Occurrence Of Tumors Research Articles

ARL8B promotes hepatocellular carcinoma progression and inhibits antitumor activity of lenvatinib via MAPK/ERK signaling by interacting with RAB2A

Tumor recurrence and metastasis are important factors affecting postoperative survival in hepatocellular carcinoma (HCC) patients. ADP Ribosylation factor-like GTPase 8B (ARL8B) plays a crucial role in many biological processes, including lysosomal function, immune response, and cellular communication, all of which are related to the occurrence and development of tumors. However, its role in HCC remains unclear. Herein, we revealed that ARL8B is consistently elevated in HCC tissues compared to normal liver tissues, suggesting an unfavorable outcome in HCC patients. Increased ARL8B levels promoted the malignant phenotype of HCC in vitro and in vivo. Notably, ARL8B also induced epithelial-to-mesenchymal transition (EMT) in HCC cells. Mechanistically, the results of bioinformatics analysis combined with mass spectrometry revealed the potential downstream target molecule RAB2A of ARL8B. ARL8B directly interacted with RAB2A and increased the levels of GTP-bound RAB2A, thereby contributing to the activation of the extracellular signal-regulated kinase (ERK) signaling pathway. Interestingly, knockout of ARL8B in Hep3B cells enhanced the antitumor activity of lenvatinib in vitro and in vivo. Furthermore, AAV-shARL8B enhanced the inhibition of HCC growth through lenvatinib, providing new insights into its mechanism of action in lenvatinib-insensitive patients. In conclusion, ARL8B promotes the malignant phenotype of HCC and EMT via RAB2A mediated activation of the MAPK/ERK signaling pathway and is expected to be a valuable prognostic indicator and therapeutic target for HCC patients.

MiR-155-5p regulates autophagy and apoptosis of glioma cells through RICTOR.

Glioma characterized by the high degree of drug resistance and the poor prognosis is the most common primary malignant tumors of the brain. And miRNA is involved in a variety of biological behaviors of tumors, enhancing or inhibiting the occurrence and development of tumors. Therefore, the present study aims to explore whether miR-155-5p can regulate autophagy and apoptosis of glioma through RICTOR. The significantly differential gene miR-155-5p was identified from the Gene Expression Omnibus (GEO; http://www.ncbi.nlm.nih.gov/geo) databases GSE165937 and GSE138764 using bioinformatics analysis, and its expression was validated by quantitative real-time polymerase chain reaction (qRT-PCR). The putative target genes of miR-155-5p were predicted through interrogation of relevant databases, followed by identification of key target genes. Subsequently, core target genes were selected for functional enrichment analysis. The U87MG cell line was utilized as the experimental model and divided into Negative Control1 (NC1) group, Mimic group, Negative Control2 (NC2) group, Inhibitor group, and NC + 3-methyladenine (3-MA) group. The expression levels of miR-155-5p, RICTOR, P62, LC-3, Bax, Bcl-2, and Caspase-3 were assessed using qRT-PCR, cellular fluorescence imaging, and Western blotting; while apoptosis in the U87MG cell line was evaluated via flow cytometry. The results showed that miR-155-5P was highly expressed in glioma cells, which could inhibit the expression of Bax, Caspase-3, LCII/LCI and Beclin-1, and increase the expression of Bcl2 and P62. Flow cytometry and cell fluorescence were used to verify the above results. Moreover, when U87MG cells treated with miR-155-5p inhibitor were inhibited by 3-MA, the results showed that miR-155-5p enhanced the anti-apoptotic ability of U87MG cells by regulating autophagy. In addition, the bioinformatics results show that miR-155-5p survival prognosis in glioma into a strong negative correlation, while the survival prognosis of RICTOR in glioma showed a strong positive correlation. The core target genes Kyoto Encyclopedia of Genes and Genomes (KEGG) mainly occurred in PI3K-AKT signaling pathway; in addition, qRT-PCR and Western blot confirmed the regulatory effect of miR-155-5P on RICTOR. MiR-155-5p regulates autophagy and apoptosis-related proteins in glioma cells through RICTOR, affecting the occurrence and development of glioma.

