American journal of cancer research最新文献

[This corrects the article on p. 275 in vol. 7, PMID: 28337376.].

Disulfidptosis is a novel Nicotinamide Adenine Dinucleotide Phosphate (NADPH) deficiency-driven cell death pathway characterized by cystine overload and aberrant disulfide bond formation in actin cytoskeletal proteins, distinct from apoptosis, ferroptosis, and other programmed cell death modalities. In gynecological tumors (ovarian, cervical, and endometrial cancers), this process is orchestrated by dysregulated SLC7A11 expression, impaired thioredoxin system function, and Rac-WRC-Arp2/3-mediated actin network collapse. Bioinformatic analyses of The Cancer Genome Atlas (TCGA)/Gene Expression Omnibus (GEO) datasets have revealed that disulfidptosis-related genes (e.g., SLC7A11, GYS1, NCKAP1) and lncRNAs (e.g., PRDX6-AS1, EMSLR) correlate with patient prognosis, chemoresistance, and tumor immune microenvironment (TME) remodeling. Therapeutic strategies to induce disulfidptosis include glucose deprivation to limit NADPH supply, inhibition of NADPH-generating enzymes (e.g., G6PD inhibition), and nanodelivery systems (e.g., FeOOH@Fe-Ap@Au) that synchronize disulfidptosis with ferroptosis. Preliminary evidence proposes that disulfidptosis inducers may synergize with immune checkpoint inhibitors (ICIs) through TME modulation, though experimental validation remains ongoing. Beyond malignancies, disulfidptosis-related pathways have been implicated in endometriosis, where disulfidptosis-related genes (DRGs; e.g., PDLIM1, ACTB) regulate ectopic lesion progression via immune-metabolic crosstalk. This review comprehensively summarizes the molecular mechanisms, disease associations, and translational potential of disulfidptosis in gynecological disorders, proposing targeted therapeutic paradigms and future research directions.

The oxidative modification of proteins induced by hydrogen peroxide (H₂O₂) results in the formation of disulfide bond between two cysteines and affects protein conformation and biological function. Transcription factor FOXM1 participates in the development and progression of cancers and its levels are upregulated by the oxidative stress of H₂O₂-treated condition. In this study, we found that Peroxiredoxin-1 (PRDX1), one of the most H₂O₂-reactive antioxidant enzymes, interacted with FOXM1 and led to its oxidation under H₂O₂ stimulation through generating an intermolecular disulfide bond with FOXM1 C539, which was subsequently transferred to form an intramolecular disulfide bond between C167 and C175 in the oxidized FOXM1. The PRDX1-mediated oxidative modification enhanced the protein stability and transcriptional activity of FOXM1, which stimulated the transcription of FOXM1 target gene X-ray cross-complementing protein 1 (XRCC1) and improved the repair of H₂O₂-induced DNA damage in cancer cells. The disruption of PRDX1-mediated FOXM1 oxidation impaired the colony formation ability of cancer cells in vitro and the growth and DNA damage repair ability of cancer cells in vivo. The analysis of The Cancer Genome Atlas (TCGA) breast cancer patient data confirmed that PRDX1 and FOXM1 together facilitated clinical cancer progression. Overall, we established an H₂O₂-PRDX1-FOXM1 oxidation pathway that likely contribute to the development and progression of cancers.

Cancer remains a leading cause of morbidity and mortality worldwide, and the abnormal activation of glycolysis is a hallmark that enables tumor cells to adapt and sustain rapid proliferation. Beyond providing energy and biosynthetic precursors, glycolysis also supports tumor cell survival, invasion, and metastasis through multiple mechanisms. Hexokinase is a key rate-limiting enzyme in glycolysis, catalyzing the phosphorylation of glucose to glucose-6-phosphate. Among its isoforms, hexokinase 2 (HK2) exhibits particularly high enzymatic activity and substrate specificity, and it plays a central role in tumor metabolic reprogramming. Recent studies have shown that HK2 is markedly upregulated in many cancer types, where it promotes tumor initiation and progression by suppressing apoptosis and enhancing proliferation and metastasis. This review summarizes current evidence on the role of HK2 in tumor development and discusses emerging therapeutic strategies targeting HK2. By clarifying the link between HK2 and cancer, we aim to provide new insights and potential clinical applications for metabolism-based therapies.

