Search

AbstractContext Tabersonine has been investigated for its role in modulating inflammation-associated pathways in various diseases. However, its regulatory effects on triple-negative breast cancer (TNBC) have not yet been fully elucidated.Objective This study uncovers the anticancer properties of tabersonine in TNBC cells, elucidating its role in enhancing chemosensitivity to cisplatin (CDDP).Materials and methods After tabersonine (10 μM) and/or CDDP (10 μM) treatment for 48 h in BT549 and MDA-MB-231 cells, cell proliferation was evaluated using the cell counting kit-8 and colony formation assays. Quantitative proteomics, online prediction tools and molecular docking analyses were used to identify potential downstream targets of tabersonine. Transwell and wound-healing assays and Western blot analysis were used to assess epithelial–mesenchymal transition (EMT) phenotypes.Results Tabersonine demonstrated inhibitory effects on TNBC cells, with IC50 values at 48 h being 18.1 μM for BT549 and 27.0 μM for MDA-MB-231. The combined treatment of CDDP and tabersonine synergistically suppressed cell proliferation in BT549 and MDA-MB-231 cells. Enrichment analysis revealed that the proteins differentially regulated by tabersonine were involved in EMT-related signalling pathways. This combination treatment also effectively restricted EMT-related phenotypes. Through the integration of online target prediction and proteomic analysis, Aurora kinase A (AURKA) was identified as a potential downstream target of tabersonine. AURKA expression was reduced in TNBC cells post-treatment with tabersonine.Discussion and conclusions Tabersonine significantly enhances the chemosensitivity of CDDP in TNBC cells, underscoring its potential as a promising therapeutic agent for TNBC treatment.

AbstractContext Cholangiocarcinoma with highly heterogeneous, aggressive, and multidrug resistance has a poor prognosis. Although babaodan (BBD) combined with cisplatin improved non-small cell lung cancer efficacy, its impact on overcoming resistance in cholangiocarcinoma remains unexplored.Objective This study explored the role and mechanism of BBD on cisplatin resistance in cholangiocarcinoma cells (CCAs).Materials and methods Cisplatin-resistant CCAs were exposed to varying concentrations of cisplatin (25–400 μg/mL) or BBD (0.25–1.00 mg/mL) for 48 h. IC50 values, inhibition ratios, apoptosis levels, DNA damage, glutathione (GSH) levels, oxidized forms of GSH, total GSH content, and glutaminase relative activity were evaluated using the cell counting kit 8, flow cytometry, comet assay, and relevant assay kits.Results BBD-reduced the cisplatin IC50 in CCAs from 118.8 to 61.83 μg/mL, leading to increased inhibition rate, apoptosis, and DNA damage, and decreased expression of B-cell lymphoma-2, p-Yes-associated protein 1/Yes-associated protein 1, solute carrier family 1 member 5, activating transcription factor 4, and ERCC excision repair 1 in a dose-dependent manner with maximum reductions of 78.97%, 51.98%, 54.03%, 56.59%, and 63.22%, respectively; bcl2-associated X and gamma histone levels were increased by 0.43–115.77% and 22.15–53.39%. The impact of YAP1 knockdown on cisplatin-resistant CCAs resembled BBD. GSH, oxidized GSH species, total GSH content, and glutaminase activity in cisplatin-resistant CCAs with BBD treatment also decreased, while YAP1 overexpression countered BBD’s effects.Discussion and conclusion This study provides a scientific basis for BBD clinical application and provides a new direction for BBD biological mechanism research.

Abstract Pazopanib (PAZ), an oral multi-tyrosine kinase inhibitor, demonstrates promising cytostatic activities against various human cancers. However, its clinical utility is limited by substantial side effects and therapeutic resistance. We developed a nanoplatform capable of delivering PAZ for enhanced anti-breast cancer therapy. Nanometer-sized PAZ@Fe-MOF, compared to free PAZ, demonstrated increased anti-tumor therapeutic activities in both syngeneic murine 4T1 and xenograft human MDA-MB-231 breast cancer models. High-throughput single-cell RNA sequencing (scRNAseq) revealed that PAZ@Fe-MOF significantly reduced pro-tumorigenic M2-like macrophage populations at tumor sites and suppressed M2-type signaling pathways, such as ATF6-TGFBR1-SMAD3, as well as chemokines including CCL17, CCL22, and CCL24. PAZ@Fe-MOF reprogramed the inhibitory immune microenvironment and curbed tumorigenicity by blocking the polarization of M2 phenotype macrophages. This platform offers a promising and new strategy for improving the cytotoxicity of PAZ against breast cancers. It provides a method to evaluate the immunological response of tumor cells to PAZ-mediated treatment.

Abstract Background Renal cell carcinoma (RCC) is a malignant tumor. Radix Actinidiae chinensis (RAC) is the root of Actinidia arguta (Sieb. et Zucc) Planch. ex Miq. In clinical research, RAC was confirmed to have a certain anti-tumor effect, including liver cancer and cholangiocarcinoma. This study investigated the anticancer effect and mechanism of RAC in RCC cells. Methods The 786-O and A498 cells were intervened with varying concentrations of RAC (0–100 mg/mL) to detect the half maximal inhibitory concentration (IC50) of RAC. The cells were then co-cultured with 0–50 mg/mL RAC for 0–72 h to assess the effect of RAC on cell viability using the cell counting kit-8. The effects on cell proliferation, cell cycle or apoptosis, migration or invasion, and autophagy were detected using cloning, flow cytometry, Transwell, AOPI assay and Western blot. The number of autophagolysosomes was quantified using a transmission electron microscope. PI3K/AKT/mTOR pathway-related proteins were detected by Western blot. Additionally, an autophagy inhibitor 3-MA was used to explore the underlying mechanism of RAC. Results IC50 values of RAC in 786-O and A498 were 14.76 mg/mL and 13.09 mg/mL, respectively. RAC demonstrated the ability to reduce the cell malignant phenotype of RCC cells, blocked the S phase of cells, promoted apoptosis and autophagy in cells. Furthermore, RAC was observed to increase autophagy-related proteins LC3II/I and Beclin-1, while decreasing the level of P62. The expression of apoptosis-related proteins was increased, while the ratios of p-PI3K/PI3K, p-AKT/AKT, p-mTOR/mTOR, p-P38/P38 and p-ERK/ERK were reduced by RAC. However, the addition of 3-MA reduced the apoptosis and autophagy- promotion effects of RAC on RCC cells. Conclusion RAC induced the apoptosis and autophagy, to inhibit the progression of RCC cells. This study may provide a theoretical and experimental basis for clinical anti-cancer application of RAC for RCC.

Abstract Temozolomide (TMZ) represents a standard-of-care chemotherapeutic agent in glioblastoma (GBM). However, the development of drug resistance constitutes a significant hurdle in the treatment of malignant glioma. Although specific innovative approaches, such as immunotherapy, have shown favorable clinical outcomes, the inherent invasiveness of most gliomas continues to make them challenging to treat. Consequently, there is an urgent need to identify effective therapeutic targets for gliomas to overcome chemoresistance and facilitate drug development. This investigation used mass spectrometry to examine the proteomic profiles of six pairs of GBM patients who underwent standard-of-care treatment and surgery for both primary and recurrent tumors. A total of 648 proteins exhibiting significant differential expression were identified. Gene Set Enrichment Analysis (GSEA) unveiled notable alterations in pathways related to METABOLISM_OF_LIPIDS and BIOLOGICAL_OXIDATIONS between the primary and recurrent groups. Validation through glioma tissue arrays and the Xiangya cohort confirmed substantial upregulation of inositol 1,4,5-triphosphate (IP3) kinase B (ITPKB) in the recurrence group, correlating with poor survival in glioma patients. In TMZ-resistant cells, the depletion of ITPKB led to an increase in reactive oxygen species (ROS) related to NADPH oxidase (NOX) activity and restored cell sensitivity to TMZ. Mechanistically, the decreased phosphorylation of the E3 ligase Trim25 at the S100 position in recurrent GBM samples accounted for the weakened ITPKB ubiquitination. This, in turn, elevated ITPKB stability and impaired ROS production. Furthermore, ITPKB depletion or the ITPKB inhibitor GNF362 effectively overcome TMZ chemoresistance in a glioma xenograft mouse model. These findings reveal a novel mechanism underlying TMZ resistance and propose ITPKB as a promising therapeutic target for TMZ-resistant GBM.

