Expression landscape of cancer-FOXP3 and its prognostic value in pancreatic adenocarcinoma.

FOXP3, a key identifier of Treg, has also been identified in tumor cells, which is referred to as cancer-FOXP3 (c-FOXP3). Human c-FOXP3 undergoes multiple alternative splicing events, generating several isoforms, like c-FOXP3FL and c-FOXP3Δ3. Previous research on c-FOXP3 often ignore its cellular source (immune or tumor cells) and isoform expression patterns, which may obscure our understanding of its clinical significance. Our immunohistochemistry investigations which conducted across 18 tumors using validated c-FOXP3 antibodies revealed distinct expression landscapes for c-FOXP3 and its variants, with the majority of tumors exhibited a predominantly expression of c-FOXP3Δ3. In pancreatic ductal adenocarcinoma (PDAC), we further discovered a potential link between nuclear c-FOXP3Δ3 in tumor cells and poor prognosis. Overexpression of c-FOXP3Δ3 in tumor cells was associated with metastasis. This work elucidates the expression pattern of c-FOXP3 in pan-cancer and indicates its potential as a prognostic biomarker in clinical settings, offering new perspectives for its clinical application.

Identification of FOXP3+ epithelial cells contributing to pancreatic proliferation and angiogenesis.

Forkhead box protein 3 (FOXP3), traditionally recognized as a specific transcription factor for regulatory T cells (Tregs), has also been identified in various tumor epithelial cells (named as cancer-FOXP3, c-FOXP3). However, the natural state and functional role of FOXP3 positive tumor epithelial cells remain unknown. Monoclonal cells expressing varying levels of c-FOXP3 were isolated from established PANC-1 cells using limited dilution. Whole transcriptome sequencing and weighted gene co-expression network analysis (WGCNA) were conducted on these subsets, followed by in vitro and in vivo functional investigations. In addition, we identified c-FOXP3+E-cadherin- epithelial cells in human pancreatic cancer tissues after radical resection by immunofluorescence co-staining. We also investigated the connection between c-FOXP3+E-cadherin- epithelial cells and their clinicopathological features. Our study uncovered a distinct subset of c-FOXP3+ tumor epithelial cells characterized by reduced E-cadherin expression. C-FOXP3+E-cadherin- cells displayed significant proliferation potential and pro-angiogenic effect through the expression of chemokines, including C-X-C motif ligand 1 (CXCL1), C-X-C motif ligand 5 (CXCL5), and C-X-C motif ligand 8 (CXCL8). Notably, higher counts of c-FOXP3+E-Cadherin- cells correlated with poorer prognosis, lower tumor differentiation, lymph node metastasis, and vascular invasion in pancreatic ductal adenocarcinoma (PDAC). In conclusion, this work revealed the stable expression of FOXP3 in tumor epithelial cells, marking a distinct subset. C-FOXP3+E-cadherin- epithelial cells exhibit active proliferation and promote angiogenesis in a vascular endothelial growth factor A (VEGFA) independent manner. These findings provide novel insights into PDAC prognosis and therapeutic avenues.NEW & NOTEWORTHY In this study, we revealed a novel c-FOXP3+ tumor epithelial cell subset marked by diminished E-cadherin and stable FOXP3 expression. These subpopulations not only show robust proliferation and drive angiogenesis via CXCL1, CXCL5, and CXCL8, bypassing VEGFA pathways, but their heightened presence also correlates with adverse PDAC outcomes. By challenging traditional epithelial cell definitions and extending lymphocyte markers to these cells, our findings present innovative targets for PDAC treatment and enrich our understanding of cell biology.

WITHDRAWN: HCST Expression Distinguishes Immune-hot and Immune-cold Subtypes in Pancreatic Ductal Adenocarcinoma

Since the authors are not responding to the editor's requests to fulfill the editorial requirement, therefore, the article has been withdrawn.Bentham Science apologizes to the readers of the journal for any inconvenience this may have caused.The Bentham Editorial Policy on Article Withdrawal can be found at https://benthamscience.com/editorial-policies-main.php BENTHAM SCIENCE DISCLAIMER: It is a condition of publication that manuscripts submitted to this journal have not been published and will not be simultaneously submitted or published elsewhere. Furthermore, any data, illustration, structure or table that has been published elsewhere must be reported, and copyright permission for reproduction must be obtained. Plagiarism is strictly forbidden, and by submitting the article for publication the authors agree that the publishers have the legal right to take appropriate action against the authors, if plagiarism or fabricated information is discovered. By submitting a manuscript, the authors agree that the copyright of their article is transferred to the publishers if and when the article is accepted for publication.

Human FOXP3 and tumour microenvironment.