Endogenous enzyme-activated AND-gate DNA nanomachines for intracellular miRNA detection and cell-selective imaging

The occurrence and development of tumors are accompanied by the abnormal expression of specific microRNAs (miRNAs). Therefore, miRNAs are considered as an important biomarker. The establishment of efficient, simple and sensitive miRNA imaging methods in living cells will contribute to the early diagnosis, treatment and drug development of diseases. In this study, we developed an endogenous enzyme-initiated AND logic circuit using gold nanocubes (AuNCs) as carriers for simultaneous detection of miRNA-21 and miRNA-210 in cells. Apurinic/apyrimidinic endonuclease 1 (APE1) and telomerase (TE), which are overexpressed in cancer cells, act as control switches in a logic circuit that enables sensitive in situ analysis of intracellular miRNAs without additional external intervention. At the same time, due to the lack of necessary enzymes as activation switches, the DNA circuit in normal cells remains in an inactive state. This strategy effectively reduces the risk of false positive signal generation. Our research results show that the logic circuit can not only distinguish between cancer cells and normal cells, and able to distinguish between different types of cancer cells. This finding provides a promising approach to accurately identify cell types.

The mechanism of cytokine regulation of cancer occurrence and development in the tumor microenvironment and its application in cancer treatment: a narrative review.

The occurrence and development of tumors in human tissues widely depend on their surrounding environment, known as the tumor microenvironment (TME), which comprises various cells, molecules, and blood vessels. Through modifications, organization, and integration, these elements serve as potential therapeutic targets in anti-cancer therapy, supporting and promoting the proliferation, invasion, and metabolism of tumor cells. Cytokines within TME are responsible for immune cell activation, proliferation, and differentiation, thereby influencing the tumor's behavior. This article reviews the use of cytokines in tumor immunotherapy and combs the network signals that cytokines mediate in the development of malignancies. A literature search of international sources was carried out on the PubMed and Web of Science databases, using main keywords such as "tumor immunotherapy", "cytokines", "chemokines", "tumor microenvironment", "recombinant cytokine engineering", and "tumor necrosis factor superfamily". The review provides a thorough summary of the functions of tumor necrosis factor superfamilies, chemokines, and interleukins within the TME as well as their therapeutic uses. Their potential as novel targets for tumor treatment is also evaluated. Furthermore, this paper focuses on various feasible strategies for recombinant cytokines reported in recent years, especially the cytokine engineering methods for targeting tumors. Ultimately, this paper contributes to an enhanced understanding among researchers of the mechanisms underlying the impact of the TME on disease development, thereby laying a solid foundation for the future development of new tumor therapies based on cytokines within the TME. Cytokine immunotherapy holds promise on antitumor therapy. It is anticipated that the effectiveness of tumor treatment and the quality of life for tumor patients will continue to improve with ongoing research and development in this field.

Ferroptosis:Mechanisms and Application in Tumor Treatment

Ferroptosis is a form of regulated cell death that depends on iron and reactive oxygen species.Different from apoptosis,necrosis,and autophagy,ferroptosis is characterized by the accumulation of lipid peroxides in cells.Studies have discovered that ferroptosis is closely associated with the occurrence and development of tumors and inducing ferroptosis in tumor cells can enhance the therapeutic effects of drugs on tumors.This article summarizes the latest research progress in ferroptosis regarding its mechanisms and associations with tumors,aiming to provide a reference for further understanding the interaction mechanisms between ferroptosis and tumors and offering new insights and targets for the treatment of tumors.