Abstract The cGAS-STING signaling pathway has emerged as a critical mediator of innate immune responses, playing a crucial role in improving antitumor immunity through immune effector responses. Targeting the cGAS-STING pathway holds promise for overcoming immunosuppressive tumor microenvironments (TME) and promoting effective tumor elimination. However, systemic administration of current STING agonists faces challenges related to low bioavailability and potential adverse effects, thus limiting their clinical applicability. Recently, nanotechnology-based strategies have been developed to modulate TMEs for robust immunotherapeutic responses. The encapsulation and delivery of STING agonists within nanoparticles (STING-NPs) present an attractive avenue for antitumor immunotherapy. This review explores a range of nanoparticles designed to encapsulate STING agonists, highlighting their benefits, including favorable biocompatibility, improved tumor penetration, and efficient intracellular delivery of STING agonists. The review also summarizes the immunomodulatory impacts of STING-NPs on the TME, including enhanced secretion of pro-inflammatory cytokines and chemokines, dendritic cell activation, cytotoxic T cell priming, macrophage re-education, and vasculature normalization. Furthermore, the review offers insights into co-delivered nanoplatforms involving STING agonists alongside antitumor agents such as chemotherapeutic compounds, immune checkpoint inhibitors, antigen peptides, and other immune adjuvants. These platforms demonstrate remarkable versatility in inducing immunogenic responses within the TME, ultimately amplifying the potential for antitumor immunotherapy.

Environmental pollution, including air pollution, plastic contamination, and heavy metal exposure, is a pressing global issue. This crisis contributes significantly to pollution-related diseases and is a critical risk factor for chronic health conditions, including cancer. Mounting evidence underscores the pivotal role of N6-methyladenosine (m6A) as a crucial regulatory mechanism in pathological processes and cancer progression. Governed by m6A writers, erasers, and readers, m6A orchestrates alterations in target gene expression, consequently playing a vital role in a spectrum of RNA processes, covering mRNA processing, translation, degradation, splicing, nuclear export, and folding. Thus, there is a growing need to pinpoint specific m6A-regulated targets in environmental pollutant-induced carcinogenesis, an emerging area of research in cancer prevention. This review consolidates the understanding of m6A modification in environmental pollutant-induced tumorigenesis, explicitly examining its implications in lung, skin, and bladder cancer. We also investigate the biological mechanisms that underlie carcinogenesis originating from pollution. Specific m6A methylation pathways, such as the HIF1A/METTL3/IGF2BP3/BIRC5 network, METTL3/YTHDF1-mediated m6A modification of IL 24, METTL3/YTHDF2 dynamically catalyzed m6A modification of AKT1, METTL3-mediated m6A-modified oxidative stress, METTL16-mediated m6A modification, site-specific ATG13 methylation-mediated autophagy, and the role of m6A in up-regulating ribosome biogenesis, all come into play in this intricate process. Furthermore, we discuss the direction regarding the interplay between pollutants and RNA metabolism, particularly in immune response, providing new information on RNA modifications for future exploration.

Manganese (Mn) is an essential micronutrient required for various biological processes but excess exposure to Mn can cause neurotoxicity. However, there are few reports regarding the toxicity effect of Mn on the kidney as well as the underlying molecule mechanism. Herein, in vivo experiments were adopted to assess the toxicity effects associated with Mn, and found that chronic Mn treatment induced the injury of glomerular podocytes but not renal tubule in rats. Genome-wide CRISPR/Cas9 knockout screen was then employed to explore the biotargets of the toxic effect of Mn on podocytes. Through functional analyses of the enriched candidate genes, NLRP10 was found to be significantly up-regulated and mediated Mn-induced podocyte apoptosis. Further mechanism investigation revealed that NLRP10 expression was regulated by demethylase AlkB homolog 5 (ALKBH5) in an m6A-dependent fashion upon Mn treatment. Moreover, Mn could directly bind to Metadherin (MTDH) and promoted its combination with ALKBH5 to promote NLRP10 expression and cell apoptosis. Finally, logistic regressions, restricted cubic spline regressions and uniform cubic B-spline were used to investigate the association between Mn exposure and the risk of chronic kidney disease (CKD). A U-shaped nonlinear relationship between CKD risk and plasma Mn level, and a positive linear relationship between CKD risk and urinary Mn levels was found in our case-control study. To sum up, our findings illustrated that m6A-dependent NLRP10 regulation is indispensable for podocyte apoptosis and nephrotoxicity induced by Mn, providing fresh insight into understanding the health risk of Mn and a novel target for preventing renal injury in Mn-intoxicated patients.

Pyroptosis is a regulated cell death pathway involved in numerous human diseases, especially malignant tumors. Recent studies have identified multiple pyroptosis-associated signaling molecules, like caspases, gasdermin family and inflammasomes. In addition, increasing in vitro and in vivo studies have shown the significant linkage between pyroptosis and immune regulation of cancers. Pyroptosis-associated biomarkers regulate the infiltration of tumor immune cells, such as CD4+ and CD8+ T cells, thus strengthening the sensitivity to therapeutic strategies. In this review, we explained the relationship between pyroptosis and cancer immunology and focused on the significance of pyroptosis in immune regulation. We also proposed the future application of pyroptosis-associated biomarkers in basic research and clinical practices to address malignant behaviors. Exploration of the underlying mechanisms and biological functions of pyroptosis is critical for immune response and cancer immunotherapy.

Abstract Gliomas are the most prevalent primary tumor in the central nervous system, with an abysmal 5-year survival rate and alarming mortality. The current standard management of glioma is maximum resection of tumors followed by postoperative chemotherapy with temozolomide (TMZ) or radiotherapy. Low chemosensitivity of TMZ in glioma treatment eventuates limited therapeutic efficacy or treatment failure. Hence, overcoming the resistance of glioma to TMZ is a pressing question. Our research centered on identifying the drug metabolism-related genes potentially involved in TMZ-treated resistance of glioma through several bioinformatics datasets and cell experiments. One efflux transporter, ATP-binding cassette transporter subfamily A1 (ABCA1), was discovered with an upregulated expression level and signaled poor clinical outcomes for glioma patients. The transcript level of ABCA1 significantly elevated across the TMZ-resistant glioma cells in contrast with non-resistant cells. Over-expressed ABCA1 restrained the drug activity of TMZ, and ABCA1 knockdown improved the treatment efficacy. Meanwhile, the results of molecular docking between ABCA1 protein and TMZ showed a high binding affinity. Additionally, co-expression and immunological analysis revealed that ABCA1 facilitates the immune infiltration of M2 macrophages in glioma, thereby stimulating tumor growth and aggravating the poor survival of patients. Altogether, we discovered that the ABCA1 transporter was involved in TMZ chemoresistance and the immune infiltration of M2 macrophages in glioma. Treatment with TMZ after ABCA1 knockdown enhances the chemosensitivity, suggesting that inhibition of ABCA1 may be a potential strategy for improving the therapeutic efficacy of gliomas.

Abstract Staging lymph nodes (LN) is crucial in diagnosing and treating cancer metastasis. Biotechnologies for the specific localization of metastatic lymph nodes (MLNs) have attracted significant attention to efficiently define tumor metastases. Bioimaging modalities, particularly magnetic nanoparticles (MNPs) such as iron oxide nanoparticles, have emerged as promising tools in cancer bioimaging, with great potential for use in the preoperative and intraoperative tracking of MLNs. As radiation-free magnetic resonance imaging (MRI) probes, MNPs can serve as alternative MRI contrast agents, offering improved accuracy and biological safety for nodal staging in cancer patients. Although MNPs’ application is still in its initial stages, exploring their underlying mechanisms can enhance the sensitivity and multifunctionality of lymph node mapping. This review focuses on the feasibility and current application status of MNPs for imaging metastatic nodules in preclinical and clinical development. Furthermore, exploring novel and promising MNP-based strategies with controllable characteristics could lead to a more precise treatment of metastatic cancer patients.

