Cancer Biology & Therapy最新文献

The incidence of papillary thyroid cancer (PTC) has been steadily rising, though the underlying mechanism remains unclear. This study aims to elucidate the biological role of TM4SF4 in the PTC progression. Our differential expression analysis indicated that TM4SF4 was significantly upregulated in PTC, which was corroborated in both our local cohort and the data from Human Protein Atlas. Additionally, clinical characteristics analysis and receiver operating characteristic curves (ROC) demonstrated that TM4SF4 served as a significant diagnostic marker for PTC. Correlation and enrichment analysis of TM4SF4-related partners suggested that it was involved in cell junction and cohesion processes. Furthermore, immune infiltration analysis revealed a positive correlation between TM4SF4 expression and the immune activation in PTC. Importantly, in vitro experiments demonstrated that TM4SF4 downregulation suppressed the proliferation and metastasis of PTC cell lines while inducing apoptosis. We further discovered that the AKT activator SC79 was able to reverse the malignant behaviors suppression caused by TM4SF4 knockdown, suggesting that TM4SF4 may promote PTC progression via the AKT pathway. In conclusion, our study highlights the oncogenic role of TM4SF4 in PTC and identifies it as a novel biomarker for diagnosis and treatment.

Anti-CTLA-4 and anti-PD-1/PD-L1 antibodies have significantly revolutionized cancer immunotherapy. However, the persistent challenge of low patient response rates necessitates novel approaches to overcome immune tolerance. Targeting immunostimulatory signaling may have a better chance of success for its ability to enhance effector T cell (Teff) function and expansion for antitumor immunity. Among various immunostimulatory pathways, the evidence underscores the potential of activating OX40-OX40L signaling to enhance CD8⁺ T cell generation and maintenance while suppressing regulatory T cells (Tregs) within the tumor microenvironment (TME). In this study, we introduce a potent agonistic anti-OX40 antibody, SHR-1806, designed to target OX40 receptors on activated T cells and amplify antitumor immune responses. SHR-1806 demonstrates a high affinity and specificity for human OX40 protein, eliciting FcγR-mediated agonistic effects, T cell activation, antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) activities in vitro. In human OX40 knock-in mice bearing MC38 tumor, SHR-1806 shows a trend toward a higher potency than the reference anti-OX40 antibody produced in-house, GPX4, an analog of pogalizumab, the most advanced drug candidate developed by Roche. Furthermore, SHR-1806 displays promising anti-tumor activity alone or in combination with toll-like receptor 7 (TLR7) agonist or PD-L1 inhibitor in mouse models. Evaluation of SHR-1806 in rhesus monkeys indicates a favorable safety profile and typical pharmacokinetic characteristics. Thus, SHR-1806 emerges as a robust OX40 agonist with promising therapeutic potential.

The development of an effective treatment for myelodysplastic syndrome (MDS) is needed due to the insufficient efficacy of current therapies. Gambogenic acid (GNA) is a xanthone constituent of gamboge, a resin secreted by Garcinia hanburyi Hook. f. GNA exhibits antitumor and apoptosis-inducing activities against some cancer cells, but the mechanism is unknown. This study aimed to validate the anti-proliferative and apoptosis-inducing effects of GNA on MDS cells and to elucidate the mechanisms underlying those activities. Apoptosis, proliferation and cell cycle of MDS-L cells were assessed by the caspase 3/7 assay, cell counting and flow cytometry, respectively. The levels of apoptotic, tubulin, NF-κB pathways, and Fas proteins were determined by Western blotting. CRISPR/Cas9 knockout (KO) plasmids were used to generate KO cells of p65 and Fas. MDS cell growth in a xenograft model was evaluated by the AkaBLI system. GNA induced MDS cell apoptosis, accompanied by a reduction in the anti-apoptotic protein MCL-1 expression, and inhibited their growth in vitro and in vivo. GNA combined with the MCL-1 inhibitor MIK665 potently suppressed the proliferation of MDS cells. GNA interfered with tubulin polymerization, resulting in G2/M arrest. GNA induced NF-κB activation and upregulation of Fas, the latter of which was inhibited by p65 KO. GNA-induced apoptosis was attenuated in either p65 KO or Fas KO cells. These results demonstrate that GNA inhibited tubulin polymerization and induced apoptosis of MDS cells through upregulation of Fas expression mediated by the NF-κB signaling pathway, suggesting a chemotherapeutic strategy for MDS by microtubule dynamics disruption.