MALIGNANT NEOPLASMS OF THE REPRODUCTIVE SYSTEM IN MEN AND THEIR CONNECTION WITH THE HUMAN PAPILLOMAVIRUS. (REVIEW)

The issue of malignant tumor occurrence associated with viral infections is a particularly significant one. Approximately 15-20% of tumors have some connection with various viral infections. An extensive amount of data has been gathered on neoplasms of the female reproductive system linked to the human papillomavirus (HPV). However, the connection between papillomavirus infection and malignant neoplasms in the male reproductive system requires further investigation. The aim of this review is to examine the association between malignant neoplasms of the male reproductive system and HPV, as well as to consider the issue of male vaccination. A research team conducted a literature review on the topic using databases such as the National Library of Medicine, Web of Science, and CyberLeninka. Data was collected on three types of malignant tumors in the male reproductive system: penile cancer, testicular cancer, and prostate cancer. In the context of the relationship between HPV and penile and prostate cancers, data on the presence of viral DNA in tumor tissue samples have been isolated. A study found that HPV DNA was present in semen samples from 34.9% of patients with testicular cancer, compared to only 2.4% in a control group. However, understanding of the HPV lifecycle raises questions about the link between HPV and testicular cancer. HPV multiplies in dividing epithelial cells, but testicular tissue is of mesodermal origin, and may not provide a suitable environment for HPV reproduction. Based on these findings, it is possible to draw the following conclusions: there are pathogenic reasons for the association between HPV and male reproductive system neoplasms. Further systematic review and meta-analysis are needed to fully understand this complex relationship.

Tyrosine kinase inhibitors in the treatment of leptomeningeal carcinomatosis.

Leptomeningeal carcinomatosis (LMC) is a devastating complication of advanced cancers, such as lung cancer and breast cancer, which is usually indicative of a poor prognosis. The current treatments for LMC include palliative care, with others aiming to prolong survival and relieve neurological symptoms. Traditional treatments for LMC include radiotherapy, systemic chemotherapy, and intrathecal injection. Furthermore, the application of molecularly targeted agents, such as antiepidermal growth factor receptor (anti-EGFR), antihuman epidermal growth factor receptor 2 (anti-HER2), and anti-PD-1 monoclonal antibody, have prolonged the survival of LMC patients. Targeted therapy with tyrosine kinase inhibitors has also been proven to be an effective treatment. Tyrosine kinases can be overactive or expressed at high levels in some cancer cells; therefore, the use of tyrosine kinase inhibitors may prevent the activation of tumor-related pathways, preventing cancer cell growth. The EGFR family are cell surface receptors directly related to tumor occurrence with tyrosine kinase activity; it is the most widely used target for tyrosine kinase inhibitors in the treatment of LMC. In this review, we introduced the clinical manifestation and diagnostic criteria of LMC, clarified the treatment mechanism of tyrosine kinase inhibitors for LMC with mutations in EGFR, HER2, or anaplastic lymphoma kinase, reviewed the current application of various generation tyrosine kinase inhibitors in patients with LMC, and discussed new clinical trials and the future directions of tyrosine kinase inhibitor therapy.

Diagnosis and management of pituitary adenomas in children and adolescents.

Pituitary adenomas (PAs)-also now called pituitary neuroendocrine tumours or Pit-NETS-are rare in children and adolescents and exceptional below the age of 10. Most evidence-based high-quality data are derived from larger studies in adult patients. We will review recent knowledge on the epidemiology, clinical features, diagnosis, and treatment modalities of the different types of pituitary adenomas diagnosed in children and adolescents, emphasizing the many reasons why these cases should be discussed within pituitary-specific multidisciplinary teams with experts from both paediatric and adult practice. Paediatric PA presents multiple peculiarities that may challenge their adequate management. They are overall proportionally larger and more aggressive than in adults, with potential mass effects including hypopituitarism. Hormonal hypersecretion is frequent, resulting in clinical syndromes affecting normal growth and pubertal development. Prolactinomas represent the most frequent subtype of PA found during childhood, followed by adrenocorticotropin (ACTH) and growth hormone (GH)-secreting adenomas, while clinically non-functioning adenomas are exceptionally diagnosed before the age of 16. The occurrence of a pituitary tumour in a young individual should also prompt genetic testing in each case, searching for either germline mutations in one of the known genes that may drive inherited/familial PA (such as the multiple endocrine neoplasia type 1 or MEN1 gene, or the aryl hydrocarbon receptor interacting protein or AIP gene), or for a mosaic activating mutation of GNAS as found in the McCune-Albright syndrome.