Abstract Dihydroartemisinin (DHA), a natural product derived from the herbal medicine Artemisia annua, is recently used as a novel anti-cancer agent. However, some intrinsic disadvantages limit its potential for clinical management of cancer patients, such as poor water solubility and low bioavailability. Nowadays, the nanoscale drug delivery system emerges as a hopeful platform for improve the anti-cancer treatment. Accordingly, a metal-organic framework (MOF) based on zeolitic imidazolate framework-8 was designed and synthesized to carry DHA in the core (ZIF-DHA). Contrast with free DHA, these prepared ZIF-DHA nanoparticles (NPs) displayed preferable anti-tumor therapeutic activity in several ovarian cancer cells accompanied with suppressed production of cellular reactive oxygen species (ROS) and induced apoptotic cell death. 4D-FastDIA-based mass spectrometry technology indicated that down-regulated reactive oxygen species modulator 1 (ROMO1) might be regarded as potential therapeutic targets for ZIF-DHA NPs. Overexpression of ROMO1 in ovarian cancer cells significantly reversed the cellular ROS-generation induced by ZIF-DHA, as well as the pro-apoptosis effects. Taken together, our study elucidated and highlighted the potential of zeolitic imidazolate framework-8-based MOF to improve the activity of DHA to treat ovarian cancer. Our findings suggested that these prepared ZIF-DHA NPs could be an attractive therapeutic strategy for ovarian cancer.

Abstract Background The past few years have witnessed a significant increase in research related to plant-derived extracellular vesicles (PDEVs) in biological and medical applications. Using biochemical technologies, multiple independent groups have demonstrated the important roles of PDEVs as potential mediators involved in cell-cell communication and the exchange of bio-information between species. Recently, several contents have been well identified in PDEVs, including nucleic acids, proteins, lipids, and other active substances. These cargoes carried by PDEVs could be transferred into recipient cells and remarkably influence their biological behaviors associated with human diseases, such as cancers and inflammatory diseases. Main body of the abstract This review summarizes the latest updates regarding PDEVs and focuses on its important role in nanomedicine applications, as well as the potential of PDEVs as drug delivery strategies to develop diagnostic and therapeutic agents for the clinical management of diseases, especially like cancers. Conclusion Considering its unique advantages, especially high stability, intrinsic bioactivity and easy absorption, further elaboration on molecular mechanisms and biological factors driving the function of PDEVs will provide new horizons for the treatment of human disease.

Several types of modifications have been proven to participate in the metabolism and processing of different RNA types, including non-coding RNAs (ncRNAs). N-6-methyladenosine (m6A) is a dynamic and reversible RNA modification that is closely involved in the ncRNA homeostasis, and serves as a crucial regulator for multiple cancer-associated signaling pathways. The ncRNAs usually regulate the epigenetic modification, mRNA transcription and other biological processes, displaying enormous roles in human cancers. In this review, we summarized the significant implications of m6A-ncRNA interaction in various types of cancers. In particular, the interplay between m6A and ncRNAs in cancer pathogenesis and therapeutic resistance are being widely recognized. We also discussed the relevance of m6A-ncRNA interaction in immune regulation, followed by the interference on cancer immunotherapeutic procedures. In addition, we briefly highlighted the computation tools that could identify the accurate features of m6A methylome among ncRNAs. In summary, this review would pave the way for a better understanding of the biological functions of m6A-ncRNA crosstalk in cancer research and treatment.

Abstract Ferroptosis is a cell death process caused by metabolic dysfunction with the feature of aberrant iron accumulation. Emerging studies have identified that ferroptosis is an important biological function involving in the tumorigenesis, and targeting ferroptosis could provide promising therapeutic targets for lung cancer. However, such therapeutic strategies show limited therapeutic effect owing to drug resistance and other unknown underlying mechanisms. In this study, lysine-specific demethylase 1 (LSD1/KDM1A) was found to be significantly upregulated in lung cancer cells and tissues. The patients with KDM1A downregulation displayed the good prognosis. Using gene set enrichment analysis (GSEA), we demonstrated that KDM1A-associated genes might participate in the regulation of cell ferroptosis and Myc signaling in lung cancer. Knockdown of KDM1A inhibited the level of c-Myc and increased the concentration of malondialdehyde (MDA) and irons in human lung cancer cells H1299 and A549. Downregulation of c-Myc could facilitate KDM1A knockdown-mediated ferroptosis. Our study has elucidated the effect of KDM1A/c-Myc regulatory axis in the ferroptosis resistance of lung cancer cells.

Abstract RET (rearranged during transfection), encoding a tyrosine kinase receptor, is a novel therapeutic target for cancers. The aberrations of RET are commonly found in cancers. Here, we profiled a comprehensive genomic landscape of RET mutations, copy number variants (CNVs), co-occurrence of RET and its mRNA expression and methylation levels in pan cancer, paving the way to the development of new RET-targeted therapies in clinic. Analysis of RET somatic mutations, CNVs, co-occurrence, mRNA expression and methylation were performed among 32 cancer types from The Cancer Genome Atlas (TCGA) dataset covering a total of 10,953 patients with 10,967 samples. RET aberrations were found in 3.0% of diverse cancers. The top two RET-altered tumors were skin cutaneous melanoma (SKCM) and uterine corpus endometrial carcinoma (UCEC) with dominant mutations in the other and PKinase_Tyr domains. RET-G823E and RET-S891L were most commonly found in SKCM and UCEC. Thyroid carcinoma (THCA) demonstrated the highest rate of coiled-coil domain containing 6 (CCDC6)-RET fusions, which constitutively activate RET kinase. Two FDA-approved RET inhibitors—pralsetinib and selpercatinib have been implied for the treatment of patients with RET S891L mutant UCEC and the treatment of patients with metastatic RET-fusion positive THCA and non-small cell lung cancer (NSCLC) at therapeutic level 1. We also identified four RET M918T-altered cases in patients with pheochromocytoma and paraganglioma (PCPG), which may induce drug resistance against multikinase inhibitors. Next, 273 co-occurring aberrations, most frequently in Notch signaling, TGF-β pathway, cell cycle, and Ras-Raf-MEK-Erk/JNK signaling, were uncovered among 311 RET altered cases. TP53 mutations (162 patients) leads to the most significant co-occurrence associated with RET aberrations. Furthermore, the RET expression was found most significantly increased in breast invasive carcinoma (BRCA) and neck squamous cell carcinoma (HNSC), as compared to their corresponding normal tissues. At last, patients with higher expression and sequence variant frequency have a worse prognosis, such as sarcoma patients. This work provided a profound and comprehensive analysis of RET and co-occurred alterations, RET mRNA expression and the clinical significance in pan cancer, offering new insights into targeted therapy for patients with RET anomalies.

Natural compounds are widely used to prevent and treat various diseases due to their antioxidant and anti-inflammatory effects. As a kind of promising natural compound, plant-derived exosome-like nanoparticles (PELNs) are extracted from multivesicular bodies of various edible plants, including vegetables, foods, and fruits, and mainly regulate the cellular immune response to pathogen attacks. Moreover, PELNs could remarkably interfere with the dynamic imbalance between pro-inflammatory and anti-inflammatory effects, facilitating to maintain the homeostasis of cellular immune microenvironment. PELNs may serve as a better alternative to animal-derived exosomes (ADEs) owing to their widespread sources, cost-effectiveness, and easy accessibility. PELNs can mediate interspecies communication by transferring various cargoes such as proteins, lipids, and nucleic acids from plant cells to mammalian cells. This review summarizes the biogenesis, composition, and classification of exosomes; the common separation, purification, and characterization methods of PELNs, the potential advantages of PELNs over ADEs; and the anti-inflammatory and immunomodulatory functions of PELNs in various diseases including colitis, cancer, and inflammation-associated metabolic diseases. Additionally, the future perspectives of PELNs and the challenges associated with their clinical application are discussed.

Background: Immune cell death (ICD) is a type of tumor cell death that has recently been shown to activate and regulate tumor immunity. However, the role of ICD-related long non-coding RNAs (lncRNAs) in gastric cancer remains to be clarified.Methods: We obtained 375 tumor samples from the Cancer Genome Atlas (TCGA) database and randomly assigned them to training and verification groups. LASSO and Cox regression analysis were utilized to identify ICD-related lncRNAs and establish a risk model. The changes in the immune microenvironment of the two groups were compared by examining the tumor-infiltrating immune cells.Results: We established a tumor signature based on nine ICD-related lncRNAs. In light of the receiver operating characteristic and Kaplan–Meier curves, the prognostic values of this risk model were verified. Multivariate regression analysis showed that the risk score was an independent risk factor for the prognosis of patients in both the training cohort (HR 2.52; 95% CI: 1.65–3.87) and validation cohort (HR 2.70; 95% CI: 1.54–4.8). A nomogram was developed to predict the 1-, 3-, and 5-year survival of patients with gastric cancer, and the signature was linked to high levels of immunological checkpoint expression (B7-H3, VSIR).Conclusions: An ICD-related lncRNA signature could predict the immune response and prognosis of patients with gastric cancer. This prognostic signature could be employed to independently monitor the efficacy of immunotherapy for gastric cancer patients.