The tumour microenvironment (TME) is a complex system composed of cancer cells, stromal cells and immune cells. Regulatory T cells (Tregs) in the TME impede immune surveillance of tumours and suppress antitumor immune responses. Transcription factor forkhead box protein 3 (FOXP3) is the main marker of Tregs, which dominates the function of Tregs. FOXP3 was originally thought to be a Tregs-specific expression molecule, and recent studies have found that FOXP3 is expressed in a variety of tumours with inconsistent functional roles. This review summarizes the recent progress of infiltrating Treg-FOXP3 and tumour-FOXP3 in TME, discusses the communication mechanism between FOXP3+ cells and effector T cells in TME, the relationship between FOXP3 and clinical prognosis, and the potential of FOXP3-targeted therapy.

Design of Audio-Augmented-Reality-Based O&M Orientation Training for Visually Impaired Children.

Orientation and Mobility training (O&M) is a specific program that teaches people with vision loss to orient themselves and travel safely within certain contexts. State-of-the-art research reveals that people with vision loss expect high-quality O&M training, especially at early ages, but the conventional O&M training methods involve tedious programs and require a high participation of professional trainers. However, there is an insufficient number of excellent trainers. In this work, we first interpret and discuss the relevant research in recent years. Then, we discuss the questionnaires and interviews we conducted with visually impaired people. On the basis of field investigation and related research, we propose the design of a training solution for children to operate and maintain direction based on audio augmented reality. We discuss how, within the perceptible scene created by EasyAR's map-aware framework, we created an AR audio source tracing training that simulates a social scene to strengthen the audiometric identification of the subjects, and then to verify the efficiency and feasibility of this scheme, we implemented the application prototype with the required hardware and software and conducted the subsequential experiments with blindfolded children. We confirm the high usability of the designed approach by analyzing the results of the pilot study. Compared with other orientation training studies, the method we propose makes the whole training process flexible and entertaining. At the same time, this training process does not involve excessive economic costs or require professional skills training, allowing users to undergo training at home or on the sports ground rather than having to go to rehabilitation sites or specified schools. Furthermore, according to the feedback from the experiments, the approach is promising in regard to gamification.

Synergistic effects of sodium butyrate and cisplatin against cervical carcinoma in vitro and in vivo.

Backgrounds: Cisplatin-based chemotherapy has been considered as the pivotal option for treating cervical cancer. However, some patients may present a poor prognosis due to resistance to chemotherapy. As a metabolite of natural products, sodium butyrate (NaB) could inhibit the proliferation of several malignant cells, but little is known about its combination with cisplatin in the treatment of cervical cancer. Materials and methods: Flow cytometry, CCK-8 assay, and Transwell assay were utilized to analyze the cellular apoptosis, viability, cellular migration and invasion upon treating with NaB and/or cisplatin. The allograft mice model was established, followed by evaluating the tumor volume and necrotic area in mice treated with NaB and/or cisplatin. Western blot was performed for detecting protein expression involved in epithelial-mesenchymal transition (EMT) and the expression of MMPs. Immunohistochemical staining was conducted with the tumor sections. The transcription, expression, and cellular translocation of ß-catenin were determined using luciferase reporter gene assay, Real-Time PCR, Western blot, and confocal laser scanning microscope, respectively. Results: NaB combined with cisplatin inhibited cell viability by promoting apoptosis of cervical cancer cells. In vivo experiments indicated that NaB combined with cisplatin could inhibit tumor growth and induce cancer cell necrosis. Single application of NaB activated the Wnt signaling pathway and induced partial EMT. NaB alone up-regulated MMP2, MMP7 and MMP9 expression, and promoted the migration and invasion of cervical cancer cells. The combination of cisplatin and NaB inhibited cellular migration and invasion by abrogating the nuclear transition of ß-catenin, reverse EMT and down-regulate MMP2, MMP7 and MMP9. Immunohistochemical staining indicated that NaB combined with cisplatin up-regulated the expression of E-cadherin and reverse the EMT phenotype in the mice model. Conclusions: NaB serves as a sensitizer for cisplatin, which may be a promising treatment regimen for cervical cancer when combined both. NaB alone should be utilized with caution for treating cervical cancer as it may promote the invasion and migration of cervical cancer cells.

Development and validation of a ferroptosis-related lncRNAs signature to predict prognosis and microenvironment for melanoma.

Ferroptosis plays an important role in cancer. However, studies about ferroptosis-related lncRNAs (FRLs) in skin cutaneous melanoma (SKCM) are scarce. Moreover, the relationship between prognostic FRLs and tumor microenvironment (TME) in melanoma remains unclear. This study investigates the potential prognostic value of FRLs and their association with TME in SKCM. The RNA-sequencing data of SKCM were downloaded from The Cancer Genome Atlas (TCGA) database. Melanoma patients were randomly divided into training and testing groups in a 1:1 ratio. A signature composed of 19 FRLs was developed by the least absolute shrinkage and selection operator (LASSO) regression analysis to divide patients into a low-risk group with a better prognosis and a high-risk group with a poor prognosis. Multivariate Cox regression analysis suggested that the risk score was an independent prognostic factor. The Area Under Curve (AUC) value of the risk score reached 0.768 in the training group and 0.770 in the testing group. Subsequent analysis proved that immune-related signaling pathways were significantly enriched in the low-risk group. The tumor immune cell infiltration analysis demonstrated that melanoma in the high-risk group tended to be immunologically "cold". We identified a novel FRLs signature which could accurately predict the prognosis of patients with melanoma.