This study aimed to investigate the long-term clinical outcomes of patients with esophageal squamous cell carcinoma (ESCC) undergoing neoadjuvant chemoradiotherapy (nCRT) followed by esophagectomy with residual disease and to identify relevant clinicopathological prognostic factors. A total of 106 patients who underwent nCRT and surgery were identified. The chemotherapy regimen consisted of cisplatin plus 5-fluorouracil every 4 weeks, along with weekly carboplatin combined with paclitaxel, and the prescribed radiotherapy dose was either 41.4 Gy or 50.4 Gy. Most patients experienced tumor stage migration following nCRT and esophagectomy, such as upstaging or downstaging. Patients with ESCC undergoing trimodality therapy were categorized into three groups based on residual tumor status: ypT+N+, ypT+N0, and ypT0N+. In our cohort, the median disease-free survival (DFS) and overall survival (OS) were 8.2 months and 14.0 months, respectively. Pathological T status emerged as an independent prognostic factor associated with DFS and OS in both univariate and multivariate analyses. Patients with upstaging demonstrated inferior DFS and OS compared to those without upstaging, while patients experiencing downstaging showed superior DFS and OS compared to those without downstaging. Furthermore, DFS and OS appeared relatively worse in patients with ypT+N+ compared to those with ypT+N0 and ypT0N+. In conclusion, pathological T status serves as an independent prognostic factor for DFS and OS in ESCC patients with residual disease following nCRT and surgery, and prognosis is significantly correlated with upstaging or downstaging after nCRT. Identifying patients with the poorest prognosis is important, as additional adjuvant treatment may be necessary.

[This corrects the article on p. 1835 in vol. 7, PMID: 28979807.].

Objective: To evaluate the diagnostic value of bone metabolism and immune cell indexes in screening for tumor bone metastasis.

Methods: A retrospective study was conducted on 247 patients with malignant tumors. conducted on 247 patients with malignant tumors. According the presence of tumor bone metastasis, patients were divided into a bone metastasis group (156 cases) and a non-bone metastasis group (91 cases). Bone metabolism markers [calcium ion (Ca²⁺), β-Carbox-terminal telopeptide of type I collagen (β-CTX), type I procollagen N-terminal peptide (P1NP), osteocalcin (OC)] and immune cell indicators (CD3⁺CD4⁺ T cells, CD3⁺CD8⁺ T cells, CD4⁺CD25⁺CD127^low Treg cells) were compared between groups. Correlations among these indices were analyzed using Pearson correlation, and interaction effects were evaluated using multiple linear regression with interaction terms. Receiver operating characteristic (ROC) curves were used to evaluate the screening efficacy of each index for tumor bone metastasis.

Results: Compared with the non-bone metastasis group, the bone metastasis group showed significantly higher levels of Ca²⁺, β-CTX, P1NP, CD3⁺CD4⁺ T cells, and CD4⁺CD25⁺CD127^low Treg cells (P<0.05), and lower levels of OC and CD3⁺CD8⁺ T cells (P<0.05). According to the Soloway classification, levels of Ca²⁺, β-CTX, P1NP, CD3⁺CD4⁺ T cells, and CD4⁺CD25⁺CD127^low Treg cells increased progressively from grade I to grade III (P<0.05), whereas OC and CD3⁺CD8⁺ T cells decreased (grade I > grade II > grade III) (P<0.05). Ca²⁺, β-CTX and P1NP were positively correlated with CD3⁺CD4⁺ T cells and CD4⁺CD25⁺CD127^low Treg cells (P<0.05) but negatively correlated with CD3⁺CD8⁺ T cells (P<0.05). In contrast, OC was negatively correlated with CD3⁺CD4⁺ T cells and CD4⁺CD25⁺CD127^low Treg cells (P<0.05) and positively correlated with CD3⁺CD8⁺ T cells (P<0.05). A significant interactive effect was observed between bone metabolism and immune indicators (P<0.05). The AUC the combined model (0.899) was higher than that of individual indicators - Ca²⁺ (0.835), β-CTX (0.843), P1NP (0.817), OC (0.750), CD3⁺CD4⁺ T cells (0.837), CD3⁺CD8⁺ T cells (0.771), CD4⁺CD25⁺CD127^low Treg cells (0.848). Internal validation showed that the accuracy of the combined model in diagnosing tumor bone metastasis was 88.26%.