Autophagy is a self-recycling and conserved process, in which the senescent cytoplasmic components are degraded in cells and then recycled to maintain homeostatic balance. Emerging evidence has suggested the involvement of autophagy in oncogenesis and progression of various cancers, such as ovarian cancer (OC). Meanwhile, the non-coding RNAs (ncRNAs) frequently regulate the mRNA transcription and other functional signaling pathways in cell autophagy, displaying promising roles in human cancer pathogenesis and therapeutic response. This article mainly reviews the cutting-edge research advances about the interactions between ncRNAs and autophagy in OC. This review not only summarizes the underlying mechanisms of dynamic ncRNA-autophagy association in OC, but also discusses their prognostic implications and therapeutic biomarkers. The aim of this review was to provide a more in-depth knowledge framework exploring the ncRNA-autophagy crosstalk and highlight the promising treatment strategies for OC patients.

Exosomes are nanoscale extracellular vesicles secreted by a variety of cells, affecting the physiological and pathological homeostasis. They carry various cargoes including proteins, lipids, DNA, and RNA and have emerged as critical mediators of intercellular communication. During cell–cell communication, they can internalize either by autologous or heterologous recipient cells, which activate different signaling pathways, facilitating malignant progression of cancer. Among different types of cargoes in exosomes, the endogenous non-coding RNAs, such as circular RNAs (or circRNAs), have gained tremendous attention for their high stability and concentration, playing promising functional roles in cancer chemotherapeutic response by regulating the targeted gene expression. In this review, we primarily described the emerging evidence demonstrating the important roles of circular RNAs derived from exosomes in the regulation of cancer-associated signaling pathways that were involved in cancer research and therapeutic interventions. Additionally, the relevant profiles of exosomal circRNAs and their biological implications have been discussed, which is under investigation for their potential effect on the control of cancer therapeutic resistance.

Pyruvate dehydrogenase E1 subunit beta (PDHB) is located in mitochondria and catalyzes the conversion of glucose-derived acetyl-CoA. The detailed roles of PDHB in human cancers is unclear. Here, through comprehensive bioinformatics analysis, we found that PDHB was aberrantly expressed in multiple human cancers and is associated with patients' clinical stage. The abnormal expression of PDHB was related to the prognostic values of cancers, such as kidney renal clear cell carcinoma (KIRC) and kidney renal papillary cell carcinoma (KIRP). The Wanderer database with clinical data from Cancer Genome Atlas (TCGA) showed a significant correlation between PDHB expression and the pathologic stage of KIRP patients. We also evaluated the mutation profiles of PDHB in pan-cancer, and showed its roles on the patients’ prognosis. At last, from several immunity algorithms, we demonstrated that the expression of PDHB was correlated with the infiltration of various immune cells in pan-cancer. Moreover, the aberrant PDHB had effects on the response to immune checkpoint inhibitors in cancer patients, such as anti-PD-1. Taken together, our study demonstrated the prognostic values of PDHB in pan-cancers. PDHB may be a potential molecular marker to predicting the immune response in cancer patients.

Ferroptosis is a novel type of cell death associated with iron accumulation and excessive lipid peroxidation. Elucidating the underlying molecular mechanisms of ferroptosis is intensively related to the development and treatment of multiple diseases, including musculoskeletal disorders. Moreover, in vitro and in vivo studies have shown the importance of oxidative stress in musculoskeletal conditions such as osteoporosis, osteoarthritis, rheumatoid arthritis, and osteosarcoma. Ferroptosis-derived clinical management of musculoskeletal diseases offers tremendous and attractive opportunities. Notably, ferroptosis agonists have been proven to enhance the sensitivity of osteosarcoma cells to conventional therapeutic strategies. In this review, we have mainly focused on the implications of ferroptosis regulation in the pathophysiology and therapeutic response of musculoskeletal disorders. Understanding roles of ferroptosis for controlling musculoskeletal diseases might provide directions for ferroptosis-driven therapies, which could be promising for the development of novel therapeutic strategies.

Background Chemotherapy is one of the primary treatments for ovarian cancer patients. Autophagy has been linked to chemotherapy resistance in tumor cells. Recent studies have suggested that fibroblast growth factor 19 (FGF19) may be involved in the onset and progression of malignancies. However, the relationship between FGF19 and autophagy in ovarian cancer is still unknown. Methods Next-generation sequencing (NGS) was conducted to analyze gene mutation profiles of 62 cases of high grade serous ovarian cancer (HGSOC). Fluorescence in situ hybridization (FISH) was performed to validate the amplification of FGF19 in HGSOC tissues. Quantitative PCR (qPCR) and immunohistochemistry (IHC) were used to analyze the difference of FGF19 in mRNA and protein expression. Meanwhile, bioinformatics techniques were used to analyze the expression profiles of FGF19 and the correlation with prognosis. Besides, immunofluorescence, transmission electron microscopy and Cell Counting Kit 8 (CCK-8) were used to investigate the potential mechanisms. Results In this study, we found that FGF19 promotes cisplatin resistance in ovarian cancer cells by inducing autophagy. NGS analysis of 62 HGSOC cases identified a significantly amplified gene, FGF19. In addition, the expression level of FGF19 in ovarian cancer samples was higher than that in normal samples. FISH results showed a positive correlation between amplification and expression of FGF19. Knockdown of FGF19 inhibited the cell autophagy through decrease in the expression of LC3 and Beclin 1, and increase in the expression of SQSTM1/p62. Furthermore, we observed that p38 MAPK phosphorylation was down-regulated after FGF19 knockdown. IFN-γ, a potential p38 MAPK activator, counteracted the inhibition of cell autophagy and the anti-proliferation effect of cisplatin induced by FGF19 knockdown in ovarian cancer cells. Conclusion FGF19 increases autophagy and chemoresistance in ovarian cancer by activating the p38 MAPK pathway. These results could point to FGF19 being a potential therapeutic target for ovarian cancer.

Ferroptosis is a cell death form that has been reported to be involved in the progression of gastric cancer (GC). However, the underlying mechanism of ferroptosis in GC still needs to be further explored. This study conducted a survey regarding the biological functions of ferroptosis-related gene AKR1C2 in GC. Multiple bioinformatic platforms were applied to indicate that the expression level of AKR1C2 was downregulated in GC tissues, which displayed good prognostic value. Clinical statistics proved that AKR1C2 expression was correlated with several tumor characteristics of GC patients, such as characteristics of N-stage tumor or residual tumor. Additionally, LinkedOmics was employed to explore the co-expression network and molecular pathways of AKR1C2 in GC. Eventually, AKR1C2 was found to be involved in several immune-related signatures, such as immunostimulators, immunoinhibitors, chemokines and chemokine receptors. To sum up, these results may provide a novel insight into the significance and biological functions of ferroptosis-related gene AKR1C2 in GC tumorigenesis.

Artificial intelligence (AI) is a general term that refers to the use of a machine to imitate intelligent behavior for performing complex tasks with minimal human intervention, such as machine learning; this technology is revolutionizing and reshaping medicine. AI has considerable potential to perfect health-care systems in areas such as diagnostics, risk analysis, health information administration, lifestyle supervision, and virtual health assistance. In terms of immunotherapy, AI has been applied to the prediction of immunotherapy responses based on immune signatures, medical imaging and histological analysis. These features could also be highly useful in the management of cancer immunotherapy given their ever-increasing performance in improving diagnostic accuracy, optimizing treatment planning, predicting outcomes of care and reducing human resource costs. In this review, we present the details of AI and the current progression and state of the art in employing AI for cancer immunotherapy. Furthermore, we discuss the challenges, opportunities and corresponding strategies in applying the technology for widespread clinical deployment. Finally, we summarize the impact of AI on cancer immunotherapy and provide our perspectives about underlying applications of AI in the future.

