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Results and discussion Ectopic tsRNA signatures in pancreatic cancer serum To explore whether serum tsRNAs could serve as novel biomarkers for PC, we performed preliminary screening by small RNA sequencing followed by qRT-PCR validation on individual basis. Elevated serum tRF-Pro-AGG-004 and tRF-Leu-CAG-002 originate from tumor cells To determine whether the high levels of the two tsRNAs in PC serum were induced by perturbations in PC tissues, we first examined the tissue and paired serum levels of tRF-Pro-AGG-004 and tRF-Leu-CAG-002 from the same patients in a independent clinical cohort (n = 20, Table S4) and observed an positive correlation (Fig. 2A). [...]treatment by two tsRNAs inhibitors in cells showed decreased tsRNAs levels in culture medium (Fig. 2C), suggesting that tsRNAs in culture medium were directly released from PC cells. Traditional pathological staging systems may have reached their limit for predicting outcomes, and new molecular biomarkers may add values. [...]we checked and scored the two-tsRNAs expression in 2 clinical PC cohorts by ISH analysis in standard process.

Colorectal cancer (CRC) is among the most frequently occurring cancers worldwide. Baicalin is isolated from the roots of Scutellaria baicalensis and is its dominant flavonoid. Anticancer activity of baicalin has been evaluated in different types of cancers, especially in CRC. However, the molecular mechanisms underlying the contribution of baicalin to the treatment of CRC are still unknown. Here, we confirmed that baicalin can effectively induce and enhance apoptosis in HT-29 cells in a dose-dependent manner and suppress tumour growth in xenografted nude mice. We further performed a miRNA microarray analysis of baicalin-treated and untreated HT-29 cells. The results showed that a large number of oncomiRs, including miR-10a, miR-23a, miR-30c, miR-31, miR-151a and miR-205, were significantly suppressed in baicalin-treated HT-29 cells. Furthermore, our in vitro and in vivo studies showed that baicalin suppressed oncomiRs by reducing the expression of c-Myc. Taken together, our study shows a novel mechanism for anti-cancer action of baicalin, that it induces apoptosis in colon cancer cells and suppresses tumour growth by reducing the expression of c-Myc and oncomiRs.

KRAS is one of the most frequently activated oncogenes in human cancers. Although the role of KRAS mutation in tumorigenesis and tumor maintenance has been extensively studied, the relationship between KRAS and the tumor immune microenvironment is not fully understood. Here, we identified a role of KRAS in driving tumor evasion from innate immune surveillance. In samples of lung adenocarcinoma from patients and Kras-driven genetic mouse models of lung cancer, mutant KRAS activated the expression of cluster of differentiation 47 (CD47), an antiphagocytic signal in cancer cells, leading to decreased phagocytosis of cancer cells by macrophages. Mechanistically, mutant KRAS activated PI3K/STAT3 signaling, which restrained miR-34a expression and relieved the posttranscriptional repression of miR-34a on CD47. In 3 independent cohorts of patients with lung cancer, the KRAS mutation status positively correlated with CD47 expression. Therapeutically, disruption of the KRAS/CD47 signaling axis with KRAS siRNA, the KRASG12C inhibitor AMG 510, or a miR-34a mimic suppressed CD47 expression, enhanced the phagocytic capacity of macrophages, and restored innate immune surveillance. Our results reveal a direct mechanistic link between active KRAS and innate immune evasion and identify CD47 as a major effector underlying the KRAS-mediated immunosuppressive tumor microenvironment.

Autoimmune diseases involve a complex dysregulation of immunity. Autoimmune diseases include many members [e.g., rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE)], and most of them are classified according to what organs and tissues are targeted by the damaging immune response. Many studies have focused on finding specific biomarkers for single autoimmune diseases, but so far, there are no universal biomarkers for detecting almost all autoimmune diseases. Serum miRNAs have served as potential biomarkers for detecting various diseases. The purpose of this study was to find a universal biomarker for diagnosing autoimmune diseases. Regulatory T cells (Tregs) play a crucial role in protecting an individual from autoimmunity, and depletion of Tregs in mice is considered a representative animal model of autoimmune disease. Two mouse models for Treg depletion, in which Treg was depleted by CD25mAb (in C57 mice) or by diphtheria toxin (DT) (in Foxp3 mice), were investigated, and 381 miRNAs were identified in the serum of mice with Treg depletion. A distinctive circulating miRNA profile was identified in Treg-depleted mice and in patients with autoimmune disease. QRT-PCR confirmation and ROC curve analysis determined that six miRNAs (miR-551b, miR-448, miR-9, miR-124, miR-148, and miR-34c) in the Treg-depleted mouse models and three miRNAs [miR-551b (specificity 73.5%, sensitivity 88.4%), miR-448 (specificity 82.4%, sensitivity 91.3%), and miR-124 (specificity 76.5%, sensitivity 91.3%)] in patients with RA, SLE, Sjogren's syndrome (SS), and ulcerative colitis (UC) could serve as valuable specific biomarkers. These circulating miRNAs may represent potential universal biomarkers for autoimmune diseases diagnosis and prognosis.

