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Background Dihydroartemisinin (DHA) has been shown to exert anticancer activity through iron-dependent reactive oxygen species (ROS) generation, which is similar to ferroptosis, a novel form of cell death. However, whether DHA causes ferroptosis in glioma cells and the potential regulatory mechanisms remain unclear. Methods Effects of DHA on the proliferation, cell death, ROS and lipid ROS generation as well as reduced gluthione consumption were assessed in glioma cells with or without ferroptosis inhibitor. The biological mechanisms by which glioma cells attenuate the pro-ferroptotic effects of DHA were assessed using molecular methods. Results DHA induced ferroptosis in glioma cells, as characterized by iron-dependent cell death accompanied with ROS generation and lipid peroxidation. However, DHA treatment simultaneously activated a feedback pathway of ferroptosis by increasing the expression of heat shock protein family A (Hsp70) member 5 (HSPA5). Mechanistically, DHA caused endoplasmic reticulum (ER) stress in glioma cells, which resulted in the induction of HSPA5 expression by protein kinase R-like ER kinase (PERK)-upregulated activating transcription factor 4 (ATF4). Subsequent HSPA5 upregulation increased the expression and activity of glutathione peroxidase 4 (GPX4), which neutralized DHA-induced lipid peroxidation and thus protected glioma cells from ferroptosis. Inhibition of the PERK-ATF4-HSPA5-GPX4 pathway using siRNA or small molecules increased DHA sensitivity of glioma cells by increasing ferroptosis both in vitro and in vivo. Conclusions Collectively, these data suggested that ferroptosis might be a novel anticancer mechanism of DHA in glioma and HSPA5 may serve as a negative regulator of DHA-induced ferroptosis. Therefore, inhibiting the negative feedback pathway would be a promising therapeutic strategy to strengthen the anti-glioma activity of DHA.

Ferroptosis is a programmed cell death characterized by iron-dependent lipid peroxidation, which is regulated by various cellular metabolic and signaling pathways. The main regulatory mechanisms of intracellular ferroptosis include the GSH-GPX4 pathway, the FSP1-CoQ10 pathway, the GCH1-BH4 pathway, and the DHODH-CoQH2 system. As the hub of iron metabolism and energy generation, mitochondria have been increasingly implicated in ferroptosis, underscoring their pivotal role in cellular processes. Ferroptosis is a significant mode of cell demise linked to cancer progression. It is expected to combat drug-resistant tumors by triggering iron-mediated cell death. This review delves into the intricate mechanisms governing intracellular ferroptosis, emphasizing the centrality of mitochondria in regulating this process within cancer cells. Furthermore, this review explores the potential and hurdles of targeting ferroptosis as a therapeutic avenue to overcome resistance to cancer treatment.

The tumor microenvironment (TME) is related to chronic inflammation and is currently identified as a risk factor for the occurrence and development of endometrial cancer (EC). Pyroptosis is a new proinflammatory form of programmed cell death that plays a critical role in the progression of multiple diseases. However, the important role of pyroptosis in high‐glucose (HG)‐related EC and the underlying molecular mechanisms remain elusive. In the present study, transcriptome high‐throughput sequencing revealed significantly higher hexokinase domain‐containing 1 (HKDC1) expression in EC patients with diabetes than in EC patients with normal glucose. Mechanistically, HKDC1 regulates HG‐induced cell pyroptosis by modulating the production of reactive oxygen species and pyroptosis‐induced cytokine release in EC. In addition, HKDC1 regulates TME formation by enhancing glycolysis, promoting a metabolic advantage in lactate‐rich environments to further accelerate EC progression. Subsequently, miR‐876‐5p was predicted to target the HKDC1 mRNA, and HOXC‐AS2 was identified to potentially inhibit the miR‐876‐5p/HKDC1 axis in regulating cell pyroptosis in HG‐related EC. Collectively, we elucidated the regulatory role of the HOXC‐AS2/miR‐876‐5p/HKDC1 signal transduction axis in EC cell pyroptosis at the molecular level, which may provide an effective therapeutic target for patients with diabetes who are diagnosed with EC. We elucidated the regulatory role of the HOXC‐AS2/miR‐876‐5p/HKDC1 signal transduction axis in endometrial cancer (EC) cell pyroptosis at the molecular level, which may provide an effective therapeutic target for patients with diabetes who are diagnosed with EC.