N-acetyltransferase 10 affects the proliferation of intrahepatic cholangiocarcinoma and M2-type polarization of macrophages by regulating C-C motif chemokine ligand 2

BackgroundN-acetyltransferase 10 (NAT10) plays a crucial role in the occurrence and development of various tumors. However, the current regulatory mechanism of NAT10 in tumors is limited to its presence in tumor cells. Here, we aimed to reveal the role of NAT10 in intrahepatic cholangiocarcinoma (ICC) and investigate its effect on macrophage polarization in the tumor microenvironment (TME).MethodsThe correlation between NAT10 and ICC clinicopathology was analyzed using tissue microarray (TMA), while the effect of NAT10 on ICC proliferation was verified in vitro and in vivo. Additionally, the downstream target of NAT10, C-C motif chemokine ligand 2 (CCL2), was identified by Oxford Nanopore Technologies full-length transcriptome sequencing, RNA immunoprecipitation-quantitative polymerase chain reaction, and coimmunoprecipitation experiments. It was confirmed by co-culture that ICC cells could polarize macrophages towards M2 type through the influence of NAT10 on CCL2 protein expression level. Through RNA-sequencing, molecular docking, and surface plasmon resonance (SPR) assays, it was confirmed that berberine (BBR) can specifically bind CCL2 to inhibit ICC development.ResultsHigh expression level of NAT10 was associated with poor clinicopathological manifestations of ICC. In vitro, the knockdown of NAT10 inhibited the proliferative activity of ICC cells and tumor growth in vivo, while its overexpression promoted ICC proliferation. Mechanically, by binding to CCL2 messenger RNA, NAT10 increased CCL2 protein expression level in ICC and their extracellular matrix, thereby promoting the proliferation of ICC cells and M2-type polarization of macrophages. BBR can target CCL2, inhibit ICC proliferation, and reduce M2-type polarization of macrophages.ConclusionsNAT10 promotes ICC proliferation and M2-type polarization of macrophages by up-regulating CCL2, whereas BBR inhibits ICC proliferation and M2-type polarization of macrophages by inhibiting CCL2.

The MCIB Model: A Novel Theory for Describing the Spatial Heterogeneity of the Tumor Microenvironment

The tumor microenvironment (TME) can be regarded as a complex and dynamic microecosystem generated by the interactions of tumor cells, interstitial cells, the extracellular matrix, and their products and plays an important role in the occurrence, progression and metastasis of tumors. In a previous study, we constructed an IEO model (prI-, prE-, and pOst-metastatic niche) according to the chronological sequence of TME development. In this paper, to fill the theoretical gap in spatial heterogeneity in the TME, we defined an MCIB model (Metabolic, Circulatory, Immune, and microBial microenvironment). The MCIB model divides the TME into four subtypes that interact with each other in terms of mechanism, corresponding to the four major links of metabolic reprogramming, vascular remodeling, immune response, and microbial action, providing a new way to assess the TME. The combination of the MCIB model and IEO model comprehensively depicts the spatiotemporal evolution of the TME and can provide a theoretical basis for the combination of clinical targeted therapy, immunotherapy, and other comprehensive treatment modalities for tumors according to the combination and crosstalk of different subtypes in the MCIB model and provide a powerful research paradigm for tumor drug-resistance mechanisms and tumor biological behavior.