Background Systemic lupus erythematosus (SLE) is a complex autoimmune disease characterized by dysregulated inflammatory response lacking reliable diagnosis biomarkers and therapy targets. Extracellular vesicles (EVs)-derived cargo as biomarkers and mediators of SLE have garnered significant attention, however, quantitative inflammatory protein profile of SLE EVs remain uncovered. Objective Current study focuses on exploring the inflammatory protein landscape of SLE serum EVs via quantitative proximity extension assay (PEA) and evaluates their diagnostic utility for SLE and lupus nephritis (LN). Methods In this cross-sectional study, we first utilized PEA to profile inflammatory proteins derived from serum EVs in 101 individuals, including 70 SLE patients and 33 healthy controls (HCs). Subsequently, candidate EV proteins identified from this analysis were subsequently validated via ELISA in an independent cohort comprising 54 SLE patients and 58 HCs. Furthermore, machine-learning classification was utilized to generate prediction models for SLE diagnosis and LN discrimination. Finally, correlation analysis was applied to evaluate the association between EV-derived inflammatory proteins and clinical parameters. Results In the sEV PEA discovery cohort, a total of 49 significantly dysregulated inflammatory proteins with 43 elevated proteins were identified in serum EVs from SLE patients. Two precision prediction models were generated using the random Forest algorithm (RF) for SLE identification and LN discrimination, achieving AUCs of 0.999 and 0.793, respectively. Multiple EV proteins such as CCL23, IL-18R1, SCF and CSF-1 showed a significant correlation with SLE severity parameters including SLEDAI, eGFR and UACR. Furthermore, representative EV proteins including IL-18R1, CCL23 and IFN-γ were further tested in the sEV ELISA validation cohort including 54 SLE patients and 58 HCs. Conclusions The present study identified a unique pattern EV-derived inflammatory proteins in patients with SLE, which could serve as novel biomarkers for SLE diagnosis and disease monitoring.

Ferroptosis is an iron-dependent form of regulated cell death driven by the lethal lipid peroxides. Previous studies have demonstrated that inducing ferroptosis holds great potential in cancer therapy, especially for patients with traditional therapy failure. However, cancer cells can acquire ferroptosis evasion during progression. To date, the therapeutic potential of inducing ferroptosis in bladder cancer (BCa) remains unclear, and whether a ferroptosis escape mechanism exists in BCa needs further investigation. This study verified that low pathological stage BCa cells were highly sensitive to RSL3-induced ferroptosis, whereas high pathological stage BCa cells exhibited obviously ferroptosis resistance. RNA-seq, RNAi-mediated loss-of-function, and CRISPR/Cas9 experiments demonstrated that ALOX5 deficiency was the crucial factor of BCa resistance to ferroptosis in vitro and in vivo. Mechanistically, we found that ALOX5 deficiency was regulated by EGR1 at the transcriptional level. Clinically, ALOX5 expression was decreased in BCa tissues, and its low expression was associated with poor survival. Collectively, this study uncovers a novel mechanism for BCa ferroptosis escape and proposes that ALOX5 may be a valuable therapeutic target and prognostic biomarker in BCa treatment.

Bladder cancer (BLCA) is one of the most common tumors of the urinary tract. The diagnosis of BLCA is mostly by invasive tests, which are damaging and unsuitable for early screening. Current non‐invasive diagnostic modalities are insufficient in sensitivity and specificity. Therefore, novel diagnostic markers are urgently needed to facilitate early detection of bladder cancer. tRNA‐derived small RNAs (tsRNAs) are considered to be novel and potentially biologically functional non‐coding RNAs (ncRNAs). tsRNAs have been used to help early diagnosis of a variety of tumors. However, whether tsRNAs in BLCA are altered or involved in BLCA progression or regulation remains unclear. Here, we identified a group of up‐regulated tsRNAs in BLCA by sequencing tsRNAs in the plasma of BLCA patients and normal controls and further screened two highly correlated tsRNAs with BLCA in the training set and validation set, which were named as tRF‐1:28‐chrM.Ser‐TGA and tiRNA‐1:34‐Glu‐CTC‐1‐M2. ROC analyses of the expression profiles of these two tsRNAs by the validation set identified a high diagnostic value. We also found that circulating tRF‐1:28‐chrM.Ser‐TGA and tiRNA‐1:34‐Glu‐CTC‐1‐M2 were specifically expressed and released by BLCA cells and were positively correlated with the degree of disease malignancy. In vitro and in vivo experiments revealed that the two tsRNAs exacerbated BLCA progression and played a role in promoting tumor lipid metabolism. Our study screened two plasma tsRNAs that could serve as valuable early screening and diagnostic biomarkers for BLCA and is also expected to provide potential novel molecular targets for the treatment of BLCA. We found that circulating tRF‐1:28‐chrM.Ser‐TGA and tiRNA‐1:34‐Glu‐CTC‐1‐M2 were specifically expressed and released by bladder tumor cells and were positively correlated with the degree of disease malignancy. In vitro and in vivo experiments revealed that the two tsRNAs exacerbated bladder cancer progression and played a role in promoting tumor lipid metabolism. Our study screened two plasma tsRNAs that could serve as valuable early screening and diagnostic biomarkers for BLCA and is also expected to provide potential novel molecular targets for the treatment of BLCA.