Emerging evidences suggest that long noncoding RNA (lncRNA) plays a vital role in tumorigenesis and cancer progression. Here, the aim of this study is to investigate the biological function of long intervening noncoding RNA Linc00284 in colorectal cancer (CRC). The expression levels of Linc00284, miR-27a and c-Met were evaluated by qPCR and/or Western blotting. Immunohistochemistry was used to detect the expression of Ki67 and Phh3 in tumor tissues. The interaction between Linc00284, miR-27a and c-Met was validated by luciferase reporter assay and RNA immunoprecipitation (RIP) assay. Cell function experiments, including CCK-8, wound-healing and transwell invasion assays, were conducted. The in vivo studies were performed with the subcutaneous tumor xenograft mouse models. Our findings reveal that Linc00284 is upregulated in CRC tissues and colorectal cancer cell lines HCT116 and SW480 in comparison with corresponding para-carcinoma tissues and human fetal colonic mucosa cells FHC. High expression of Linc00284 in tumor tissues is associated with tumor metastasis and predicts a poor clinical outcome in CRC patients. Serum Linc00284 is increased, while miR-27a is decreased in CRC patients compared to healthy controls. ROC curve analysis indicates that serum Linc00284 and miR-27a produce the area under the curve (AUC) value of at 0.8151 and 0.7316 in patients with colorectal cancer compared to healthy individuals, respectively. Additionally, results in vitro and in vivo experiments suggest that Linc00284 silencing significantly suppresses CRC cell proliferation and/or invasion. Mechanistically, Linc00284 promotes c-Met expression by acting as miR-27a sponge, leading to the activation of downstream signaling pathways, thereby causing malignant phenotypes of CRC cells. Taken together, Linc00284 exhibits oncogenic function and the disturbance of Linc00284/miR-27a/c-Met regulatory axis contributes to CRC progression, providing new insight into the pathogenesis of colorectal cancer. Importantly, the expression levels of serum Linc00284 and miR-27a may serve as clinical biomarkers for CRC diagnosis.

Emerging evidence has indicated that microRNAs are involved in multiple processes of cancer development. Previous studies have demonstrated that microRNA-499a (miR-499a) plays both oncogenic and tumor suppressive roles in several types of malignancies, and genetic variants in miR-499a are associated with the risk of cervical cancer. However, the biological roles of miR-499a in cervical cancer have not been investigated. Quantitative real-time PCR was used to assess miR-499a expression in cervical cancer cells. Mimics or inhibitor of miR-499a was transfected into cervical cancer cells to upregulate or downregulate miR-499a expression. The effects of miR-499a expression change on cervical cancer cells proliferation, colony formation, tumorigenesis, chemosensitivity, transwell migration and invasion were assessed. The potential targets of miR-499a were predicted using online database tools and validated using real-time PCR, Western blot and luciferase reporter experiments. miR-499a was significantly upregulated in cervical cancer cells. Moreover, overexpression of miR-499a significantly enhanced the proliferation, cell cycle progression, colony formation, apoptosis resistance, migration and invasion of cervical cancer cells, while inhibiting miR-499a showed the opposite effects. Further exploration demonstrated that Sex-determining region Y box 6 was the direct target of miR-499a. miR-499a-induced SOX6 downregulation mediated the oncogenic effects of miR-499a in cervical cancer. Inhibiting miR-499a could enhance the anticancer effects of cisplatin in the xenograft mouse model of cervical cancer. Our findings for the first time suggest that miRNA-499a may play an important role in the development of cervical cancer and could serve as a potential therapeutic target.

BackgroundLong intergenic non-protein coding RNA 1140 (LINC01140), a long non-coding RNA, is highly expressed in various cancers; however, its biological functions in lung cancer (LC) progression and immune escape are still unclear.MethodsHere, to elucidate LINC01140 function, 79 paired LC and paracancerous tissues were collected. LINC01140 expression levels were determined using fluorescence in situ hybridization and qPCR analysis. Cell counting kit-8 (CCK-8) assay and transwell assays were performed. The interaction between microRNAs (miRNAs) and LINC01140 was confirmed using an RNA immunoprecipitation assay. Cytokine-induced killer (CIK) cell phenotypes were analyzed by flow cytometry. Cytokine secretion levels were determined by ELISA. CIK cytotoxicity was assessed by measuring lactate dehydrogenase release. Besides, xenograft tumor mouse models were used to unveil the in vivo function of LINC01140.ResultsWe found that LINC01140 was highly expressed in human LC tissues and cell lines. High LINC01140 levels were associated with poor survival in patients with LC. LINC01140 upregulation promoted the proliferation, migration, and invasion of LC cells through direct interaction with miR-33a-5p and miR-33b-5p, thereby contributing to c-Myc expression and also inhibited cisplatin-induced cell apoptosis. In subcutaneous tumor xenograft mice, LINC01140 knockdown markedly reduced tumor growth and lung metastasis. Additionally, LINC01140 directly repressed miR-377-3 p and miR-155-5 p expression levels, resulting in the upregulation of their common downstream target programmed death-ligand 1 (PD-L1), a crucial target in LC immunotherapy. Notably, we proved that LINC01140 knockdown, along with CIK administration, suppressed the growth of subcutaneous LC xenografts by decreasing PD-L1 expression in severe combined immunodeficient mice.ConclusionsTaken together, LINC01140 overexpression protects c-Myc and PD-L1 mRNA from miRNA-mediated inhibition and contributes to the proliferation, migration, invasion, and immune escape of LC cells. These results provide a theoretical basis that LINC01140 is a promising target for LC treatment.

