American journal of cancer research最新文献

Histone methyltransferase SETD2 is frequently downregulated in various malignancies and plays a critical role in regulating tumor progression. However, its biological role in lung adenocarcinoma (LUAD), especially its regulation of glycolysis and chemosensitivity, has not been fully elucidated. Transketolase (TKT) is a crucial enzyme in glycolysis, but whether it is involved in the regulation of LUAD progression and chemosensitivity by SETD2 remains unclear. Cisplatin (CIS)-resistant cells were established, and SETD2 and TKT expression levels were assessed via Western blot. The malignant phenotype of LUAD cells was evaluated through CCK-8 assay, scratch healing, colony formation, and Transwell assay; while apoptosis was determined by flow cytometry. The binding relationship between SETD2 and TKT was verified by ChIP and dual luciferase reporter gene assays. Glycolytic activity was measured using commercial kits. A LUAD tumor model was established in nude mice, and apoptosis and proliferation were detected by TUNEL staining and Ki-67 immunohistochemistry, respectively. SETD2 expression was diminished in LUAD tissues and CIS-resistant cell lines. Overexpression of SETD2 attenuated the malignant phenotype of LUAD cells, promoted apoptosis, and increased the chemosensitivity of CIS-resistant cells. Meanwhile, SETD2 overexpression reduced the glycolytic activity in LUAD cells, as evidenced by decreased glucose uptake, ATP and lactate production, and downregulation of key proteins in the glycolytic pathway. Mechanistically, SETD2 bound to the TKT promoter and suppressed its transcription. Furthermore, TKT overexpression partially reversed the regulatory impacts of SETD2 on LUAD cells. Additionally, SETD2 overexpression suppressed tumor growth by down-regulating TKT, reduced glycolysis level in tumor tissues, promoted apoptosis and inhibited proliferation of tumor cells. In conclusion, SETD2 inhibits glycolysis by directly suppressing TKT transcription, thereby attenuating malignant progression and enhancing chemosensitivity in LUAD.

This study aimed to investigate the role of solute carrier family 7 member 5 (SLC7A5) in osteosarcoma (OS) and its potential as a therapeutic target. Pan-cancer analysis revealed that SLC7A5 is significantly overexpressed in various tumor types, with particularly prominent upregulation in osteosarcoma. Using datasets from The Cancer Genome Atlas (TCGA), we found that high SLC7A5 expression was closely associated with poor patient prognosis, tumor multifocality, and metastatic progression. Based on SLC7A5-related genes, we constructed a prognostic risk score model using LASSO regression. This model effectively stratified patients by risk, revealing significant differences in survival outcomes between the high-risk and low-risk groups. In in vitro experiments, SLC7A5 overexpression significantly promoted the proliferation, migration, and invasion of osteosarcoma cells; conversely, silencing SLC7A5 not only inhibited these cellular behaviors but also induced apoptosis. Combining RNA sequencing with pathway enrichment analysis, we found that SLC7A5 regulates the phosphorylation levels of the mTOR pathway and its downstream target S6. In vivo experiments showed that SLC7A5 overexpression accelerated the growth of mouse xenograft tumors. Consistent with the in vitro functional assays, Ki-67 and phosphorylated mTOR levels were also elevated in tumor tissues, further validating the association between SLC7A5 and mTOR-mediated tumor progression.

Lymph node metastasis (LNM) is a key factor in the recurrence and progression of papillary thyroid carcinoma (PTC). Phosphodiesterase 4C (PDE4C) serves as a crucial regulator in cancer development and metastasis, its functional role and mechanism in LNM of PTC need further elucidation. PDE4C and embryonic lethal abnormal vision like 1 (ELAVL1) expression in PTC and adjacent normal tissues were assessed using bioinformatic analysis and immunohistochemistry (IHC). We found that PDE4C and ELAVL1 were upregulated in PTC tissues. Cell viability in BCPAP and TPC-1 cell lines was assessed via cell counting kit-8 (CCK-8) assay, while Transwell assays were employed to determine their migratory and invasive capacities. Our data revealed that silencing of PDE4C remarkably suppressed BCPAP and TPC-1 cell proliferation, migration and invasion. Besides, the association between ELAVL1 and PDE4C was predicted and verified by ENCORI, RNA pull down and RNA immunoprecipitation (RIP) assay. The mRNA of ELAVL1 and PDE4C were evaluated via quantitative real-time PCR (qRT-PCR). ELAVL1 and PDE4C expression was examined using Western blot analysis. The number of metastatic tumors in the lymph nodes was assessed by hematoxylin-eosin (HE) staining. Ki-67 level in tumor tissues were determined by IHC. ELAVL1 interacts with PDE4C, resulting in an increase in PDE4C mRNA stability, which contributes to the aforementioned malignant phenotypes. Consistently, the knockdown of PDE4C or ELAVL1 inhibited LNM of PTC cells, PTC growth, and Ki-67 expression in vivo. In summary, ELAVL1 promotes LNM in PTC by stabilising PDE4C. Our study elucidates the molecular mechanisms driving PTC metastasis, offering new therapeutic avenues for PTC treatment.

