Cervical cancer seriously threatens women's life and health, highlighting the urgent need for targeted therapies. TP53-induced glycolysis regulatory phosphatase (TIGAR), upregulated in cervical cancer and regulated by HPV E6, may be involved in cervical cancer progression, making its inhibition a potential therapeutic strategy. This study aims to investigate the role and mechanism of TIGAR in cervical cancer ferroptosis resistance and identify a TIGAR-targeting drug to suppress cervical cancer advancement. Through RNA-seq, transmission electron microscopy, and western blotting, we found that TIGAR knockdown significantly promoted ferroptosis by increasing intracellular lipid reactive oxygen species (ROS) levels. Furthermore, through molecular docking, CETSA, and SPR analysis, we identified Dioscin as a compound that binds to TIGAR. Dioscin treatment effectively inhibited cervical tumors via TIGAR both in vitro and in vivo. Mechanistically, Dioscin interacted with TIGAR and promoted ferroptosis, at least in part, through the TIGAR-ROS axis. Collectively, these findings indicate that TIGAR suppresses ferroptosis via lipid ROS reduction, while Dioscin counteracts this process, at least in part, through the TIGAR-ROS axis. Thus, Dioscin holds promise as a potential targeted therapeutic agent for cervical cancer.
Lysine-specific demethylase 1 (LSD1/KDM1A) is a potential therapeutic target in non-seminomatous testicular germ cell tumors (NSGCTs). We assessed LSD1 and Ki-67 immunostaining in 74 histologically distinct tumor components from 53 patients with testicular germ cell tumors and studied the selective LSD1 inhibitor NCL1 in embryonal carcinoma models. LSD1 positivity was higher in pooled non-seminomatous than seminomatous components (p = 0.0104). Following Bonferroni correction, teratoma and yolk sac tumor components showed higher LSD1 positivity than seminoma, whereas the embryonal carcinoma-seminoma comparison did not reach statistical significance (adjusted p = 0.08). LSD1 positivity correlated with Ki-67 positivity. In embryonal carcinoma cells, NCL1 increased H3K9me2 enrichment at SOX2 and OCT4 promoter regions, decreased pluripotency-associated proteins and survivin, and increased cleaved caspase-3 and apoptotic cell populations while reducing cell viability. NCL1 also reduced viability in cisplatin-adapted cells and further reduced viability when combined with cisplatin in parental cells. In vivo, treatment initiated before tumors became measurable suppressed subsequent xenograft outgrowth, whereas treatment of established xenografts did not significantly inhibit growth at the doses tested. Together, the histological findings and responses observed in embryonal carcinoma models support LSD1 as a potential therapeutic target for further investigation in NSGCT; NCL1 efficacy in other histological subtypes and against established tumors remains to be established.
Germline pathogenic/likely pathogenic (P/LP) variants inform cancer treatment and prevention, yet real-world detection patterns and downstream clinical management remain poorly characterized in East Asian hereditary cancer cohorts. This retrospective cohort study included 5829 patients with cancer who underwent germline testing at the National Cancer Center, Republic of Korea, between April 2006 and April 2023 using BRCA1/2-only testing or multigene panel testing. We examined P/LP variant prevalence, detection patterns under the revised national reimbursement criteria, gene group-stratified post-test clinical management, and variant reclassification outcomes. Among 5829 patients (96.6% female; median age, 51 years), 987 (16.9%) carried P/LP variants. Detection rates differed across reimbursement criteria, with the highest rates in patients with ovarian cancer (24.2%) and those meeting multiple criteria (up to 39.3%). Among P/LP carriers, 773 (78.3%) received at least one post-test clinical action; however, action rates differed substantially across gene groups, ranging from 84.3% among BRCA1/2 carriers to 46.0% among mismatch repair gene carriers. Of 1384 initial variants of uncertain significance, 25 (1.8%) were reclassified as P/LP, identifying 46 additional carriers. Overall variant frequencies were strongly shaped by the breast and ovarian cancer-predominant cohort composition, whereas documented post-test clinical actions varied across gene groups. Variant reclassification identified additional P/LP carriers, supporting the need for structured recontact and follow-up pathways.
Gastric cancer (GC) is a leading lethal malignancy globally. Gastric precancerous lesion (GPL) represents a critical step in GC, but its neural regulatory mechanisms remain largely unclear. We combined bioinformatics, patch-clamp recording, immunofluorescence, and chemogenetics to investigate serotonergic and cholinergic signaling in GPL. An N-methyl-N-nitrosourea (MNU) -induced mouse model was used for in vivo validation. High 5-HTR1D expression correlated with poor survival in gastric adenocarcinoma patients and was upregulated in AGS and MKN45 cells, as well as in gastric tissues of GPL mice. 5-HT evoked non-selective cation currents involving 5-HTR1D and TRPV4 in gastric epithelial and cancer cells, as supported by both pharmacological inhibition and siRNA-mediated TRPV4 knockdown. Blockade of 5-HTR1D or TRPV4 attenuated intestinal metaplasia and dysplasia, and this improvement was accompanied by reduced AKT/mTOR activation in GPL mice. Increased gastric M3R/5-HT co-localization was associated with elevated acetylcholine and overactivated cholinergic neurons in the dorsal motor nucleus of the vagus (DMV). Chemogenetic inhibition of DMV cholinergic neurons decreased ChAT and 5-HT levels and alleviated gastric pathology in GPL mice. These findings suggest that 5-HT/5-HTR1D signaling may promote TRPV4-involved cation currents, contributing to mucosal pathology and intestinal metaplasia in GPL model mice, whereas DMV cholinergic neurons projecting to the stomach may facilitate gastric 5-HT secretion and thereby potentially contribute to GPL progression. This work establishes a novel neuro-epithelial network linking vagal cholinergic output to serotonergic signaling that may be involved in GPL progression, providing potential targets for prevention and intervention.
Noncoding RNAs, including circular RNAs (circRNAs), have been demonstrated to play vital roles in tumorigenesis. Uncovering the functions of circRNAs in tumorigenesis and their underlying regulatory mechanisms may suggest new approaches to the development of novel diagnostic and therapeutic strategies for human cancer. Here we report the important role of hsa_circ-0080018 in diffuse large B-cell lymphoma (DLBCL) progression and the potential impact of hsa_circ-0080018 in DLBCL tumorigenesis. Hsa_circ-0080018 was evidently upregulated in newly diagnosed DLBCL patient plasma, and as a reference to classify GCB and non-GCB subtypes. The high expression of hsa_circ-0080018 also appeared in plasma exosome and can transport to tumor microenvironment (TME). In addition, we found that at the molecular level hsa_circ-0080018 acted as a decoy for miR-625-5p and regulated tumor associated macrophage (TAM) polarization by suppressing miR-625-5p that led to IGF-1/IGF-1R pathway activation. The activated IGF-1/IGF-1R pressed macrophage polarizing to M2 and ultimately promoted tumor progression. Our results provided a new potential biomarker in DLBCL plasma that is correlated with cell of origin (COO). The mechanism of circ-0080018 in tumor progression was plasma generated circ-0080018 delivered to TME by exosome and pushed macrophage polarization. Our research may provide a new target for the DLBCL treatment and prognosis in future.
