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Despite the success of immunotherapy in treating hepatocellular carcinoma (HCC), HCC remains a severe threat to health. Here, a crucial transcription factor, SOX12, is revealed that induces the immunosuppression of liver tumor microenvironment. Overexpressing SOX12 in HCC syngeneic models increases intratumoral regulatory T‐cell (Treg) infiltration, decreases CD8+T‐cell infiltration, and hastens HCC metastasis. Hepatocyte‐specific SOX12 knockout attenuates DEN/CCl4‐induced HCC progression and metastasis, whereas hepatocyte‐specific SOX12 knock‐in accelerates these effects. Mechanistically, SOX12 transcriptionally activates C‐C motif chemokine ligand 22 (CCL22) expression to promote the recruitment and suppressive activity of Tregs. Moreover, SOX12 transcriptionally upregulates CD274 expression to suppress CD8+T‐cell infiltration. Either knockdown of CCL22 or PD‐L1 dampens SOX12‐mediated HCC metastasis. Blocking of CC chemokine receptor 4 (CCR4), a receptor for CCL22, by inhibitor C‐021 or Treg‐specific knockout of CCR4 inhibits SOX12‐mediated HCC metastasis. Transforming growth factor‐β1 (TGF‐β1)/TGFβR1‐Smad2/3/4 is identified as a key upstream signaling for SOX12 overexpression in HCC cells. Combining C‐021 or TGFβR1 inhibitor galunisertib with anti‐PD‐L1 exhibits an enhanced antitumor effect in two HCC models. Collectively, the findings demonstrate that SOX12 contributes to HCC immunosuppression through the CCL22/CCR4‐Treg and PD‐L1‐CD8+T axes. Blocking of CCR4 or TGFβR1 improves the efficacy of anti‐PD‐L1 in SOX12‐mediated HCC. Transforming growth factor‐β1 (TGF‐β1)‐stimulated SOX12 overexpression remodels the immunosuppressive microenvironment of hepatocellular carcinoma (HCC), promoting tumor progression and metastasis. SOX12 boosts regulatory T cells (Tregs) through the C‐C motif chemokine ligand 22/CC chemokine receptor 4 (CCR4) axis and dampens CD8+T cells via PD‐L1 upregulation. Combining the CCR4 inhibitor C‐021 or TGF‐β1 receptor inhibitor galunisertib with anti‐PD‐L1 inhibits SOX12‐mediated effect.

Gallbladder cancer (GBC), a rare but lethal disease, is often diagnosed at advanced stages. So far, molecular characterization of GBC is insufficient, and a comprehensive molecular portrait is warranted to uncover new targets and classify GBC. We performed a transcriptome analysis of both coding and non-coding RNAs from 36 GBC fresh-frozen samples. The results were integrated with those of comprehensive mutation profiling based on whole-genome or exome sequencing. The clustering analysis of RNA-seq data facilitated the classification of GBCs into two subclasses, characterized by high or low expression levels of TME (tumor microenvironment) genes. A correlation was observed between gene expression and pathological immunostaining. TME-rich tumors showed significantly poor prognosis and higher recurrence rate than TME-poor tumors. TME-rich tumors showed overexpression of genes involved in epithelial-to-mesenchymal transition (EMT) and inflammation or immune suppression, which was validated by immunostaining. One non-coding RNA, miR125B1, exhibited elevated expression in stroma-rich tumors, and miR125B1 knockout in GBC cell lines decreased its invasion ability and altered the EMT pathway. Mutation profiles revealed TP53 (47%) as the most commonly mutated gene, followed by ELF3 (13%) and ARID1A (11%). Mutations of ARID1A, ERBB3, and the genes related to the TGF-β signaling pathway were enriched in TME-rich tumors. This comprehensive analysis demonstrated that TME, EMT, and TGF-β pathway alterations are the main drivers of GBC and provides a new classification of GBCs that may be useful for therapeutic decision-making.

Constitutive activation of TGF-β signaling pathway is a well-documented mechanism responsible for the bone metastasis of prostate cancer (PCa). MicroRNAs (miRNAs) have been reported to be crucial for the activation of TGF-β signaling via targeting downstream components of TGF-β signaling pathway. Here, we report that miR-19a-3p is downregulated in bone metastatic PCa tissues and cells. Upregulation of miR-19a-3p suppresses invasion, migration in vitro and inhibits bone metastasis in vivo in PCa cells. Conversely, silencing miR-19a-3p yields the opposite effect. Our results further demonstrate that miR-19a-3p inhibits invasion and migration abilities of PCa cells via targeting downstream effectors of TGF-β signaling, SMAD2 and SMAD4, resulting in the inactivation of TGF-β signaling. Therefore, our results uncover a novel mechanistic understanding of miR-19a-3p-induced suppressive role in bone metastasis of PCa, which will facilitate the development of effective cancer therapy methods against PCa.

