoptive transfer of TGF-β1-stimulated BMDMs restored both MMT and renal fibrosis in macrophage-depleted mice, which was prevented by silencing Pou4f1 in transferred BMDMs. These findings establish a role for Pou4f1 in MMT and renal fibrosis and suggest that Pou4f1 may be a therapeutic target for chronic kidney disease with progressive renal fibrosis.
Cancer‐associated fibroblasts (CAFs) are important in tumor microenvironment (TME) driven cancer progression. However, CAFs are heterogeneous and still largely underdefined, better understanding ...their origins will identify new therapeutic strategies for cancer. Here, the authors discovered a new role of macrophage‐myofibroblast transition (MMT) in cancer for de novo generating protumoral CAFs by resolving the transcriptome dynamics of tumor‐associated macrophages (TAM) with single‐cell resolution. MMT cells (MMTs) are observed in non‐small‐cell lung carcinoma (NSCLC) associated with CAF abundance and patient mortality. By fate‐mapping study, RNA velocity, and pseudotime analysis, existence of novel macrophage‐lineage‐derived CAF subset in the TME of Lewis lung carcinoma (LLC) model is confirmed, which is directly transited via MMT from M2‐TAM in vivo and bone‐marrow‐derived macrophages (BMDM) in vitro. Adoptive transfer of BMDM‐derived MMTs markedly promote CAF formation in LLC‐bearing mice. Mechanistically, a Smad3‐centric regulatory network is upregulated in the MMTs of NSCLC, where chromatin immunoprecipitation sequencing(ChIP‐seq) detects a significant enrichment of Smad3 binding on fibroblast differentiation genes in the macrophage‐lineage cells in LLC‐tumor. More importantly, macrophage‐specific deletion and pharmaceutical inhibition of Smad3 effectively block MMT, therefore, suppressing the CAF formation and cancer progression in vivo. Thus, MMT may represent a novel therapeutic target of CAF for cancer immunotherapy.
Here, the authors discovered a direct mechanism of tumor‐associated macrophages for de novo generating protumoral cancer‐associated fibroblasts (CAF) via macrophage‐myofibroblast transition (MMT) by resolving their transcriptome dynamics at single‐cell resolution. Encouragingly, targeting the MMT key regulator Smad3 effectively blocked the production and protumoral actions of CAF, evidencing its translational potential as a novel therapeutic target in the tumour microenvironment for cancer.
Cancer cells are high in heterogeneity and versatility, which can easily adapt to the external stresses via both primary and secondary resistance. Targeting of tumour microenvironment (TME) is a new ...approach and an ideal therapeutic strategy especially for the multidrug resistant cancer. Recently, we invented AANG, a natural compound formula containing traditional Chinese medicine (TCM) derived Smad3 inhibitor Naringenin (NG) and Smad7 activator Asiatic Acid (AA), for rebalancing TGF‐β/Smad signalling in the TME, and its implication on the multidrug resistance is still unexplored. Here, we observed that an equilibrium shift of the Smad signalling in patients with hepatocellular carcinoma (HCC), which was dramatically enhanced in the recurrent cases showing p‐glycoprotein overexpression. We optimized the formula ratio and dosage of AANG that effectively inhibit the proliferation of our unique human multidrug resistant subclone R‐HepG2. Mechanistically, we found that AANG not only inhibits Smad3 at post‐transcriptional level, but also upregulates Smad7 at transcriptional level in a synergistic manner in vitro. More importantly, AANG markedly suppressed the growth and p‐glycoprotein expression of R‐HepG2 xenografts in vivo. Thus, AANG may represent a novel and safe TCM‐derived natural compound formula for overcoming HCC with p‐glycoprotein‐mediated multidrug resistance.
Neutrophils are dynamic with their phenotype and function shaped by the microenvironment, such as the N1 antitumor and N2 pro-tumor states within the tumor microenvironment (TME), but its regulation ...remains undefined. Here we examine TGF-β1/Smad3 signaling in tumor-associated neutrophils (TANs) in non-small cell lung carcinoma (NSCLC) patients. Smad3 activation in N2 TANs is negatively correlate with the N1 population and patient survival. In experimental lung carcinoma, TANs switch from a predominant N2 state in wild-type mice to an N1 state in Smad3-KO mice which associate with enhanced neutrophil infiltration and tumor regression. Neutrophil depletion abrogates the N1 anticancer phenotype in Smad3-KO mice, while adoptive transfer of Smad3-KO neutrophils reproduces this protective effect in wild-type mice. Single-cell analysis uncovers a TAN subset showing a mature N1 phenotype in Smad3-KO TME, whereas wild-type TANs mainly retain an immature N2 state due to Smad3. Mechanistically, TME-induced Smad3 target genes related to cell fate determination to preserve the N2 state of TAN. Importantly, genetic deletion and pharmaceutical inhibition of Smad3 enhance the anticancer capacity of neutrophils against NSCLC via promoting their N1 maturation. Thus, our work suggests that Smad3 signaling in neutrophils may represent a therapeutic target for cancer immunotherapy.
Renal fibrosis is a common fate of chronic kidney diseases. Emerging studies suggest that unsolved inflammation will progressively transit into tissue fibrosis that finally results in an irreversible ...end-stage renal disease (ESRD). Renal inflammation recruits and activates immunocytes, which largely promotes tissue scarring of the diseased kidney. Importantly, studies have suggested a crucial role of innate immunity in the pathologic basis of kidney diseases. This review provides an update of both clinical and experimental information, focused on how innate immune signaling contributes to renal fibrogenesis. A better understanding of the underlying mechanisms may uncover a novel therapeutic strategy for ESRD.
Transforming growth factor-β (TGF-β) signaling shows important roles in both physiology and pathology, especially in the progression of inflammatory diseases including cancer. Interestingly, TGF-β ...was first reported as a cancer suppressor, but increasing evidence confirmed its protumoral actions. Paradoxically, TGF-β can be produced by both cancer cells and stromal cells as a signaling network, which actively shapes the tumor microenvironment (TME). Surprisingly, disruption of TGF-β signaling results in both anti-cancer and pro-tumoral phenotypes in experimental cancer models, revealing the unexpected complexity of its downstream pathways for mediating cancer progression. Thus, a better understanding of the underlying mechanisms of TGF-β signaling at the molecular level can bring new insights for developing medications that can precisely separate the anti-cancer actions from the tumor-promoting outcomes. Here, we systematically summarized the latest discoveries of TGF-β signaling in cancer cells and the TME and discussed their translational implications for cancer.
•TGF-β acts as a Tumor suppressor via inducing cell cycle arrest and apoptosis in the initial stages of carcinogenesis.•TGF-β is primary immunomodulator in TME, suppressing anticancer immunity and increasing protumoral elements for cancer growth.•TGF-β enforces immunological homeostasis and tolerance in TME, limiting expansion and function of several immune elements.•The pathogenic downstream of TGF-β signaling networks could be targeted for developing potent and safe immunotherapies.
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