Injectable Immunotherapeutic Hydrogel Containing RNA-Loaded Lipid Nanoparticles Reshapes Tumor Microenvironment for Pancreatic Cancer Therapy.

Pancreatic cancer immunotherapy is becoming a promising strategy for improving the survival rate of postsurgical patients. However, the low response rate to immunotherapy suggests a low number of antigen-specific T cells and a high number of immunosuppressive tumor-associated macrophages in the pancreatic tumor microenvironment. Herein, we developed an in situ injectable thermosensitive chitosan hydrogel loaded with lipid-immune regulatory factor 5 (IRF5) mRNA/C-C chemokine ligand 5 (CCL5) siRNA (LPR) nanoparticle complexes (LPR@CHG) that reprogram the antitumoral immune niche. The LPR@CHG hydrogel upregulates IRF5 and downregulates CCL5 secretion, which contribute to a significant increase in M1 phenotype macrophages. Tumor growth is controlled by effective M1 phenotype macrophage that initiate T cell-mediated immune responses. Overall, the LPR@CHG hydrogel is expected to be a meaningful immunotherapy platform that can reshape the immunosuppressive tumor microenvironment and improve the efficacy of current pancreatic immunotherapies while minimizing systemic toxicity.

Identification of HnRNP Family as Prognostic Biomarkers in Five Major Types of Gastrointestinal Cancer.

BACKGROUND: Heterogeneous nuclear ribonucleoproteins (hnRNPs), a large family of RNAbinding proteins, have been implicated in tumor progression in multiple cancer types. However, the expression pattern and prognostic value of hnRNPs in five gastrointestinal (GI) cancers, including gastric, colorectal, esophageal, liver, and pancreatic cancer, remain to be investigated. OBJECTIVE: The current research aimed to identify prognostic biomarkers of the hnRNP family in five major types of gastrointestinal cancer. METHODS: Oncomine, Gene Expression Profiling Interactive Analysis (GEPIA), and Kaplan-Meier Plotter were used to explore the hnRNPs expression levels concerning clinicopathological parameters and prognostic values. The protein level of hnRNPU was validated by immunohistochemistry (IHC) in human tissue specimens. Genetic alterations of hnRNPs were analyzed using cBioportal, and Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed to illustrate the biological functions of co-expressed genes of hnRNPs. RESULTS: The vast majority of hnRNPs were highly expressed in five types of GI cancer tissues compared to their adjacent normal tissues, and mRNA levels of hnRNPA2B1, D, Q, R, and U were significantly different in various GI cancer types at different stages. In addition, Kaplan-Meier analysis revealed that the increased hnRNPs expression levels were correlated with better prognosis in gastric and rectal cancer patients (log-rank p < 0.05). In contrast, patients with high levels of hnRNPs exhibited a worse prognosis in esophageal and liver cancer (log-rank p < 0.05). Using immunohistochemistry, we further confirmed that hnRNPU was overexpressed in gastric, rectal, and liver cancers. In addition, hnRNPs genes were altered in patients with GI cancers, and RNA-related processing was correlated with hnRNPs alterations. CONCLUSION: We identified differentially expressed genes of hnRNPs in tumor tissues versus adjacent normal tissues, which might contribute to predicting tumor types, early diagnosis, and targeted therapies in five major types of GI cancer.

Non-coding RNAs in Pancreatic Ductal Adenocarcinoma.

Non-coding RNAs (ncRNAs) are reported to be expressed in human cancers, including pancreatic ductal adenocarcinoma (PDAC). These ncRNAs affect the growth, migration and invasion of tumor cells by regulating cell cycle and apoptosis, as well as playing important roles in epigenetic processes, transcription and post-transcriptional regulation. It is still unclear whether alterations in ncRNAs influence PDAC development and progression. Because of this, analysis based on existing data on ncRNAs, which are crucial for modulating pancreatic tumorigenesis, will be important for future research on PDAC. Here, we summarize ncRNAs with tumor-promoting functions: HOTAIR, HOTTIP, MALAT1, lncRNA H19, lncRNA PVT1, circ-RNA ciRS-7, circ-0030235, circ-RNA_100782, circ-LDLRAD3, circ-0007534, circRHOT1, circZMYM2, circ-IARS, circ-RNA PDE8A, miR-21, miR-155, miR-221/222, miR-196b, miR-10a. While others including GAS5, MEG3, and lncRNA ENST00000480739, has_circ_0001649, miR-34a, miR-100, miR-217, miR-143 inhibit the proliferation and invasion of PDAC. Hence, we summarize the functions of ncRNAs in the occurrence, development and metastasis of PDAC, with the goal to provide guidance in the clinical diagnosis and treatment of PDAC.