As a key copper homeostasis-related molecule, lipoyltransferase 1 (LIPT1) is an essential enzyme for the activation of mitochondrial 2-ketoacid dehydrogenase, participating in fatty acylation. However, the biological significances of LIPT1 in the pan-cancer are unclear. Here, we comprehensively analyzed the functional characteristics of LIPT1 in human cancers and its roles in immune response. We found that LIPT1 was down-regulated in some cancers. And LIPT1 overexpression is associated with favorable prognosis in these patients, such as breast cancer, clear cell renal cell carcinoma, ovarian cancer and gastric cancer. We also explored the mutational status and methylation levels of LIPT1 in human cancers. Gene enrichment analysis indicated that abnormally expressed LIPT1 was significantly associated with immune cells infiltration, such as B cells, CD8+ T cells and cancer-associated fibroblast cells. The result from single cell sequencing reflected the important roles of LIPT1 in the regulation of several biological behaviors of cancer cells, such as DNA damage response and cell apoptosis. Taken together, our research could provide a comprehensive overview about the significances of LIPT1 in human pan-cancer progression, prognosis and immune.

Since most hepatocellular carcinoma (HCC) patients are diagnosed at advanced stages, there is no effective treatment to improve patient survival. Ferroptosis, a regulated cell death driven by iron accumulation and lipid peroxidation, has been reported to play an important role in tumorigenesis. However, the detailed mechanism and biological function of ferroptosis are still incompletely understood in HCC patients. In this study, we analyzed genomic profiles of three HCC datasets, GSE6764, GSE14520, and GSE14323. Venn diagrams were implemented to visualize the overlapping genes between differentially expressed genes and ferroptosis-related gene set. Then, one up-regulated gene, ACSL4, and five down-regulated genes, STEAP3, MT1G, GCH1, HAMP, and CXCL2, were screened. Based on the survival analysis performed by Kaplan-Meier plotter database, ferroptosis-related gene CXCL2 was demonstrated positively-correlated with the patients’ prognosis. Moreover, CXCL2 overexpression significantly inhibited cell growth and improved cellular ROS, Fe2+ and MDA levels in HCC cells Huh7 and MHCC97H, suggesting the roles of CXCL2 in inducing ferroptotic cell death. In addition, aberrantly expressed CXCL2 was negatively associated with malignancy clinical features, such as nodal metastasis and higher grades. The ssGSEA enrichment analysis revealed that CXCL2 co-expressed molecules were mainly involved in inflammation and immune-related pathways, such as acute inflammatory response, humoral immune response, adaptive immune response. TISIDB algorithm indicated the positive correlation between CXCL2 expression and tumor-infiltrating immune cells, including neutrophils and macrophages. Additionally, we also found that CXCL2 was positively correlated with immune infiltration score, and HCC patients with higher score harbored better prognosis. Together, these findings suggested that CXCL2 may enhance ferroptosis sensitivity and regulate immune microenvironment in HCC, and serve as a promising prognosis biomarker for HCC patients.

Abstract Alterations of mitogen-activated protein kinase kinase 1 (MEK1) are commonly associated with tumorigenesis, and MEK1 is thought to be a suitable targeted therapy for various cancers. However, abnormal MEK1 alterations and their relevant clinical implications are unknown. Our research comprehensively analyzed the MEK1 alteration spectrum and provided novel insight for targeted therapies. There were 7694 samples covering 32 types of cancer from The Cancer Genome Atlas (TCGA) database. They were used to conduct an integrative analysis of MEK1 expression, alterations, functional impacts and clinical significance. There was a dramatic difference in the alteration frequency and distribution and clinical implications in 32 types of cancer from the TCGA. Skin cutaneous melanoma (SKCM) has the most alterations and has therapeutic targets located in the protein kinase domain, and the growing expression of SKCM is positively related to patient prognosis. MEK1 expression in lung adenocarcinoma (LUAD), kidney renal papillary cell carcinoma (KIRP), esophageal carcinoma (ESCA) and liver hepatocellular carcinoma (LIHC) is decreased, which is associated with better prognosis, while MEK1 expression in thymoma (THYM), stomach adenocarcinoma (STAD), kidney renal clear cell carcinoma (KIRC), testicular germ cell tumors (TGCTs) and head and neck squamous cell carcinoma (HNSC) is increased, which is associated with better prognosis. Mesothelioma (MESO) has the second highest alterations but has no therapy targets. This study provided a great and detailed interpretation of MEK1 expression, alterations and clinical implications in 32 types of cancer and reminded us to fill the gap in MEK1 research from a new perspective.

Background: Emerging studies have shown the important roles of long noncoding RNAs (lncRNAs) in the occurrence and development of liver cancer. However, the exosome-related lncRNA signature in liver cancer remains to be clarified.Methods: We obtained 371 tumor specimens and 50 normal tissues from the TCGA database. These samples were randomly divided into the training queue and verification queue. The exosome-related lncRNA risk model was verified by correlation analysis, Lasso regression analysis, and Cox regression analysis. The differences in the immune microenvironment in the two risk groups were obtained by analyzing the infiltration of different immune cells.Results: Five exosome-related lncRNAs associated (MKLN1-AS, TMCC1-AS1, AL031985.3, LINC01138, AC099850.3) with a poor prognosis were identified and used to construct the signature. Receiver operating curve (ROC) and survival curves were used to confirm the predictive ability of this signature. Based on multivariate regression analysis in the training cohort (HR: 3.033, 95% CI: 1.762–5.220) and validation cohort (HR: 1.998, 95% CI: 1.065–3.751), the risk score was found to be an independent risk factor for patient prognosis. Subsequently, a nomogram was constructed to predict the 1-, 3-, 5-years survival rates of liver cancer patients. Moreover, this signature was also related to overexpressed immune checkpoints (PD-1, B7-H3, VSIR, PD-L1, LAG3, TIGIT and CTLA4).Conclusion: Our study showed that exosome-related lncRNAs and the corresponding nomogram could be used as a better index to predict the outcome and immune regulation of liver cancer patients. This signature might provide a new idea for the immunotherapy of liver cancer in the future.

Lipoic acid synthetase (LIAS) has been demonstrated to play a crucial role in the progression of cancer. Exploring the underlying mechanisms and biological functions of LIAS could have potential therapeutic guidance for cancer treatment. Our study has explored the expression levels and prognostic values of LIAS in pan-cancer through several bioinformatics platforms, including TIMER2.0, Gene Expression Profiling Interactive Analysis, version 2 (GEPIA2.0), and Human Protein Atlas (HPA). We found that a high LIAS expression was related to the good prognosis in patients with kidney renal clear cell carcinoma (KIRC), rectum adenocarcinoma (READ), breast cancer, and ovarian cancer. Inversely, a high LIAS expression showed unfavorable prognosis in lung cancer patients. In addition, the genetic alteration, methylation levels, and immune analysis of LIAS in pan-cancer have been evaluated. To elucidate the underlying molecular mechanism of LIAS, we conduct the single-cell sequencing to implicate that LIAS expression was related to hypoxia, angiogenesis, and DNA repair. Thus, these comprehensive pan-cancer analyses have conveyed that LIAS could be potentially significant in the progression of various cancers. Moreover, the LIAS expression could predict the efficacy of immunotherapy in cancer patients.

Pyroptosis is a cell death pathway that plays a significant role in lung adenocarcinoma (LUAD). Also, studies regarding the correlation between the expression of long non-coding RNAs (lncRNAs) and the mechanism of LUAD has aroused concern around the world. The purpose of this paper is to explore the underlying relationship of differentially expressed lncRNAs and pyroptosis-related genes. The least absolute shrinkage and selection operator (LASSO) algorithm and Cox regression were applied to construct a prognostic risk score model from the TCGA database. A pyroptosis-related five-lncRNA signature (CRNDE, HHLA3, MIR193BHG, LINC00941, LINC01843) was considered to be correlated to the prognosis and immune response of LUAD patients. In addition, the cytological experiments revealed that aberrantly expressed HHLA3 displayed a proliferation promotion role in LUAD cells A549 and H460. Next, the forest and nomogram plots have shown this lncRNA signature could be served as an independent prognostic factor for LUAD. The ROC curves further identified the prognostic value of the five-lncRNA signature. The infiltration of immune cells, such as T cells CD8, T cells CD4 memory resting, T cells CD4 memory activated and M0 macrophages were greatly different between the high-risk group and the low-risk group. It implicated that the signature is significantly effective in immunotherapy of LUAD patients. This study has supplied a novel pyroptosis-related lncRNA signature and provided a predictive model for prognosis and immune response of LUAD patients.