Bone metastasis is associated with cancer‐related death in patients with prostate cancer (PCa). Long noncoding RNAs (lncRNAs) play critical roles in tumor progression of PCa. Nevertheless, the biological function of lncRNAs in PCa bone metastasis remains unclear. PCAT7 was identified as a bone metastasis‐related lncRNA via analyzing TCGA dataset. Meanwhile, PCAT7 was found to be elevated in primary PCa tissues with bone metastasis and associated with bone metastasis status and poor prognosis of patients with PCa. Functionally, our results reveal that PCAT7 overexpression promotes PCa bone metastasis in vivo, as well as migration, invasion, and EMT of PCa cells in vitro; on the contrary, PCAT7 knockdown has an inverse effect. Mechanistically, PCAT7 activates TGF‐β/SMAD signaling by upregulating TGFBR1 expression via sponging miR‐324‐5p. In turn, TGF‐β signaling forms a positive feedback loop with PCAT7 via SMAD3/SP1 complex‐induced PCAT7 upregulation. Finally, the clinical positive correlation between PCAT7 and TGFBR1 and TGF‐β signaling activity, and the negative association with miR‐324‐5p are further demonstrated in PCa tissues and clinical primary PCa cells. This study reveals a novel mechanism that is responsible for the constitutive activation of TGF‐β signaling in PCa bone metastasis, implying that PCAT7 can act as a potential therapeutic target against bone metastasis of PCa via disrupting the constitutive active loop between PCAT7 and TGF‐β signaling. lncRNA PCAT7 is upregulated in primary prostate cancer tissues with bone metastasis. PCAT7 activates TGF‐β/SMAD signaling by upregulating TGFBR1 expression via sponging miR‐324‐5p. In turn, TGF‐β signaling forms a positive feedback loop with PCAT7 via SMAD3/SP1 complex‐induced PCAT7 upregulation. This feedback loop promotes prostate cancer bone metastasis.

Cell division cycle associated 7 (CDCA7) is a copy number amplification gene that contributes to the metastasis and invasion of tumors, including esophageal squamous cell carcinoma (ESCC). This present study aimed at clarifying whether high expression of CDCA7 promotes the metastasis and invasion of ESCC cell lines and exploring the underlying mechanisms implicated in epithelial–mesenchymal transition (EMT) of ESCC. The role of CDCA7 in the regulation of ESCC metastasis and invasion was evaluated using ESCC cell lines. Expression of EMT‐related markers including E‐cadherin, N‐cadherin, Vimentin, Snail, and Slug, transforming growth factor β (TGF‐β) signaling pathway including Smad2/3, p‐Smad2/3, Smad4, and Smad7 were detected in CDCA7 knockdown and overexpressed cell lines. Dual‐luciferase reporter assay and rescue assay were used to explore the underlying mechanisms that CDCA7 contributed to the metastasis and invasion of ESCC. High CDCA7 expression significantly promoted the metastasis and invasion of ESCC cell lines both in vivo and in vitro. Additionally, the expression of CDCA7 positively correlated with the expression of N‐cadherin, Vimentin, Snail, Slug, TGF‐β signaling pathway and negatively correlated with the expression of E‐cadherin. Furthermore, CDCA7 transcriptionally regulated the expression of Smad4 and Smad7. Knockdown of CDCA7 inhibited the TGF‐β signaling pathway and therefore inhibited EMT. Our data indicated that CDCA7 was heavily involved in EMT by regulating the expression of Smad4 and Smad7 in TGF‐β signaling pathway. CDCA7 might be a new therapeutic target in the suppression of metastasis and invasion of ESCC. High cell division cycle associated 7 (CDCA7) expression significantly promoted the metastasis and invasion of esophageal squamous cell carcinoma cell lines both in vivo and in vitro. The expression of CDCA7 positively correlated with the expression of N‐cadherin, Vimentin, Snail, Slug, transforming growth factor β signaling pathway and negatively correlated with the expression of E‐cadherin. CDCA7 transcriptionally regulated the expression of Smad4 and Smad7

