Current Cancer Drug Targets - Online First

Colorectal cancer (CRC) is among the most widespread malignancies worldwide and is a leading cause for cancer mortality. The interstitial interaction between cancer and stem cells is important during cancer cell metastasis.

In this study, we aimed to elucidate the regulatory role and the underlying mechanisms controlling the activity of exosomes derived from cancer stem cells (CSCs).

Our group isolated exosomes from CSCs and non-CSCs to examine their regulatory mechanisms using Transwell migration, Cell Counting Kit-8 (CCK-8), and 5-ethynyl-2′-deoxyuridine (EdU) assays.

The role of Eukaryotic Translation Initiation Factor 3 Subunit B (EIF3B) in CRC was examined using an in vivo tumorigenesis mouse model. It was found that treatment with exosomes isolated from CD133⁺ cells (CD133+Exos) promoted the proliferation and migration of SW480 cells. The downregulation of EIF3B reduced the proliferation and migration-promoting effects of CD133⁺ Exos on SW480 cells. Furthermore, CD133⁺ Exos treatment promoted the tumorigenesis of SW480 cells.

Our findings demonstrate that CSC-derived exosomes transport EIF3B into CRC cells to initiate epithelial-to-mesenchymal transition (EMT) and promote metastasis.

Numerous studies have suggested a close association between cancer stem cells (CSCs) and the tumor microenvironment (TME), suggesting that cancer stemness might also contribute to ICI resistance. However, the interplay between these physiological processes in urothelial bladder cancer (UBC) remains unclear.

A meta-analysis was performed using the UBC Single-cell RNA sequencing (scRNA-seq) dataset, and tumor stemness gene sets (Ste.genes) were obtained. The relationship between Ste.genes and ICI response, as well as response to drug therapy, was investigated using Tumour Immune Dysfunction and Exclusion (TIDE) and drug sensitivity analyses. Machine learning based on Ste.genes was also used to predict ICI response.

A hypoxia-related tumor subgroup associated with angiogenesis and tumor metastasis was identified, and prognostic models were constructed based on hypoxic tumor subgroups. It was also found that the Ste.genes score was associated with cellular immunity, tumor immunotherapy response, and drug sensitivity. Multiple machine learning models were used to predict ICI response based on Ste.genes, and the AUC was greater than 0.7, indicating that Ste.genes can predict ICI response effectively.

In this study, the analysis of UBC scRNA-seq data provided further insight into the role of hypoxic tumor subpopulations in tumor development in UBC, and a prognostic model was constructed. Additionally, an association was found between cell stemness and resistance to immunotherapy as well as drug sensitivity in UBC. Ste.genes were extracted and utilized to predict the ICI response.

This study aims to explore the potential mechanisms by which Raddeanoside R13 (R13) inhibits the proliferation, invasion, and metastasis of gastric cancer (GC) cells through network pharmacology analysis and experimental validation.

First, network pharmacology was used to explore the potential mechanisms of R13 in treating GC. The effects of R13 on GC cell proliferation were assessed using CCK-8 and colony formation assays. Apoptosis was measured by flow cytometry, while the effects of R13 on invasion and metastasis were evaluated through wound healing and Transwell invasion assays. Finally, Western blotting was performed to investigate the impact of R13 on the expression of epithelial-to-mesenchymal transition (EMT) markers, PI3K/AKT signaling pathway proteins, and apoptosis-related proteins in GC cells.

A total of 58 potential targets of R13 in the treatment of GC were identified. R13 was found to affect the development of GC by regulating pathways, such as NFKB1, mTOR, apoptosis, and the PI3K-AKT signaling pathway. In vitro experiments confirmed that R13 inhibited the proliferation, invasion, and metastasis of GC cells while promoting apoptosis. Additionally, we found that R13 suppressed the EMT of GC cells and reduced the phosphorylation levels of PI3K, AKT, and mTOR. When this pathway was activated, it partially reversed these effects.

R13 inhibited the proliferation, invasion, and metastasis of GC cells while inducing apoptosis. Furthermore, R13 may suppress the EMT process in GC cells by inhibiting the PI3K/AKT/mTOR signaling pathway. These findings provide a foundation for the potential use of R13 as a therapeutic strategy for GC.