Novel Oncogenic Value of C10orf90 in Colon Cancer Identified as a Clinical Diagnostic and Prognostic Marker

C10orf90, a tumor suppressor, can inhibit the occurrence and development of tumors. Therefore, we investigated the gene function of C10orf90 in various tumors using multiple pan-cancer datasets. Pan-cancer analysis results reveal that the expression levels of C10orf90 vary across different tumors and hold significant value in the clinical diagnosis and prognosis of patients with various tumors. In some cancers, the expression level of C10orf90 is correlated with CNV, DNA methylation, immune subtypes, immune cell infiltration, and drug sensitivity in the tumors. In particular, in COAD, the C10orf90 gene is implicated in multiple processes associated with COAD. Cell experiments demonstrate that C10orf90 suppresses the proliferation and migration of colon cancer cells while promoting apoptosis. In summary, C10orf90 plays a role in the onset and progression of various cancers and could potentially serve as an effective diagnostic and prognostic marker for cancer patients. Notably, in COAD, C10orf90 inhibits the proliferation and migration of colon cancer cells, induces apoptosis, and is linked to the advancement of colon cancer.

FBXO2 promotes the progression of papillary thyroid carcinoma through the p53 pathway

Emerging evidence have demonstrated that F-box only protein 2 (FBXO2) is intimately associated with malignant tumor development and occurrence. However, neither the functions nor the molecular mechanisms underlying FBXO2 have been determined in the papillary thyroid carcinoma (PTC). The quantitative real-time PCR (qRT-PCR), western blotting and immunohistochemistry were carried out to detect the FBXO2 expression in PTC tissues. CCK-8 assay, EdU assay and flow cytometry were used to assess cell proliferation, cell cycle and apoptosis. The trans-well assay was conducted to determine the cell invasiveness. The effect of FBXO2 on PTC cell proliferation in vivo was observed through a subcutaneous tumor formation experiment in nude mice. Immunoprecipitation were conducted to detect the interaction between FBXO2 and p53. The ubiquitination assays were conducted to assess the regulation of p53 ubiquitination by FBXO2. FBXO2 was overexpressed in both PTC tissues and cell lines. FBXO2 expression positively correlated with PTC tumor size, lymphatic metastasis, and extramembranous invasion. Furthermore, silencing FBXO2 inhibited PTC cell proliferation and promoted apoptosis. The overexpression of FBXO2 significantly promotes PTC cell proliferation. Mechanistic studies revealed that FBXO2 could directly bind to p53 and promote its ubiquitination degradation. Knockdown of p53 partially reversed the progression arrest induced by FBXO2 Knockdown in PTC cells. FBXO2 knockdown inhibited PTC cell proliferation and promoted apoptosis by targeting p53 for ubiquitination and degradation. This process represents a research foundation for its diagnostic and therapeutic applications.

E242-E261 region of MYC regulates liquid-liquid phase separation and tumor growth by providing negative charges

MYC is one of the most extensively studied oncogenic proteins and is closely associated with the occurrence and progression of many tumors. Previous studies have shown that MYC regulates cell fate through its liquid-liquid phase separation (LLPS) mechanism, which is dependent on two disordered domains within its N-terminal transcriptional activation regions. In this study, we revealed that the negatively charged conserved region (E242-E261) of the MYC protein controls its condensation formation and irreversible aggregation through multivalent electrostatic interactions (MEIs). Furthermore, deletion or mutation of the E242-E261 amino acids in the MYC protein enhances the transcriptional function of MYC by altering its aggregation capacity and subsequently promoting cancer cell proliferation. The discovery of the negatively charged region and its regulatory action on the phase separation of MYC provides a new understanding on the aggregation and function of MYC.