Cadherin 2 (CDH2, N-cadherin) and cadherin 13 (CDH13, T-cadherin, H-cadherin) affect the progress and prognoses of many cancers. However, their roles in adrenocortical carcinoma (ACC), a rare endocrine cancer, remain unclear. To decipher the roles of these proteins in ACC and to identify their regulatory targets, we analyzed their expression levels, gene regulatory networks, prognostic value, and targets in ACC, using various bioinformatic analyses. CDH2 was strongly downregulated and CDH13 was strongly upregulated in patients with ACC; the expression levels of these genes affected the prognosis. In 75 patients, the expression of CDH2 and CDH13 was altered by 8% and 5%, respectively. CDH2 and CDH13, as well as their neighboring genes, were predicted to form a complex network of interactions, mainly through coexpression and physical and genetic interactions. CDH2 and its altered neighboring genes (ANGs) mainly affect tumor-related gene expression, cell cycle, and energy metabolism. The regulation of tumor-related integrin function, gene transcription, metabolism, and amide and phospholipid metabolism are the main functions of CDH13 and its ANGs. MiRNA and kinase targets of CDH2 and CDH13 in ACC were identified. CDH13 expression in patients with ACC was positively associated with immune cell infiltration. Anti-PD1/CTLA-4/PD-L1 immunotherapy significantly downregulated the expression of CDH13 in patients with ACC. Foretinib and elesclomol were predicted to exert strong inhibitory effects on SW13 cells by inhibiting the expression of CDH2 and CDH13. These data indicate that CDH2 and CDH13 are promising targets for precise treatment of ACC and may serve as new biomarkers for ACC prognosis.

Prostate cancer has heterogeneous growth patterns, and its prognosis is the poorest when it progresses to a neuroendocrine phenotype. Using bioinformatic analysis, we evaluated RNA expression of neuroendocrine genes in a panel of five different cancer types: prostate adenocarcinoma, breast cancer, kidney chromophobe, kidney renal clear cell carcinoma and kidney renal papillary cell carcinoma. Our results show that specific neuroendocrine genes are significantly dysregulated in these tumors, suggesting that they play an active role in cancer progression. Among others, synaptophysin (SYP), a conventional neuroendocrine marker, is upregulated in prostate adenocarcinoma (PRAD) and breast cancer (BRCA). Our analysis shows that SYP is enriched in small extracellular vesicles (sEVs) derived from plasma of PRAD patients, but it is absent in sEVs derived from plasma of healthy donors. Similarly, classical sEV markers are enriched in sEVs derived from plasma of prostate cancer patients, but weakly detectable in sEVs derived from plasma of healthy donors. Overall, our results pave the way to explore new strategies to diagnose these diseases based on the neuroendocrine gene expression in patient tumors or plasma sEVs.

Hepatocellular carcinoma (HCC) is one of the most lethal malignant tumors worldwide. Brahma-related gene 1 (BRG1), as a catalytic ATPase, is a major regulator of gene expression and is known to mutate and overexpress in HCC. The purpose of this study was to investigate the mechanism of action of BRG1 in HCC cells. In our study, BRG1 was silenced or overexpressed in human HCC cell lines. Transwell and wound healing assays were used to analyze cell invasiveness and migration. Mitochondrial membrane potential (MMP) and mitochondrial permeability transition pore (mPTP) detection were used to evaluate mitochondrial function in HCC cells. Colony formation and cell apoptosis assays were used to evaluate the effect of BRG1/TOMM40/ATP5A1 on HCC cell proliferation and apoptosis/death. Immunocytochemistry (ICC), immunofluorescence (IF) staining and western blot analysis were used to determine the effect of BRG1 on TOMM40, ATP5A1 pathway in HCC cells. As a result, knockdown of BRG1 significantly inhibited cell proliferation and invasion, promoted apoptosis in HCC cells, whereas BRG1 overexpression reversed the above effects. Overexpression of BRG1 can up-regulate MMP level, inhibit mPTP opening and activate TOMM40, ATP5A1 expression. Our results suggest that BRG1, as an oncogene, promotes HCC progression by regulating TOMM40 affecting mitochondrial function and ATP5A1 synthesis. Targeting BRG1 may represent a new and effective way to prevent HCC development.