The role of Trimethylamine N-oxide (TMAO) in oocyte maturation and embryogenesis remains unclear, particularly its impact on ovarian granulosa cells (OGCs) and its underlying mechanisms.

This study examined the effects of TMAO (100-400 µmol/L) on oocyte maturation, cumulus cell expansion, mitochondrial distribution, and embryonic development in vitro and in a BALB/c mouse model. The involvement of the NF-κB/NLRP3 signaling pathway in TMAO-induced ovarian dysfunction was assessed using Western blotting and gene expression analyses. The potential therapeutic effect of miRNA-146, an NF-κB inhibitor, was also explored.

Western blotting confirmed that TMAO activates the NF-κB signaling pathway and induces the synthesis of caspase 3 and NLRP3 complexes. However, pretreatment with miRNA-146, an NF-κB inhibitor, significantly reduced inflammation and inflammatory gene expression during TMAO therapy. Additionally, miRNA-146 pretreatment promoted oocyte maturation by suppressing NF-κB/NLRP3 activation, OGCs apoptotic inflammatory factor expression, and the gene expression of NF-κB, caspase 3, and NLRP3.

Findings demonstrate that TMAO disrupts oocyte development through NF-κB/NLRP3 activation, contributing to ovarian dysfunction. Notably, targeting TMAO and its downstream signaling could serve as a novel therapeutic strategy for premature ovarian insufficiency (POI).

Lung cancer is the most commonly diagnosed cancer type and the leading cause of cancer death worldwide. Non-small cell lung cancer (NSCLC) accounts for more than 80% of all lung cancer cases and includes two main subtypes: lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC). Understanding the differences in genes causing the proliferation of LUAD and LUSC is key to advancing the diagnosis and targeted treatment development.

The aim of this study was to identify candidate genes and potential tumorigenesis mechanisms distinguishing LUAD and LUSC.

Three pooled transcriptomic datasets (GSE10245, GSE37745, and GSE43580) were analyzed from the Gene Expression Omnibus (GEO) database, with each dataset statistically tested for differentially expressed genes (DEGs). DEGs between lung LUAD and LUSC of the three datasets were analyzed with Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses. A protein-protein interaction (PPI) network was constructed to screen candidate genes.

This study identified 138 shared DEGs among three patient-level gene expression datasets, containing 39 upregulated genes and 99 downregulated genes. The GO and KEGG enrichment analysis results showed the functions of DEGs to be mainly associated with epidermis development, cornified envelope, structural constituent of epidermis, and estrogen signaling pathway. Finally, through the PPI network, eight core genes were identified, including KRT14, KRT5, KRT6A, KRT16, SPRR1A, SPRR1B, SPRR3, and KRT6B.

We have elucidated key genes and molecular mechanisms linked to NSCLC subtypes. These findings have the potential to facilitate improved diagnostic and therapeutic targets for LUAD and LUSC biomarkers.

This study aims to provide a comprehensive understanding of the crucial role of MCM4 in melanoma progression regarding the regulatory communication between macrophages and cancer cells mediated by extracellular vesicles.

Initially, a preliminary analysis was conducted using the Tumor Immune Estimation Resource (TIMER) database. Subsequently, the role of MCM4 knockdown on the polarization of THP-1 and RAW264.7 macrophages was observed. Finally, the biological functionalities of exosomes derived from A375 cells overexpressing MCM4 on normal melanocytes (HEM-L) were explored.

On the one hand, MCM4 knockdown resulted in the upregulation of M1 macrophage markers and downregulation of M2 macrophage markers, indicating that MCM4 could facilitate polarization of macrophages toward the M2 phenotype and suggesting its oncogenic potential. On the other hand, MCM4 overexpression in melanocytes increased the secretion of exosomes, enhancing the proliferation, clonogenic, and DNA synthesis abilities of normal melanocytes. In addition, MCM4 overexpression-induced secretion of exosomes promoted the migration and invasion capabilities of normal melanocytes.

Exosomes secreted by MCM4-overexpressed melanocytes could stimulate their proliferation, migration, and invasion abilities. MCM4 promoted M2 polarization of macrophages, indicating its crucial role in tumor microenvironment formation and thereby facilitating tumor development.