Identification of key ferroptosis genes and subtypes in kidney renal clear cell carcinoma

Tumour immunity is highly important for the occurrence and development of tumours, and many cancers are resistant to ferroptosis. This study aims to explore the relationship between ferroptosis-related genes (FRGs) and the immunological characteristics of kidney renal clear cell carcinoma (KIRC). We obtained RNA-seq profiles and clinical data of KIRC patients from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases and identified CD44 and GLRX5 as the key FRGs involved in KIRC immune infiltration through Spearman’s correlation analysis. Based on the expression of CD44 and GLRX5, the consensus clustering algorithm was used to classify the TCGA-KIRC samples into two clusters. A nomogram was constructed to evaluate the prognosis of KIRC patients. ESTIMATE, CIBERSORT, and single-sample gene set enrichment analysis (ssGSEA) were performed to evaluate immune infiltration between the two clusters. A weighted gene co-expression network analysis (WGCNA) was used to identify the most relevant genes to the clusters and immunity. Then, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed. The external dataset GSE53757 was used to validate the immunological features between the two clusters. Cluster 2 patients had more active immune infiltration and might be more sensitive to immunotherapy; Cluster 2 patients also had a worse prognosis and might be at a more advanced stage of KIRC. We identified key ferroptosis-related genes and subgroups involved in the immune infiltration of KIRC, which is highly important for exploring the molecular mechanisms and treatments of KIRC.

Role of Exosomes in Salivary Gland Tumors and Technological Advances in Their Assessment.

Backgroud: Salivary gland tumors (SGTs) are rare and diverse neoplasms, presenting significant challenges in diagnosis and management due to their rarity and complexity. Exosomes, lipid bilayer vesicles secreted by almost all cell types and present in all body fluids, have emerged as crucial intercellular communication agents. They play multifaceted roles in tumor biology, including modulating the tumor microenvironment, promoting metastasis, and influencing immune responses. Results: This review focuses on the role of exosomes in SGT, hypothesizing that novel diagnostic and therapeutic approaches can be developed by exploring the mechanisms through which exosomes influence tumor occurrence and progression. By understanding these mechanisms, we can leverage exosomes as diagnostic and prognostic biomarkers, and target them for therapeutic interventions. The exploration of exosome-mediated pathways contributing to tumor progression and metastasis could lead to more effective treatments, transforming the management of SGT and improving patient outcomes. Ongoing research aims to elucidate the specific cargo and signaling pathways involved in exosome-mediated tumorigenesis and to develop standardized techniques for exosome-based liquid biopsies in clinical settings. Conclusions: Exosome-based liquid biopsies have shown promise as non-invasive, real-time systemic profiling tools for tumor diagnostics and prognosis, offering significant potential for enhancing patient care through precision and personalized medicine. Methods like fluorescence, electrochemical, colorimetric, and surface plasmon resonance (SPR) biosensors, combined with artificial intelligence, improve exosome analysis, providing rapid, precise, and clinically valid cancer diagnostics for difficult-to-diagnose cancers.

Association between microsatellite instability status, clinicopathological features and mitochondrial DNA amplification in patients with colorectal cancer.

The relationship between BRAF-V600E mutations, mitochondrial DNA amplification and microsatellite instability-high (MSI-H) in colorectal cancer (CRC) has yet to be fully elucidated. The aim of the present study was to assess the association between the MSI status and BRAF-V600E gene mutations/clinicopathological features/mitochondrial DNA amplification in CRC. A non-interventional study analysis was performed using the clinicopathological features of 455 patients with CRC. Immunohistochemistry was used to evaluate four mismatch repair proteins (MutS homolog 2, MutS homolog 6, MutL homolog 1 and postmeiotic segregation increased 2), Ki-67 index, and programmed cell death protein 1 (PD-1) and programmed cell death-ligand 1 (PD-L1) expression. Additionally, PCR coupled with capillary electrophoresis were used to ascertain the MSI status. Moreover, amplification refractory mutation system-PCR was used to detect BRAF-V600E gene mutation and fluorescence in situ hybridization analysis was used to assess mitochondrial DNA. A total of 455 patients were divided into the MSI high (MSI-H) group (n=52) and microsatellite stability (MSS) group (n=403) based on their MSI status. Compared with the results of immunohistochemistry of four mismatch repair proteins, the consistency rate between mismatch repair protein deficiency and MSI was 94.23%. There were significant differences in PD-L1, primary tumor site, clinical stage, degree of differentiation, tumor size, lymph node metastasis and the occurrence of multiple primary tumors between the MSI-H group and MSS group (P<0.05 or P<0.001). However, there were no significant differences for sex, age, PD-1, Ki-67 expression and BRAF-V600E. The 24-60-month survival rate of the patients in the MSI-H group was significantly higher than that of those in the MSS group (P<0.05). Furthermore, the number of mitochondrial DNA was significantly amplified in the MSI-H group. In conclusion, the present study demonstrated that the combined detection of PD-L1 and MSI in patients with CRC can provide more accurate and effective guidance for personalized treatment.