Objectives Pulp regeneration brings big challenges for clinicians, and vascularization is considered as its determining factor. We previously accomplished pulp regeneration with autologous stem cells from deciduous teeth (SHED) aggregates implantation in teenager patients, however, the underlying mechanism needs to be clarified for regenerating pulp in adults. Serving as an important effector of mesenchymal stem cells (MSCs), exosomes have been reported to promote angiogenesis and tissue regeneration effectively. Here, we aimed to investigate the role of SHED aggregate‐derived exosomes (SA‐Exo) in the angiogenesis of pulp regeneration. Materials and Methods We extracted exosomes from SHED aggregates and utilized them in the pulp regeneration animal model. The pro‐angiogenetic effects of SA‐Exo on SHED and human umbilical vein endothelial cells (HUVECs) were evaluated. The related mechanisms were further investigated. Results We firstly found that SA‐Exo significantly improved pulp tissue regeneration and angiogenesis in vivo. Next, we found that SA‐Exo promoted SHED endothelial differentiation and enhanced the angiogenic ability of HUVECs, as indicated by the in vitro tube formation assay. Mechanistically, miR‐26a, which is enriched in SA‐Exo, improved angiogenesis both in SHED and HUVECs via regulating TGF‐β/SMAD2/3 signalling. Conclusions In summary, these data reveal that SA‐Exo shuttled miR‐26a promotes angiogenesis via TGF‐β/SMAD2/3 signalling contributing to SHED aggregate‐based pulp tissue regeneration. These novel insights into SA‐Exo may facilitate the development of new strategies for pulp regeneration. The underlying mechanisms of the SHED aggregate involved in pulp regeneration is revealed in this paper. SHED aggregate‐derived exosomes (SA‐Exo) shuttled miR‐26a promote SHED endothelial differentiation and enhance the angiogenic ability of HUVECs via TGF‐β/SMAD2/3 signalling, which contributing to angiogenesis in pulp tissue regeneration.

Dysregulation of the transforming growth factor‐β (TGF‐β) signaling pathway regulates cancer stem cells (CSCs) and drug sensitivity, whereas it remains largely unknown how feedback regulatory mechanisms are hijacked to fuel drug‐resistant CSCs. Through a genome‐wide CRISPR activation screen utilizing stem‐like drug‐resistant properties as a readout, the TGF‐β receptor‐associated binding protein 1 (TGFBRAP1) is identified as a TGF‐β‐inducible positive feedback regulator that governs sensitivity to tyrosine kinase inhibitors (TKIs) and promotes liver cancer stemness. By interacting with and stabilizing the TGF‐β receptor type 1 (TGFBR1), TGFBRAP1 plays an important role in potentiating TGF‐β signaling. Mechanistically, TGFBRAP1 competes with E3 ubiquitin ligases Smurf1/2 for binding to TGFΒR1, leading to impaired receptor poly‐ubiquitination and proteasomal degradation. Moreover, hyperactive TGF‐β signaling in turn up‐regulates TGFBRAP1 expression in drug‐resistant CSC‐like cells, thereby constituting a previously uncharacterized feedback mechanism to amplify TGF‐β signaling. As such, TGFBRAP1 expression is correlated with TGFΒR1 levels and TGF‐β signaling activity in hepatocellular carcinoma (HCC) tissues, as well as overall survival and disease recurrence in multiple HCC cohorts. Therapeutically, blocking TGFBRAP1‐mediated stabilization of TGFBR1 by selective inhibitors alleviates Regorafenib resistance via reducing CSCs. Collectively, targeting feedback machinery of TGF‐β signaling pathway may be an actionable approach to mitigate drug resistance and liver cancer stemness. TGFBRAP1 protects TGFBR1 from ubiquitination and degradation by competing with SMURF1/2 for binding to TGFBR1, thereby promoting the activation of the TGF‐β signaling pathway and enhancing cancer stemness and resistance to regorafenib in HCC. Moreover, TGFBRAP1 is transcriptionally up‐regulated by the SMAD2/3 complex, thus forming a positive feedback regulation of the TGF‐β signaling pathway.

