The Mechanism of Celastrol in the Treatment of Metastatic Lung Adenocarcinoma Revealed by Network Pharmacology and Molecular Docking

Background: Celastrol is an active ingredient extracted from Traditional Chinese Medicine (TCM), which can restrain the progression of lung cancer, whereas its underlying mechanism is unclear. In our study, the underlying mechanism of celastrol in the treatment of lung adenocarcinoma (LUAD) with metastasis was investigated by network pharmacology and molecular docking. Method: Potential targets of celastrol were collected from TCMSP, Batman-TCM and GeneCard database, and its potential targets were predicted using the STP platform and the TargetNet server. Metastasis marker genes (MGs) were obtained from the HCMDB. The genes correlated with LUAD were gathered from the GeneCard and OMIM database. And the common targets among celastrol potential targets, MGs and LUAD were analyzed. The protein-protein interaction (PPI) networks were obtained from the STRING database. SangerBox and the Xiantao bioinformatics tool were applied to visualize GO and KEGG analysis. Molecular docking tested the binding affinity between celastrol and core genes. Result: A total of 107 targets of celastrol against metastasis LUAD were obtained. The core targets were obtained from the PPI network, namely AKT1, JUN, MYC, STAT3, IL6, TNF, NFKB1, BCL2, IL1B, and HIF1A. GO and KEGG enrichment analysis indicated celastrol for the treatment of metastasis LUAD most refers to cellular response to chemical stress, DNA-binding transcription factor binding, transcription regulator complex and pathways in cancer. And some of these targets are associated with differential expressions and survival rates in LUAD. Moreover, Molecular docking shows celastrol can bind with BCL2 well by hydrogen bond and hydrophobic interaction. Conclusion: This finding roundly expounded the core genes and potential mechanisms of celastrol for the treatment of metastasis LUAD, offering the theoretical basis and antitumor mechanism of TCM in the treatment of lung cancer.

Single-cell transcriptomics reveals cell atlas and identifies cycling tumor cells responsible for recurrence in ameloblastoma

Ameloblastoma is a benign tumor characterized by locally invasive phenotypes,leading to facial bone destruction and a high recurrence rate.However,the mechanisms governing tumor initiation and recurrence are poorly understood.Here,we uncovered cellular landscapes and mechanisms that underlie tumor recurrence in ameloblastoma at single-cell resolution.Our results revealed that ameloblastoma exhibits five tumor subpopulations varying with respect to immune response(IR),bone remodeling(BR),tooth development(TD),epithelial development(ED),and cell cycle(CC)signatures.Of note,we found that CC ameloblastoma cells were endowed with stemness and contributed to tumor recurrence,which was dominated by the EZH2-mediated program.Targeting EZH2 effectively eliminated CC ameloblastoma cells and inhibited tumor growth in ameloblastoma patient-derived organoids.These data described the tumor subpopulation and clarified the identity,function,and regulatory mechanism of CC ameloblastoma cells,providing a potential therapeutic target for ameloblastoma.

Single cell analysis unveils B cell-dominated immune subtypes in HNSCC for enhanced prognostic and therapeutic stratification

Head and neck squamous cell carcinoma(HNSCC)is characterized by high recurrence or distant metastases rate and the prognosis is challenging.There is mounting evidence that tumor-infiltrating B cells(TIL-Bs)have a crucial,synergistic role in tumor control.However,little is known about the role TIL-Bs play in immune microenvironment and the way TIL-Bs affect the outcome of immune checkpoint blockade.Using single-cell RNA sequencing(scRNA-seq)data from the Gene Expression Omnibus(GEO)database,the study identified distinct gene expression patterns in TIL-Bs.HNSCC samples were categorized into TIL-Bs inhibition and TIL-Bs activation groups using unsupervised clustering.This classification was further validated with TCGA HNSCC data,correlating with patient prognosis,immune cell infiltration,and response to immunotherapy.We found that the B cells activation group exhibited a better prognosis,higher immune cell infiltration,and distinct immune checkpoint levels,including elevated PD-L1.A prognostic model was also developed and validated,highlighting four genes as potential biomarkers for predicting survival outcomes in HNSCC patients.Overall,this study provides a foundational approach for B cells-based tumor classification in HNSCC,offering insights into targeted treatment and immunotherapy strategies.

Aberrant translation regulated by METTL1/WDR4-mediated tRNA N7-methylguanosine modification drives head and neck squamous cell carcinoma progression

Background:Cancer cells selectively promote the translation of oncogenic tran-scripts to stimulate cancer progression.Although growing evidence has revealed that tRNA modifications and related genes participate in this process,their roles in head and neck squamous cell carcinoma(HNSCC)remain largely unchar-acterized.Here,we sought to investigate the function and mechanisms of the transfer RNA(tRNA)N7-methylguanosine(m'G)modification in regulating the occurrence and development of HNSCC.Methods:Cell lost of-function and gain-of function assays,xenograft models,conditional knockout and knockin mouse models were used to study the physi-ological functions of tRNA m'G modification in HNSCC tumorigenesis.tRNA modification and expression profiling,mRNA translation profiling and res-cue assays were performed to uncover the underlying molecular mechanisms.Single-cell RNA sequencing(scRNA seq)was conducted to explore the tumor microenvironment changes.Results:The tRNA.m7G methyltransferase complex components Methyltransferase-like 1(METTL1)/WD repeat domain 4(WDR4)were upregulated in HNSCC and associated with a poor prognosis.Functionally,METTL1/WDR4 promoted HNSCC progression and metastasis in cell-based and transgenic mouse models.Mechanistically,ablation of METTL1 reduced the m'G levels of 16 tRNAS,inhibiting the translation of a subset of oncogenic transcripts,including genes related to the phosphatidylinositol-3-kinase/protein kinase B/mammalian target of rapamycin(PI3K/AKT/mTOR)signaling pathway.In addition,chemical modulators of the PI3K/Akt/mTOR signaling pathway reversed the effects of Mettll in mouse HNSCC.Furthermore,scRNA-seq results revealed that Mettll knockout in mouse tumor cells altered the immune landscape and cell-cell interaction between the tumor and stromal compartment.Conclusions:The tRNA m?G methyltransferase METTLI was found to promote the development and malignancy of HNSCC through regulating global mRNA translation,including the PI3K/AKT/mTOR signaling pathway,and found to alter immune landscape.METTLI could be a promising treatment target for HNSCC patients.