Synchronous Head and Neck Squamous Cell Carcinoma and Hematologic Malignancies

Synchronous occurrence of solid tumors and hematological malignancy is a rare condition. There is no standard management or therapy for this complicated situation. The authors systematically reviewed articles searched using online databases. The patients are predominantly male, and the average age is similar to each malignancy. According to these studies, most patients are treated in order of aggressiveness. However, when a patient has multiple primary malignancies, all of which are aggressive, the treatment decision is challenging. Due to the limited number of cases, it is hard to have a firm conclusion about an optimal treatment policy. It appears that poor outcomes are mostly related to less adequate therapy. Because the condition is complicated in such cases and there is no standardized treatment, patients should be treated on an individual basis with treatments customized to a given patient’s particular circumstances. In addition, multidisciplinary communication and cooperation are crucial in the management of these patients. More in-depth research is still needed to reach a more conclusive treatment strategy and predictable outcomes.

Can alterations in cathepsin levels restrain the development of skin cancer?: A bidirectional multivariate Mendelian-randomization study.

Malignant skin tumors mainly include basal cell carcinoma, squamous cell carcinoma, and malignant melanoma. There is currently observational research suggesting that changes in cathepsin (CTS) may be a factor in the development of malignant skin tumors, but no studies have yet demonstrated a causal relationship between tissue protease changes and the occurrence of malignant skin tumors. Current studies have shown that cathepsin is involved in tumor cell invasion and metastasis by regulating growth factors and cellular immune function in tumor microenvironment, decomposing extracellular matrix and basement membrane, and promoting angiogenesis. In this study, we conducted a bidirectional Mendelian-randomization study using publicly available genome-wide association study (GWAS; GWAS Catalog) data. This study applies a bidirectional multivariate Mendelian randomization (MR) approach to investigate the causal relationship between cathepsin, basal cell carcinoma, squamous cell carcinoma, and malignant melanoma. In cases where multiple cathepsins are implicated as etiological factors in certain diseases, a multivariable analysis is conducted to assess the direct and indirect causal effects of the exposure factors. In this study, we present a comprehensive MR analysis to investigate the relationship between 9 cathepsin and basal cell carcinoma, squamous cell carcinoma, and malignant melanoma. Based on our MR analysis using the largest GWAS Catalog dataset available, we are able to draw relatively reliable conclusions. In the MR study, we found that tissue protease L2 can promote skin cancer, Cathepsin O, and Cathepsin F are associated with an increased risk of basal cell carcinoma. Cathepsin H can inhibit basal cell carcinoma and malignant melanoma. In the reverse MR study, it was found that squamous cell carcinoma may cause an increase in Cathepsin O expression. In the multivariate analysis, it was found that Cathepsin H is a direct factor in reducing the occurrence of skin cancer and melanoma, with no apparent causal relationship to non-melanoma skin cancer. Cathepsin has a dual impact on skin cancer cells, and the expression of different cathepsins at the edge of skin tumors may indicate different developmental tendencies of skin cancer. Cathepsin may serve as effective biomarkers for predicting tumors.

Exosomal miR-142-3p from M1-polarized macrophages suppresses cell growth and immune escape in glioblastoma through regulating HMGB1-mediated PD-1/PD-L1 checkpoint.