Gastric cancer (GC) is a highly aggressive malignancy with limited treatment options for advanced‐stage patients. Recent studies have highlighted the role of circular RNA (circRNA) as a novel regulator of cancer progression in various malignancies. However, the underlying mechanisms by which circRNA contributes to the development and progression of GC remain poorly understood. In this study, we utilized microarrays and real‐time quantitative polymerase chain reaction (qRT‐PCR) to identify and validate a downregulated circRNA, hsa_circ_0003251 (referred to as circWNK1), in paired GC and normal tissues. Through a series of in vitro and in vivo gain‐of‐function and loss‐of‐function assays, we demonstrated that circWNK1 exerts inhibitory effects on the proliferation, migration, invasion, and epithelial–mesenchymal transition (EMT) of GC cells. Additionally, we discovered that circWNK1 acts as a competitive endogenous RNA (ceRNA) for SMAD7 by sequestering miR‐21‐3p. Our findings were supported by comprehensive biological information analysis, as well as RNA pull‐down, luciferase reporter gene, and western blot assays. Notably, the downregulation of circWNK1 in GC cells resulted in reduced SMAD7 expression, subsequently activating the TGF‐β signaling pathway. Collectively, our study reveals that circWNK1 functions as a tumor suppressor in GC by regulating the miR‐21‐3p/SMAD7‐mediated TGF‐β signaling pathway. Furthermore, circWNK1 holds promise as a potential biomarker for the diagnosis and treatment of GC. In this study, we investigated the role of circWNK1, a specific circular RNA, in the development of gastric cancer (GC). Our findings revealed that circWNK1 expression is downregulated in GC and is associated with a poorer prognosis. Overexpressing circWNK1 inhibited GC cell proliferation, migration, invasion, and epithelial–mesenchymal transition (EMT). Mechanistically, circWNK1 acted as a competitive endogenous RNA (ceRNA) for SMAD7 by sequestering miR‐21‐3p, thereby activating the TGF‐β signaling pathway. These results suggest that circWNK1 may serve as a potential biomarker and therapeutic target for GC.

Programmed death ligand 1 (PDL1) suppresses T‐cell immunity by engaging programmed cell death protein 1 (PD1), and its blockade can activate T‐cell responses. Although PDL1 is a transmembrane protein, its intrinsic signaling role in regulating oncogenesis remains unclear. Our study reveals lung adenocarcinomas (ADCs) exhibit deficient PDL1 expression, which correlates with poor patient prognosis. TGF‐β stimulation induced PDL1 expression, while silencing PDL1 in PDL1‐high lung ADC cells enhanced colony formation, and PDL1 overexpression inhibited lung cancer cell growth. Cell cycle analysis indicated that PDL1 silencing increased S‐phase entry in lung ADC cells. Furthermore, PDL1 expression reduced FAK, ERK, and AKT phosphorylation, increasing cell detachment from the substrate. Gene expression profiling identified TGFBI as a downstream molecule of PDL1. TGF‐β induced TGFBI expression, and knockdown of TGFBI increased the growth of lung ADC cells. Given that TGF‐β regulates CITED2 and p21CIP1 to initiate cell growth arrest, we examined the PDL1‐TGFBI axis's impact on these molecules. Knockdown of PDL1 or TGFBI induced CITED2 expression but decreased p21CIP1 expression in lung ADC cells. Moreover, inhibiting FAK via pharmacologic or genetic approaches decreased CITED2 but increased p21CIP1 expression in PDL1‐silenced lung ADC cells. These findings suggest that intrinsic PDL1‐TGFBI signaling inhibits FAK activation, affecting the CITED2 molecular switch, which induces p21CIP1, ultimately leading to cell growth arrest. Our study provides insights into intrinsic PDL1 signaling in lung ADC oncogenesis and indicates that PDL1 expression could be a biomarker for lung ADC progression. Programmed death ligand 1 (PDL1) is known for suppressing T‐cell immunity, but its intrinsic role in oncogenesis remains unclear. This study demonstrates that PDL1 expression in lung adenocarcinoma (ADC) inhibits tumor cell growth by reducing FAK activation and regulating the CITED2‐p21CIP1 axis, leading to cell growth arrest. These findings reveal PDL1's dual role in immune regulation and tumor suppression, suggesting it as a potential biomarker for lung ADC progression.

ETS homologous factor (EHF) plays a critical function in epithelial cell differentiation and proliferation. However, the roles of EHF in cancer remain largely unknown. In the present study, we investigated the expression levels, precise function and mechanism of EHF in colorectal carcinoma (CRC). We observed significantly elevated EHF expression in CRC cell lines and tissues. EHF overexpression correlated positively with poor differentiation, advanced T stage, and shorter overall survival of CRC patients. Function experiments revealed that EHF overexpression promoted CRC cell proliferation, migration, and invasion in vitro and in vivo. Mechanistically, EHF could directly upregulate transforming growth factor β1 (TGF‐β1) expression at the transcription level, thereby activating canonical TGF‐β signaling. Our findings provide novel insights into the mechanisms of EHF in tumorigenesis, invasion, and metastasis of CRC, which may help to provide new therapeutic targets for CRC intervention. 1, EHF is upregulated in colorectal carcinoma (CRC). 2, The EHF overexpressing contributes to CRC cell proliferation, invasion and metastasis in vitro and in vivo. 3, EHF is a transcript activator for promoting TGF‐β1 transcription, thereby activating the canonical TGF‐β signaling.