Linc-ROR is a long non-coding RNA, that is found aberrantly expressed in various human cancers. We aim here to unveil the role of Linc-ROR in gastric cancer (GC) progression. qPCR was used to determine gene expression. Cell viability was measured by CCK-8 assay. Transwell assays were performed to evaluate the GC cells' migratory and invasive abilities. Xenograft mouse model was conducted to measure tumor growth. We found that Linc-ROR were overexpressed in GC tissues compared to the adjacent tissues. High Linc-ROR predicts poor prognosis of GC patients. The prediction of bioinformatics online revealed that Linc-ROR could bind to miR-212-3p. Further, dual-luciferase reporter assay confirmed a direct interaction between Linc-ROR and miR-212-3p. Overexpression of miR-212-3p facilitated GC cells' migration and invasion, while the silencing of miR-212-3p attenuated GC cell migratory and invasive abilities. Moreover, Linc-ROR knockdown significantly suppressed the proliferation, migration, and invasion of GC cells, whereas miR-212-3p antagomir partially reversed Linc-ROR knockdown-induced phenotypes. Fibroblast growth factor 7 (FGF7), a downstream molecule of miR-212-3p, was overexpressed in GC cells. The recovery of FGF7 expression partially reversed the phenotypes caused by Linc-ROR silencing. Mechanistically, silencing of Linc-ROR contributed to the downregulation of CDK4, CDK6, Cyclin D1, N-Cadherin, Vimentin, MMP-9, MMP-2, but caused the upregulation of P21, P27, E-Cadherin, CK-19 in MGC-803 cells; however, FGF7 treatment could reverse the results induced by Linc-ROR silencing. Results in vivo further suggested that Linc-ROR knockdown repressed GC tumor growth, where the expression of miR-212-3p was up-regulated and FGF7 expression was downregulated in tumor tissues of mice. These findings indicated that Linc-ROR/miR-212-3p/FGF7 axis played an important role in gastric cancer progression. Linc-ROR expression level was associated with the prognosis of GC patients.

We aimed to explore the association of plasma TP53-induced glycolysis and apoptosis regulator (TIGAR) level with colorectal cancer (CRC) metastasis. A cross-sectional study of 126 CRC patients was conducted in Xiamen, China. Multivariable logistic regression was used to calculate adjusted OR and 95% CIs of plasma TIGAR concentration for CRC metastasis in different models with adjustment for potential confounders. Area under the curve (AUC) of receiver operating characteristic (ROC) curve was used to evaluate the diagnostic value. CRC patients with metastasis showed significantly decreased plasma TIGAR concentration compared to their controls (1.97±0.64 vs 2.49±0.69 ng/mL [log transformed], =0.002). Higher plasma TIGAR was significantly associated with the decreased risk of CRC metastasis, and the adjusted OR (95% CI) was 0.134 (0.027-0.676, =0.015) for per SD increase in plasma TIGAR concentration, and the trend test for increasing tertiles showed a negative trend of plasma TIGAR on risk of CRC metastasis ( for trend test: 0.005). Pearson correlation coefficients of plasma TIGAR with other cancer biomarkers (carbohydrate antigen 50 [CA50], carbohydrate antigen 199 [CA199], carbohydrate antigen 125 [CA125], carbohydrate antigen 724 [CA724], carcinoembryonic antigen [CEA], and ferritin [FER]) was low ( >0.05). AUC (95% CI) of ROC curve of plasma TIGAR for CRC metastasis was comparable to the values of cancer biomarkers (all -values <0.05). Higher level of plasma TIGAR was significantly and independently associated with lower risk of CRC metastasis, and its prognostic value on CRC metastasis was comparable to the common cancer biomarkers.