The primary or acquired resistance to anti-VEGF inhibitors remains a common problem in cancer treatment. Therefore, identifying potential biomarkers enables a better understanding of the precise mechanism. Through the GEO database, three profiles associated with bevacizumab (BV) resistance to ovarian cancer, glioma, and non-small-cell lung carcinoma, respectively, were collected for the screening process, and two genes were found. A-kinase anchor protein 12 (AKAP12), one of these two genes, correlates with tumorigenesis of some cancers. However, the role of AKAP12 in pan-cancer remains poorly defined. The present study first systematically analyzed the association of AKAP12 with anti-VEGF inhibitors’ sensitivity, clinical prognosis, DNA methylation, protein phosphorylation, and immune cell infiltration across various cancers via bioinformatic tools. We found that AKAP12 was upregulated in anti-VEGF therapy-resistant cancers, including ovarian cancer (OV), glioblastoma (GBM), lung cancer, and colorectal cancer (CRC). A high AKAP12 expression revealed dismal prognoses in OV, GBM, and CRC patients receiving anti-VEGF inhibitors. Moreover, AKAP12 expression was negatively correlated with cancer sensitivity towards anti-VEGF therapy. Clinical prognosis analysis showed that AKAP12 expression predicted worse prognoses of various cancer types encompassing colon adenocarcinoma (COAD), OV, GBM, and lung squamous cell carcinoma (LUSC). Gene mutation status may be a critical cause for the involvement of AKAP12 in resistance. Furthermore, lower expression of AKAP12 was detected in nearly all cancer types, and hypermethylation may explain its decreased expression. A decreased phosphorylation of T1760 was observed in breast cancer, clear-cell renal cell carcinoma, and lung adenocarcinoma. For the immunologic significance, AKAP12 was positively related to the abundance of pro-tumor cancer-associated fibroblasts (CAFs) in various types of cancer. The results of Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis suggested that “cell junction organization” and “MAPK pathway” participated in the effect of AKAP12. Importantly, we discovered that AKAP12 expression was greatly associated with metastasis of lung adenocarcinoma as well as differential and angiogenesis of retinoblastoma through investigating the single-cell sequencing data. Our study showed that the dual role of AKAP12 in various cancers and AKAP12 could serve as a biomarker of anti-VEGF resistance in OV, GBM, LUSC, and COAD.

B-Raf proto-oncogene serine/threonine-protein kinase (BRAF) is frequently altered in multiple cancer types, and BRAF V600 mutations act as a prime target for precision therapy. Although emerging evidence has investigated the role of BRAF, the comprehensive profiling of BRAF expression, alteration and clinical implications across various cancer types has not been reported. In this study, we used the TCGA dataset, covering 10,967 tumor samples across 32 cancer types, to analyze BRAF abnormal expression, DNA methylation, alterations (mutations and amplification/deletion), and their associations with patient survival. The results showed that BRAF expression, alteration frequency, mutation site distribution, and DNA methylation patterns varied tremendously among different cancer types. The expression of BRAF was found higher in PCPG and CHOL, and lower in TGCT and UCS compared to normal tissues. In terms of pathological stages, BRAF expression was significantly differentially expressed in COAD, KIRC, LUSC, and OV. The methylation levels of BRAF were significantly lower in LUSC, HNSC, and UCEC compared to normal tissue. The expression of BRAF and downstream gene (ETS2) was negatively correlated with methylation levels in various cancers. The overall somatic mutation frequency of BRAF was 7.7% for all cancer samples. Most fusion transcripts were found in THCA and SKCM with distinct fusion patterns. The majority of BRAF mutations were oncogenic and mainly distributed in the Pkinase_Tyr domain of THCA, SKCM, COADREAD, and LUAD. The BRAF mutations were divided into five levels according to the clinical targeted therapy implication. The results showed level 1 was mainly distributed in SKCM, COADREAD, and LUAD, while level 3B in THCA. The overall BRAF CNV frequency was about 42.7%, most of which was gain (75.9%), common in GBM, TGCT, and KIRP. In addition, the forest plot showed that increased BRAF expression was associated with poor patient overall survival in LIHC, OV, and UCEC. Taken together, this study provided a novel insight into the full alteration spectrum of BRAF and its implications for treatment and prognosis.

The RNA-sensing pathway has been associated with type I interferon (IFN) production induced by DNA damaging agents. Here the authors reveal that RIG-I, a cytosolic RNA sensor that recognizes RNA virus and initiates IFN signaling, is recruited to double-stranded breaks and suppresses non-homologous end joining.

Background: The different pharmacological effects of drugs in different people can be explained by the polymorphisms of drug metabolism-related genes. Emerging studies have realized the importance of drug metabolism-related genes in the treatment and prognosis of cancers, including ovarian cancer (OV). In this study, using comprehensive bioinformatics and western blot, we identified that the drug metabolism-related gene, ADH1B, was significantly down-regulated in OV cells and tissues. The patients with a high level of ADH1B presented a good prognosis. We also found a negative correlation between ADH1B expression and the activity of chemotherapeutic agents, such as cyclophosphamide. In addition, positive correlations were observed between ADH1B expression and multiple immune checkpoints, including LAG3 and HAVCR2. The immune infiltration analysis further indicated that aberrantly expressed ADH1B might have important roles in regulating the infiltration of macrophages and neutrophils in OV tissues. Then, the co-expression analysis was conducted and the top three enriched KEGG pathways were spliceosome, RNA transport, and DNA replication. In conclusion, the drug metabolism-related gene ADH1B and its interactive network play an essential role in the immune regulation and therapeutic response and maybe identified as promising therapeutic targets for OV patients.

Pyroptosis, characterized as an inflammasome-mediated cell death pathway, may be participated in tumorigenesis and progression. However, the underlying molecular function and mechanism of pyroptosis in BRCA remain unclear. In our study, we aimed to develop a prognostic signature in BRCA based on pyroptosis-associated genes. Data was downloaded from TCGA database, and then we screened 760 female BRCA samples and 104 normal breast tissues as the training set. Seven pyroptosis-related genes (CASP9, GPX4, IL18, NLRC4, SCAF11, TIRAP, and TNF) were identified as the pyroptosis-related prognostic model for BRCA using LASSO Cox regression. We subsequently tested the prognostic value of pyroptosis-associated gene signature in a validation set, GSE 20685. Time-dependent receiver operating characteristic analysis demonstrated the credible predictive capacity of this pyroptosis-associated gene signature. The area under the curves were 0.806 at 3 years, 0.787 at 5 years, 0.775 at 8 years, and 0.793 at 10 years in the training set, and 0.824 at 5 years, 0.808 at 8 years, and 0.790 at 10 years in the validation set. Furthermore, there are currently few data on SCAF11 regulating pyroptosis. To clarify this issue, we performed integrative bioinformatics and experimental analysis. Knocking down SCAF11 possessed an anti-cancer effect in terms of inhibiting cell viability and suppressing colony-formation in in-vitro functional assays. Meanwhile, the biological functions of SCAF11 in BRCA were further validated with several algorithms, such as Xiantao tool, LinkedOmics, GEPIA2, and TISIDB. These findings indicated that the expression of SCAF11 was significantly correlated with diverse tumor-infiltrating lymphocytes (TILs), including T central memory cell (Tcm), and type 2 T helper cell (Th2), etc. Functional enrichment analysis suggested that co-expression genes of SCAF11 primarily participated in inflammation and immune-related signaling pathways, such as oxidative phosphorylation, antimicrobial humoral response, and immunoglobulin complex. Moreover, SCAF11 expression was positively correlated with several immune checkpoints, including PD-L1, B7H3, and PDCD1LG2. Taken together, this study uncovered that pyroptosis-associated gene signature might be applied as an effective independent predictor in patients with BRCA. The pyroptosis-related gene SCAF11 might play potential roles in the regulation of immune microenvironment in BRCA.