Conclusions: The combine

Transactivation response RNA-binding protein 2 (TRBP) mediates microRNA (miRNA) biogenesis and regulates messenger RNA (mRNA) stability. It is a pivotal regulator of post-transcriptional gene expression, influencing processes including cellular senescence and tumorigenesis. Elevated TRBP expression correlates with poor prognosis in breast cancer, underscoring its potential as a therapeutic target. We identified a 3,4-diamino-substituted coumarin derivative (3ai), a novel small-molecule compound inhibitor of miR-21 biogenesis. Compound 3ai increased the expression of tumor-suppressor proteins targeted by miR-21. Further mechanistic studies revealed that 3ai binds TRBP and disrupts the biogenesis of senescence-associated miRNAs. This interaction induces cell cycle arrest and DNA damage in tumor cells, ultimately promoting cellular senescence in breast cancer cells and suppressing their proliferation and metastasis potential. Our study reveals that 3ai directly engages TRBP to modulate miRNA biogenesis, thereby inducing cellular senescence. These results support TRBP as a therapeutic target in breast cancer and warrant further development of 3ai as a candidate therapeutic for breast cancer.

Exosomes, as important intercellular message transporters, can be secreted by hepatocellular carcinoma (HCC) cells and transported to adjacent cells, thus promoting their migration and invasion in turn. However, whether the exosomes secreted by HCC are affected by physical abnormalities, such as fluid shear stress (FSS), is still largely unknown. Here, we observed that 1.4 dyn/cm² FSS could significantly increase the release of exosomes by up-regulating Rab27a and down-regulating Rab7 in HCC cells. Exosomes from FSS-induced HCC cells were more effective at encouraging recipient cell migration and invasion. Exosomes produced by static or FSS-stimulated cells were thoroughly analyzed using quantitative proteomics, and more than 1000 exosome proteins were found. Based on the differentially expressed proteins, IGF2, a potential migration-related protein, was discovered to be strongly expressed in FSS-stimulated cells, HCC tissues, as well as HCC patient-derived exosomes. Furthermore, we verified that exosomal IGF2 aggravated HCC migration and invasion via activating Ras/Raf/Erk signaling in recipient cells. Collectively, our data demonstrated that exosomes from FSS-stimulated HCC cells promote recipient cell migration through IGF2-Ras/Raf/Erk signaling, which might serve as potential targets for both cancer treatment and cancer prevention.

Circulating amino acid levels differ between patients with cancer and healthy individuals, and plasma histidine levels are lower in patients with periampullary cancer. This study examines histidine-related metabolic signaling in ampullary cancer. In total, 106 cancer specimens and 49 plasma samples from ampullary cancer patients were analyzed using immunohistochemistry, high-performance liquid chromatography for histidine levels, and enzyme-linked immunosorbent assays for histamine levels. Additionally, three ampullary cancer cell lines (TGBC-18 TKB, SNU-478, and SNU-869) were treated with histidine or histamine to assess growth. Plasma histidine levels were lower in patients with ampullary cancer than in healthy controls, whereas plasma histamine levels were similar between these groups. Elevated plasma histidine level was correlated with improved recurrence-free and overall survival in patients with ampullary cancer, as demonstrated by Kaplan-Meier survival analysis and multivariate Cox proportional hazards modeling. Expression of histidine-catabolic enzymes, namely histidine decarboxylase and histidine ammonia-lyase, was synergistic and positively correlated with early-stage cancer. Histidine treatment suppressed cancer cell proliferation, whereas histamine promoted cell proliferation of TGBC-18 TKB ampullary cancer cells. These findings suggest that plasma histidine is a prognostic survival factor, and combined treatment with histidine may offer therapeutic potential in patients with ampullary cancer.