The prognosis of lung metastatic osteosarcoma (OS) remains disappointing. siRNA-based gene silencing of VEGFR2 is a promising treatment strategy for lung metastatic OS, but there is a lack of safe and efficient delivery systems to encapsulate siRNAs for in vivo administration. This study presented a synthetic biological strategy that remolds the host liver with synthesized genetic circuits for efficient in vivo VEGFR2 siRNA delivery. After being taken-up by hepatocytes, the genetic circuit (in the form of a DNA plasmid) reprogrammed the liver to drive the autonomous intrahepatic assembly and encapsulation of VEGFR2 siRNAs into secretory small extracellular vesicles (sEVs), thus allowing for the transport of self-assembled VEGFR2 siRNAs towards the lung. The results showed that our strategy was superior to the positive medicine (Apatinib) for OS lung metastasis in terms of therapeutic efficacy and toxic adverse effects and may provide a feasible and viable therapeutic solution for lung metastatic OS.

Objectives Exosomes are essential mediators of intercellular communication as they transport proteins and RNAs between cells. Owing to their tumor‐targeting capacity, immune compatibility, low toxicity, and long half‐life, mesenchymal stem cell‐derived exosomes have great potential for the development of novel antitumor strategies. In this context, the role of exosomes produced by adipose‐derived mesenchymal stem cells (ADSCs) for the treatment of bladder cancer (BC) remains unclear. Here, we investigated the use of ADSCs as a source of therapeutic exosomes, as well as their efficacy in delivering the tumor suppressor miR‐138‐5p in BC. Methods ADSCs stably expressing miR‐138‐5p were established using Lentivirus infection, and ADSC‐derived miR‐138‐5p exosomes (Exo‐miR‐138‐5p) were isolated from the cell culture medium. The effect of Exo‐miR‐138‐5p on BC cell migration, invasion, and proliferation was evaluated in vitro using wound healing, transwell invasion, and proliferation assays. The in vivo effect of Exo‐miR‐138‐5p was investigated using a subcutaneous xenograft mouse model. Results Exo‐miR‐138‐5p prevented the migration, invasion, and proliferation of BC cells in vitro. Moreover, ADSC‐derived exosomes could penetrate tumor tissues and successfully deliver miR‐138‐5p to suppress the growth of xenograft tumors in vivo. Conclusions The present results reveal that ADSC‐derived exosomes are an effective delivery vehicle for small molecule drugs in vivo, and exosome‐delivered miR‐138‐5p is a promising therapeutic agent for BC treatment. We found Exo‐miR‐138‐5p exerted anti‐migration, anti‐invasion and anti‐proliferation effects on the BC cells in vitro. Moreover, we observed that ADSCs‐exo could penetrate the tumor tissues and delivery RNA agents to suppress the growth of xenograft tumors in vivo.Our results not only reveal that ADSCs‐exo are an effective delivery vehicle for small molecule drugs in vivo but also confirm that ADSCs‐exo miR‐138‐5p is a promising therapeutic agent for BC treatment.

Immunotherapies, such as immune-checkpoint blockade and adoptive T-cell therapy, offer novel treatment options with good efficacy for patients with urothelial bladder cancer. However, heterogeneity and therapeutic resistance have limited the use of immunotherapy. Further research into immune-regulatory mechanisms in bladder cancer is urgently required. Emerging evidence demonstrates that the commensal microbiota and its interactions with host immunity play pivotal roles in a variety of physiological and pathological processes, including in cancer. The gut microbiota has been identified as a potentially effective target of treatment that can be synergized with immunotherapy. The urothelial tract is also a key site for multiple microbes, although the immune-regulatory role of the urinary microbiome in the process of carcinogenesis of bladder cancer remains to be elucidated. We performed a comprehensive analysis of the expression and biological functions of C-type lectin receptors (CLRs), which have been recognized as innate pathogen-associated receptors for fungal microbiota, in bladder cancer. In line with previous research on fungal colonization of the urothelial tract, we found that CLRs, including Dectin-1, Dectin-2, Dectin-3, and macrophage-inducible Ca 2+ -dependent lectin receptor (Mincle), had a significant association with immune infiltration in bladder cancer. Multiple innate and adaptive pathways are positively correlated with the upregulation of CLRs. In addition, we found a significant correlation between the expression of CLRs and a range of immune-checkpoint proteins in bladder cancer. Based on previous studies and our findings, we hypothesize that the urinary mycobiome plays a key role in the pathogenesis of bladder cancer and call for more research on CLR-mediated anti-fungal immunity against bladder cancer as a novel target for immunotherapy in urothelial bladder cancer.