Glioblastoma (GBM) is one of the most prevalent cancerous brain tumors. Former studies have reported that exosomes derived from M1-polarized macrophages (M1 exosomes) inhibit tumor occurrence and development through delivery of tumor suppressor genes. Also, microRNA-142-3p (miR-142-3p) has been verified to function as a tumor suppressor. GBM cell proliferation was evaluated by Cell Counting Kit-8 (CCK-8), colony formation assay and 5-ethynyl-2'-deoxyuridine (EdU) assay; cell apoptosis was determined by flow cytometry analysis and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay. Mechanism investigations were conducted for analyzing the molecular mechanism by which miR-142-3p and M1 exosomes affect GBM progression. Upregulation of miR-142-3p expression was detected in M1-polarized macrophages and M1 exosomes. M1 exosomes inhibit GBM cell proliferation and trigger cell apoptosis. Functionally, miR-142-3p silencing promotes the proliferation and inhibits the apoptosis of GBM cells treated with M1 exosomes. As for molecular mechanism, miR-142-3p inhibits GBM cell growth via targeting high-mobility group box1 (HMGB1). In addition, miR-142-3p/HMGB1 axis affects GBM cell immune escape through modulation of programmed death-1/programmed death ligand-1 (PD-1/PD-L1) checkpoint. Our study demonstrated that exosomal miR-142-3p from M1-polarized macrophages suppresses cell growth and immune escape in GBM through regulating HMGB1-mediated PD-1/PD-L1 checkpoint.

Anti-tumor Mechanism of Camellia nitidissima Based on Network Pharmacology and Molecular Docking

Background: Modern pharmacological research indicated that Camellia nitidissima (CAM) had significant anti-tumor activity, but the investigation of its mechanism was still lacking. Objective: The multi-component, multi-target and multi-pathway mechanism of CAM against tumor was investigated based on network pharmacology and molecular docking. Methods: The active ingredients and targets of CAM were selected through a literature search, Traditional Chinese Medicine Systems Pharmacology database and PharmMapper database, and tumor-related targets were selected by GeneCards database, then to obtain the anti-tumor related targets of CAM. The protein interaction relationship was obtained through STRING database, protein-protein interaction network was constructed using Cytoscape 3.7.2 software, and enrichment analysis of GO and KEGG was conducted. AutoDock Tools 1.5.6 software was used to verify the molecular docking between the key ingredients and the key targets. Results: Catechin, epicatechin and luteolin were identified as the key anti-tumor related ingredients, and ESR1, EGFR, MAPK8, MAPK10, AR, PGR, F2 and PIK3CG were identified as the key targets. The GO entries mainly involved metabolic process, cellular process, response to stimulus, organelle, cytosol, etc. The KEGG enrichment showed that the key pathways included pathways in cancer, prostate cancer, pancreatic cancer, breast cancer, estrogen signaling pathway, MAPK signaling pathway, PI3K-Akt signaling pathway, etc. KEGG pathway maps indicated that the anti-tumor effect of CAM may be mainly achieved by intervening related targets in the following pathways: AR-HSP/AR-AR/PSA/proliferation and evading apoptosis; F2/GPCR/…/ROCK/tissue invasion and metastasis; F2/GPCR/…/Raf/MAPK signaling pathway/proliferation and sustained angiogenesis; EGFR/PI3K-Akt signaling pathway/proliferation, evading apoptosis and sustained angiogenesis; EGFR/Grb2/…/Raf/MAPK signaling pathway/proliferation and sustained angiogenesis; ER/Estrogen signaling pathway/proliferation; PR/PR-COR/Wnts-RANKL/proliferation; oxidative stress (.O₂-, .OH, H₂O₂)/KEAP1/NRF2/.../proliferation and evading apoptosis. The results of molecular docking showed that the key active ingredients had a good binding activity with each key target. Conclusion: It was predicted that the main active ingredients of CAM could bind to tumor-related targets, such as receptor and coagulation-promoting factor, scavenge free radicals, and then interfere with the occurrence and development of tumors.