Trophoblast cell-surface antigen 2 (TROP2)-directed antibody–drug conjugate (ADC) is a promising anticancer agent that has shown remarkable efficacy in several malignancies. However, in lung cancer, two phase 3 trials on TROP2-ADCs in unselected patients with advanced non-small-cell lung cancer (NSCLC) have both failed. Sacituzumab tirumotecan (sac-TMT) is a novel TROP2-directed ADC. Here we report the efficacy and safety of sac-TMT in previously treated, advanced NSCLC with or without activating EGFR mutations from the phase 1/2 KL264-01 and phase 2 SKB264-II-08 studies. Primary endpoint was objective response rate (ORR). KL264-01 enrolled EGFR -wild-type and EGFR -mutant NSCLC ( n  = 43). Confirmed ORR was 40% (17 of 43; 95% confidence interval (CI), 25–56). Median progression-free survival (PFS) was 6.2 months (95% CI, 5.3–11.3). Post-hoc subgroup analyses found better outcomes in the EGFR -mutant subset (22 of 43, 51%) with a confirmed ORR of 55% (12 of 22) and median PFS of 11.1 months. These findings were independently supported by results from SKB264-II-08, where sac-TMT led to confirmed ORR of 34% (22 of 64; 95% CI, 23–47) and median PFS of 9.3 months (95% CI, 7.6–11.4) in 64 patients with EGFR -mutant NSCLC. For a total of 107 patients receiving sac-TMT, the most common treatment-related adverse events were hematologic toxicities. Diarrhea (4%) and interstitial lung disease (1%) were uncommon. Exploration of potential mechanisms revealed that the presence of EGFR mutation substantially increased the internalization and activity of sac-TMT in vitro. Overall, sac-TMT showed encouraging single-agent activity and manageable tolerability in previously treated, advanced NSCLC with EGFR mutations. Randomized phase 3 trials in treatment-naive and previously treated patients with EGFR-mutant NSCLC are ongoing. ClinicalTrials.gov Identifiers: NCT04152499 , NCT05631262 . In a phase 1/2 trial in patients with advanced non-small-cell lung cancer (NSCLC), followed by a phase 2 trial in an EGFR -mutant selected population, treatment with the TROP2-targeting antibody–drug conjugate sacituzumab tirumotecan led to encouraging clinical response rates, especially in patients with EGFR -mutant NSCLC, which was supported by mechanistic data.

Colorectal cancer (CRC) is one of the leading causes of cancer-associated mortality. Asiaticoside (AC) exhibits antitumor effects; however, to the best of our knowledge, the biological function of AC in CRC cells remains unclear. Therefore, the aim of the present study was to investigate the effect of AC on CRC cells. In the present study, CCK-8 and colony formation assays were performed to assess the effects of AV on human CRC cell lines (HCT116, SW480 and LoVo). Mitochondrial membrane potential was examined by JC-1 staining. Cell apoptosis and cell cycle were monitored by flow cytometry, and the expression of genes was evaluated using RT-qPCR and western blot analysis. Furthermore, the biological effect of AC in vivo was detected using a xenograft mouse model. The findings revealed that 2 µM AC suppressed the proliferation of CRC cells in a time- and dose-dependent manner, but had no adverse effects on normal human intestinal FHC cells at a range of concentrations. AC decreased the mitochondrial membrane potential and increased the apoptosis of CRC cells in a dose-dependent manner. Furthermore, AC induced cell cycle arrest at the G0/G1 phase. AC attenuated IκBα phosphorylation in a dose-dependent manner, thereby preventing P65 from entering the nucleus, and resulting in inhibition of the NF-κB signaling pathway. In addition, AC significantly reduced the expression of CDK4 and Cyclin D1 in a dose-dependent manner, significantly upregulated the activation of caspase-9 and caspase-3, and decreased the Bcl-2/Bax mRNA ratio. Furthermore, treatment with the NF-κB signaling pathway inhibitor JSH-23 significantly increased the cytotoxicity of AC in CRC cells. Findings of the xenograft mice model experiments revealed that AC significantly inhibited colorectal tumor growth in a dose-dependent manner. Overall, AC suppressed activation of the NF-κB signaling pathway by downregulating IκBα phosphorylation. This resulted in inhibition of CRC cell viability and an increase of cell apoptosis, which may form the basis of AC use in the treatment of patients with CRC.