To explore role of NAALADL2-AS2 as ceRNA in DLBCL. Fluorescence in situ hybridization was used to determine location of NAALADL2-AS2 in cells and to verify its expression in DLBCL tissues. The miRNAs interacting with NAALADL2-AS2 and related regulatory genes were identified by small interfering RNA (siRNA) assay, luciferase reporter assay, fluorescent quantitative polymerase chain reaction, western blotting. DLBCL cells transfected with NAALADL2-AS2 siRNA or control siRNA were treated with doxorubicin, rituximab at different concentrations alone or in combination. The growth curves, drug sensitivity changes of cells before and after transfection were detected by MTT assay, ATP-TCA drug sensitivity test. Cell proliferation was detected by BrdU cell proliferation assay, and apoptosis was detected by Annexin V-fluorescein isothiocyanate/propidium iodide staining. The effects and mechanisms of NAALADL2-AS2 on proliferation, apoptosis, drug resistance of DLBCL cells were studied at cellular level. We confirmed expression of NAALADL2-AS2 in both cytoplasm and nuclei of DLBCL cells. Additionally, we observed elevated levels of NAALADL2-AS2 in DLBCL tissues. We discovered that NAALADL2-AS2 functions as ceRNA to inhibit expression of miR-34a, miR-125a, whereas overexpression of NAALADL2-AS2 indirectly upregulates expression of BCL-2. Interfering with NAALADL2-AS2 promoted apoptosis in DLBCL cells, resulting in approximately a 40% increase in sensitivity to doxorubicin and rituximab. In vivo experiments further confirmed that targeting NAALADL2-AS2 effectively suppressed tumor growth, leading to upregulation of miR-34a and miR-125a, downregulation of BCL-2, and enhanced apoptosis in DLBCL cells, which significantly improved their sensitivity to doxorubicin and rituximab by approximately 50%. These results indicate that NAALADL2-AS2/miR-34a, miR-125a/BCL-2 networks hold promise as therapeutic targets for treatment of DLBCL.

Background: Breast cancer (BC) is the most prevalent malignant tumor in women globally. Triple-negative breast cancer (TNBC) represents the most malignant and invasive subtype of BC. New therapeutic targets are urgently needed for TNBC owing to its receptor expression characteristics, which render it insensitive to traditional targeted and endocrine therapies for BC. The role and mechanisms of dihydrolipoamide S-acetyltransferase (DLAT) as a crucial molecule in glycometabolism and cuproptosis-related biological processes in tumors remain to be explored.

Methods: DLAT expression was investigated using bioinformatics methods and quantitative real-time polymerase chain reaction. Subsequently, the MTT assay, colony formation assay, and migration-invasion assay were performed to validate the effect of DLAT on TNBC cell viability, proliferation, and migration. Cytoplasmic-nuclear separation experiments, western blot analysis, and co-immunoprecipitation assays were performed to elucidate the underlying molecular mechanisms.

Results: This study revealed a robust correlation between elevated DLAT expression in BC and unfavorable prognosis in patients, with higher expression of DLAT compared to other subtypes in TNBC. Functional cytology experiments indicated that DLAT plays a tumor-promoting role in TNBC. Mechanistic studies showed that DLAT directly interacts with YAP1, leading to the dephosphorylation and activation of YAP1 and its increased nuclear translocation, thereby transcriptionally activating and regulating downstream oncogenes, promoting the malignant phenotype of TNBC. Rescue experiments indicated that DLAT promotes the malignant behavior of TNBC through a YAP1-dependent pathway.

Conclusions: Our research unveiled the significant involvement of DLAT in TNBC, along with the potential for modulating DLAT/YAP1 activity as a targeted treatment strategy for TNBC.

Cancer-associated fibroblasts (CAFs) can interact with macrophages in the tumor microenvironment by secreting extracellular vesicles (EVs), thereby affecting tumor progression. However, the mechanisms of CAF-secreted EVs in gastric cancer (GC) remain not well understood. Here, we investigated the effect of CAF-EVs on macrophage polarization in GC and the underlying mechanisms. Macrophage polarization was evaluated using flow cytometry and quantitative real-time polymerase chain reaction. GC cell proliferation was determined using cell counting kit-8, EdU, and colony formation assays. The molecular mechanism was explored using microarray analysis, dual-luciferase reporter assay, and RNA pull-down analysis. The results showed that CAFs secreted EVs that inhibit macrophage M1 polarization and promote M2 polarization. Moreover, miR-4253 expression was increased in CAF-EVs, and inhibition of miR-4253 reversed the macrophage polarization induced by EVs. IL6R was identified as the target of miR-4253. Additionally, macrophages treated with EVs that encapsulated miR-4253 promote GC cell proliferation. In conclusion, CAF-secreted EVs packaging miR-4253 facilitate macrophage polarization from M1 to M2 phenotype by targeting IL6R, thereby accelerating GC cell proliferation. The findings suggest that EV-encapsulated miR-4253 may be a promising therapeutic target of GC.