Abstract In the era of the rapid development of cancer immunotherapy, there is a high level of interest in the application of cell-released small vesicles that stimulate the immune system. As cell-derived nanovesicles, exosomes show great promise in cancer immunotherapy because of their immunogenicity and molecular transfer function. The cargoes carried on exosomes have been recently identified with improved technological advances and play functional roles in the regulation of immune responses. In particular, exosomes derived from tumor cells and immune cells exhibit unique composition profiles that are directly involved in anticancer immunotherapy. More importantly, exosomes can deliver their cargoes to targeted cells and thus influence the phenotype and immune-regulation functions of targeted cells. Accumulating evidence over the last decade has further revealed that exosomes can participate in multiple cellular processes contributing to cancer development and therapeutic effects, showing the dual characteristics of promoting and suppressing cancer. The potential of exosomes in the field of cancer immunotherapy is huge, and exosomes may become the most effective cancer vaccines, as well as targeted antigen/drug carriers. Understanding how exosomes can be utilized in immune therapy is important for controlling cancer progression; additionally, exosomes have implications for diagnostics and the development of novel therapeutic strategies. This review discusses the role of exosomes in immunotherapy as carriers to stimulate an anti-cancer immune response and as predictive markers for immune activation; furthermore, it summarizes the mechanism and clinical application prospects of exosome-based immunotherapy in human cancer.

Abstract Extrachromosomal circular DNA was recently found to be particularly abundant in multiple human cancer cells, although its frequency varies among different tumor types. Elevated levels of extrachromosomal circular DNA have been considered an effective biomarker of cancer pathogenesis. Multiple reports have demonstrated that the amplification of oncogenes and therapeutic resistance genes located on extrachromosomal DNA is a frequent event that drives intratumoral genetic heterogeneity and provides a potential evolutionary advantage. This review highlights the current understanding of the extrachromosomal circular DNA present in the tissues and circulation of patients with advanced cancers and provides a detailed discussion of their substantial roles in tumor regulation. Confirming the presence of cancer-related extrachromosomal circular DNA would provide a putative testing strategy for the precision diagnosis and treatment of human malignancies in clinical practice.

Chemoresistance, especially temozolomide (TMZ) resistance, is a major clinical challenge in the treatment of glioblastoma (GBM). Exploring the mechanisms of TMZ resistance could help us identify effective therapies. Adenosine deaminases acting on RNA (ADARs) are very important in RNA modification through regulating the A-to-I RNA editing. Recent studies have shown that ADARs regulate multiple neurotransmitter receptors, which have been linked with the occurrence and progress of GBM. Here, data from several bioinformatics databases demonstrated that adenosine deaminase RNA specific B1 (ADARB1), also named ADAR2, was upregulated in both GBM tissues and cells, and had the prognostic value in GBM patients. Moreover, ADARB1 was found to be involved in AKT-mediated TMZ resistance in GBM cells. The KEGG analysis of ADARB1-associated co-expressed genes showed that ADARB1 was potentially involved in the mitochondrial respiratory chain complex. TISIDB and GEPIA databases were further used to analyze the role of ADARB1 in tumor-immune system interactions in GBM. These findings deepened our understanding of the function of ADARB1 in tumorigenesis and therapeutic response in GBM.

Background: Colon cancer is an aggressive and heterogeneous disease associated with high morbidity and mortality. The immune system is intimately involved in tumorigenesis and can influence malignant properties at the protein, epigenetic, and even genomic levels by shaping the tumor immune microenvironment (TIM). However, immune-related molecules that can effectively predict the prognosis of colon cancer remain under exploration.Methods: A total of 606 patients from TCGA and GEO databases were employed in our study, in which 429 cases were set as the training cohort and 177 were defined as the validation cohort. The immune infiltration was evaluated by ESTIMATE, TIMER, and CIBERSORT algorithms. The risk signature was constructed by LASSO Cox regression analysis. A nomogram model was generated subsequent to the multivariate Cox proportional hazards analysis to predict 1-, 3-, and 5-year survival of patients with colon cancer.Results: Infiltrating immune cell profiling identified two colon cancer clusters (Immunity_L group and Immunity_H group). The abundances of immune cells were higher in the Immunity_H group, which indicated a better prognosis. Through further statistical analysis, we identified four genes which were highly correlated with prognosis and representative of this gene set, namely ARL4C, SERPINE1, BST2, and AXIN2. When the patients were divided into low- and high-risk groups based on their risk scores, we found that patients in the high-risk group had shorter overall survival time. Moreover, a nomogram including clinicopathologic features and the established risk signature could robustly predict 1-, 3-, and 5-year survival in patients with colon cancer.Conclusion: We identified two distinct immune patterns by analyzing clinical and transcriptomic information from colon cancer patients. A subsequently constructed immune-related gene-based prognostic model as well as a nomogram model can be used to predict the prognosis of colon cancer, thereby guiding risk stratification and treatment regimen development for colon patients.

Glioma is a highly malignant brain tumor with a poor survival rate. Novel biomarkers that act as prompt indicators of glioma are urgently needed. In this study, we identified and validated prognosis-related differentially expressed genes by datasets of glioma in the GEO and TCGA databases. Ferroptosis is a newly recognized process of cell death playing a vital role in cancer biology. Pearson correlation coefficient were used to discovery the prognosis-related genes which have the highest correlation with ferroptosis. Matrix remodeling-associated protein 8 (MXRA8) was identified as a novel prognosis indicator which may be involved in ferroptosis. The expression of MXRA8 was significantly higher in glioma compared with normal brain tissue, and increased expression of MXRA8 was associated with unfavorable survivals. Furthermore, in vitro analysis showed that knockdown of MXRA8 inhibited the cell viability in T98G and U251 cells and increased the sensitivity of glioma cells to temozolomide. We further observed that downregulation of MXRA8 elevated the levels of intracellular ferrous iron and lipid peroxidation, accompanied by upregulation of NCOA4 and suppression of FTH1. Moreover, co-expression analyses showed that GO term and KEGG pathways were mainly enriched in immunity-related pathways, such as neutrophil-related immunity, adaptive immune response, and cytokine binding. Through ssGSEA algorithm and TISIDB database, immunological analyses showed that MXRA8 was significantly correlated with various immune infiltration cells including NK cells, macrophages, and neutrophils. Meanwhile, MXRA8 was also associated with chemokines and multiple immunoinhibitory molecules, such as TGF-β1, IL-10, PD-L1, and CTLA4. We also found that MXRA8 was positively associated with immune infiltration score, and patients with higher immune score underwent worse overall survivals. Moreover, IHC staining indicated a highly positive correlation of MXRA8 with a macrophage marker CSF1R. The co-cultured models of glioma cells and M2 macrophages showed MXRA8 knockdown glioma cells alleviated the infiltration of M2 macrophage, while the reduced M2 macrophage infiltration generated by MXRA8 could be rescued by Fer-1 treatment. These results suggest that MXRA8 promotes glioma progression and highlight the pivotal role of MXRA8 in ferroptosis and immune microenvironment of glioma. Therefore, MXRA8 may serve as a novel prognostic marker and therapeutic target for glioma.

Background: Pyroptosis is a newly recognized form of cell death. Emerging evidence has suggested the crucial role of long non-coding RNAs (lncRNAs) in the tumorigenesis and progression of ovarian cancer (OC). However, there is still poor understanding of pyroptosis-related lncRNAs in OC.Methods: The TCGA database was accessed for gene expression and clinical data of 377 patients with OC. Two cohorts for training and validation were established by random allocation. Correlation analysis and Cox regression analysis were performed to identify pyroptosis-related lncRNAs and construct a risk model.Results: Six pyroptosis-related lncRNAs were included in the final signature with unfavorable survival data. Subsequent ROC curves showed promising predictive value of patient prognosis. Further multivariate regression analyses confirmed the signature as an independent risk factor in the training (HR: 2.242, 95% CI: 1.598–3.145) and validation (HR: 1.884, 95% CI: 1.204–2.95) cohorts. A signature-based nomogram was also established with a C-index of.684 (95% CI: 0.662–0.705). Involvement of the identified signature in multiple immune-related pathways was revealed by functional analysis. Moreover, the signature was also associated with higher expression of three immune checkpoints (PD-1, B7-H3, and VSIR), suggesting the potential of the signature as an indicator for OC immunotherapies.Conclusion: This study suggests that the identified pyroptosis-related lncRNA signature and signature-based nomogram may serve as methods for risk stratification of OC. The signature is also associated with the tumor immune microenvironment, potentially providing an indicator for patient selection of immunotherapy in OC.

Exosomes, the small extracellular vesicles, are released by multiple cell types, including tumor cells, and represent a novel avenue for intercellular communication via transferring diverse biomolecules. Recently, microRNAs (miRNAs) were demonstrated to be enclosed in exosomes and therefore was protected from degradation. Such exosomal miRNAs can be transmitted to recipient cells where they could regulate multiple cancer-associated biological processes. Accumulative evidence suggests that exosomal miRNAs serve essential roles in modifying the glioma immune microenvironment and potentially affecting the malignant behaviors and therapeutic responses. As exosomal miRNAs are detectable in almost all kinds of biofluids and correlated with clinicopathological characteristics of glioma, they might be served as promising biomarkers for gliomas. We reviewed the novel findings regarding the biological functions of exosomal miRNAs during glioma pathogenesis and immune regulation. Furthermore, we elaborated on their potential clinical applications as biomarkers in glioma diagnosis, prognosis and treatment response prediction. Finally, we summarized the accessible databases that can be employed for exosome-associated miRNAs identification and functional exploration of cancers, including glioma.

Background: Ovarian cancer (OV) is one of the common malignant tumors and has a poor prognosis. Chromobox (CBX) family proteins are critical components of epigenetic regulation complexes that repress target genes transcriptionally via chromatin modification. Some studies have investigated the function specifications among several CBXs members in multiple cancer types, however, little is known about the functions and prognostic roles of distinct CBXs family proteins in ovarian cancer.Methods: In this study, several bioinformatics databases and in vitro experiments were used to analyze the expression profiles, prognostic values, and therapeutic potential of the CBXs family (CBX1-8) in ovarian cancer.Results: It was found that higher expression of CBX3/8 and lower expression of CBX1/6/7 were detected in OV tissues. CBX2/4/5/8 were significantly correlated with individual cancer stages of OV. The expression of CBX1/2/3 were all significantly associated with worse overall survival (OS) and progression-free survival (PFS) for OV patients, whereas the expression of other five CBXs members showed either irrelevant (CBX5 and CBX8) or inconsistent (CBX4, CBX6, and CBX7) results for both OS and PFS in OV. These results showed that only CBX3 had consistent results in expression and prognosis. Further cell experiments also showed that CBX3 promoted the proliferation of ovarian cancer cells. CBX3 was highly expressed in chemoresistant OV tissues. These results indicated that CBX3 was the most likely prognostic indicator and new therapeutic target in OV. Furthermore, gene enrichment analysis suggests that the CBXs family was primarily involved in mast cell activation and mast cell mediated immunity. Individual CBXs members were associated with varying degrees of the infiltration of immune cells, especially B cells. Finally, a high genetic alteration rate of CBXs family (39%) was observed in OV. The low methylation status of CBX3/8 in OV may be associated with their high expression levels.Conclusions: Taken together, these findings exhibited the pivotal value of CBXs family members (especially CBX3) in the prognosis and chemoresistance of ovarian cancer. Our results may provide new insight to explore new prognostic biomarkers and therapeutic targets for ovarian cancer.

Recent studies have indicated that long non-coding RNAs (lncRNAs) may participate in the regulation of tumor cell proptosis. However, the connection between lncRNA expression and pyroptosis remains unclear in colon adenocarcinoma (COAD). This study aims to explore and establish a prognostic signature of COAD based on the pyroptosis-related lncRNAs. We identify 15 prognostic pyroptosis-related lncRNAs (ZNF667-AS1, OIP5-AS1, AL118506.1, AF117829.1, POC1B-AS1, CCDC18-AS1, THUMPD3-AS1, FLNB-AS1, SNHG11, HCG18, AL021707.2, UGDH-AS1, LINC00641, FGD5-AS1 and AC245452.1) from the TCGA-COAD dataset and use them to construct the risk model. After then, this pyroptosis-related lncRNA signature is validated in patients from the GSE17536 dataset. The COAD patients are divided into low-risk and high-risk groups by setting the median risk score as the cut-off point and represented differences in the immune microenvironment. Hence, we construct the immune risk model based on the infiltration levels of ssGSEA immune cells. Interestingly, the risk model and immune risk model are both independent prognostic risk factors. Therefore, a nomogram combined risk score, immune risk score with clinical information which is meaningful in univariate and multivariate Cox regression analysis is established to predict the overall survival (OS) of COAD patients. In general, the signature consisted of 15 pyroptosis-related lncRNAs and was proved to be associated with the immune landscape of COAD patients.

Ovarian cancer (OC) is typically diagnosed at an advanced stage and poses a significant challenge to treatment and recovery. Rencently, Adenosine deaminase RNA-specific B1 (ADARB1), an adenosine-to-inosine (A-to-I) RNA-editing enzyme, has been found to play an essential role in the development of cancer. However, the specific function of ADARB1 in ovarian cancer is still not fully understood. Here, we investigated the effects of ADARB1 on OC biology. By conducting bioinformatics analyses of several public databases, we found significantly decreased ADARB1 expression in OC cells and tissues. Moreover, RT-PCR and western blot showed lower ADARB1 expression in OVCAR3, HO8910pm and A2780 OC cells compared to human normal ovarian epithelial cell IOSE. Cell proliferation assay and clone formation assay showed that overexpression of ADARB1 (ADARB1-OE) inhibited the proliferation of tumor cells. Wound healing and transwell assay indicated that ADARB1-OE could suppress OC cell invasion and metastasis. Kaplan-Meier methods revealed that the patients with low level of ADARB1 displayed poor prognosis. TISIDB databases were further used to analyze the roles of ADARB1 in tumor-immune system interactions in OC patients. Furthermore, ADARB1-OE down-regulated the expression of phosphorylated AKT. Combination of ADARB1-OE and AKT inhibitor MK2206 exerted stronger cell growth inhibition. Thus, our investigation demonstrated that low levels of ADARB1 might be a potential target in the tumorigenesis and prognostic evaluation of OC patients.

Ferroptosis, a distinct type of regulated cell death, has been reported to be involved in the tumorigenesis of liver hepatocellular carcinoma (LIHC). However, the precise functions and potential mechanisms of ferroptosis in LIHC were still poorly understood. Herein, we investigated the biological roles of ferroptosis-related gene STEAP3 in LIHC. STEAP3 was previously proved to serve a key regulator in ferroptosis via mediating the iron metabolism. Comprehensive bioinformatics from several databases revealed that STEAP3 was significantly downregulated in LIHC tissues and exhibited the favorable prognostic significance in LIHC patients. The downregulated STEAP3 was further confirmed in two LIHC cells Huh7 and MHCC97H using real-time PCR and western blot. And STEAP3 overexpression significantly inhibited the cell proliferation in Huh7 and MHCC97H cells. In addition, clinical data identified the relationship between STEAP3 expression and several clinicopathological parameters of LIHC patients, including histologic grade, alpha fetal protein (AFP) concentration, etc. Receiver operation characteristic (ROC) curve revealed STEAP3 as a potential diagnostic biomarker for LIHC patients. Moreover, the co-expression network of STEAP3 was explored to gain a better insight into its underlying signaling pathways. Finally, aberrant STEAP3 might participate in varieties of immune-associated signatures in LIHC pathogenesis, including immunostimulators, immunoinhibitors, chemokines, and chemokine receptors. Taken together, these findings could enhance our knowledge regarding the inhibitory roles and underlying biological significance of STEAP3 in LIHC tumorigenesis.

Alantolactone (ALT) is a natural compound extracted from Chinese traditional medicine Inula helenium L. with therapeutic potential in the treatment of various diseases. Recently, in vitro and in vivo studies have indicated cytotoxic effects of ALT on various cancers, including liver cancer, colorectal cancer, breast cancer, etc. The inhibitory effects of ALT depend on several cancer-associated signaling pathways and abnormal regulatory factors in cancer cells. Moreover, emerging studies have reported several promising strategies to enhance the oral bioavailability of ALT, such as combining ALT with other herbs and using ALT-entrapped nanostructured carriers. In this review, studies on the anti-tumor roles of ALT are mainly summarized, and the underlying molecular mechanisms of ALT exerting anticancer effects on cells investigated in animal-based studies are also discussed.