Breast cancer (BC) is the most frequently diagnosed type of cancer worldwide and has become the primary cause of cancer deaths in women, presenting many difficulties for treatment due to its molecular heterogeneity, dynamic tumor microenvironment and frequent development of resistance to traditional drugs and targeted therapies. Ferroptosis is a type of genetically regulated, iron-dependent cell death that occurs due to the extensive accumulation of phospholipid hydroperoxides, and it has been identified as an essential tumor-suppressive mechanism with significant implications for the pathogenesis, progression and treatment response of BC. Recent evidence shows that epigenetic mechanisms, including DNA methylation, histone post-translational modifications, and non-coding RNA-mediated regulation (microRNA, long non-coding RNA, circular RNA), precisely control the core ferroptosis machinery system Xc^-, GPX4, ACSL4, and FSP1 in a context-dependent manner. This review introduces the systematic and mechanistic integration of the current knowledge base on the modulation of BC cells' ferroptosis susceptibility by epigenetic reprogramming across molecular subtypes. We critically assess the preclinical and translational evidence linking specific epigenetic regulators to ferroptosis evasion, identify emerging biomarkers predictive of ferroptosis vulnerability, and discuss the therapeutic potential of epigenetic-ferroptosis co-targeting strategies to restore ferroptosis sensitivity, circumvent drug resistance, and enhance survival outcomes in patients with refractory or metastatic BC.

[This corrects the article on p. 4547 in vol. 13, PMID: 37970338.].

Programmed cell death protein 1 (PD-1) antibody is facing the challenge of drug resistance in cancer therapy. RAB7 plays a key role in autophagic lysosomal fusion, but its function in tumor immune regulation, especially whether it can enhance the efficacy of PD-1 inhibitors, is not clear. RAS-associated binding protein 7 (RAB7) and stimulator of interferon gene (STING) were knocked down by siRNA in lung squamous cell carcinoma (LUSC) cells. The effects of RAB7 and STING on the malignant phenotype of cells were evaluated. The autophagy flux and cytoplasmic double-stranded DNA (dsDNA) accumulation were observed by Western blot, RFP-GFP-LC3B tandem fluorescent probe, transmission electron microscopy and immunofluorescence. The expression of STING/interferon regulatory factor 1 (IRF1) pathway was analyzed by Western blot. CD8⁺ T cells were co-cultured with lung cancer cells to investigate RAB7 knockdown effects on CD8⁺ T cell activation. Finally, mouse subcutaneous xenograft models were established to explore RAB7 knockdown combined with anti-PD-1 treatment. RAB7 was highly expressed in lung cancer, and its knockdown blocked autophagy flux, leading to cytoplasmic dsDNA accumulation, which in turn activated the STING/IRF1 signaling axis and up-regulated C-C motif chemokine ligand 5 (CCL5) and C-X-C motif chemokine ligand (CXCL) 10. In the co-culture system, knockdown of RAB7 promoted CD8⁺ T cell proliferation and cytotoxicity, up-regulated Perforin expressions, and decreased the levels of PD-1 and CD39. The combined application inhibited tumor growth, which was accompanied by activation of STING/IRF1 pathway, increased tumor infiltration and CD8⁺ T cell function. STING knockdown reversed all anti-tumor and immune activation effects mediated by RAB7 knockdown. In summary, knockdown of RAB7 activated the STING/IRF1/CCL5/CXCL10 signaling pathway by blocking autophagy flux, enhanced the activation and infiltration of CD8⁺ T cells, and significantly enhanced PD-1 antibody efficacy against lung cancer.

[This corrects the article on p. 4488 in vol. 10, PMID: 33415013.].

Dyskerin, encoded by the dyskerin pseudouridine synthase 1 (DKC1) gene, is a core component of the H/ACA ribonucleoprotein complex and plays essential roles in telomerase activity maintenance, rRNA pseudouridylation, and ribosome biogenesis. Loss of DKC1 function represents a major pathogenic basis of dyskeratosis congenita (DC) and is associated with a markedly increased risk of malignancy, particularly head and neck squamous cell carcinoma and oral squamous cell carcinoma. Traditionally, cancer susceptibility in DC has been largely attributed to telomere shortening and the resulting genomic instability; however, this explanation does not fully account for the heterogeneity observed across different genetic subtypes and clinical phenotypes. In this review, we systematically integrate three key mechanisms through which dyskerin dysfunction contributes to DC-associated carcinogenesis: disruption of telomere homeostasis, defects in selective translation regulation dependent on RNA pseudouridylation, and progressive impairment of T-cell-mediated immune surveillance. We highlight how DKC1 deficiency leads to insufficient rRNA pseudouridylation, selectively affecting the translation of internal ribosome entry site (IRES)-dependent transcripts, thereby attenuating the stress-induced expression of critical tumor suppressor proteins. In parallel, evidence from patient cohort studies is discussed to support a potentially dominant role of immunodeficiency in tumor development. Finally, we propose that future studies on DC and short telomere syndromes should emphasize genetic stratification and long-term clinical outcomes to refine cancer risk assessment and optimize preventive and therapeutic strategies.

Ovarian Sertoli-Leydig cell tumors (SLCTs) are a rare type of sex cord-stromal neoplasm. Approximately 60% of these tumors are associated with DICER1 mutations, which may occur in the context of the rare DICER1 syndrome. Due to the scarcity of these tumors, their comprehensive clinicopathologic spectrum and optimal management remain incompletely defined. We conducted a single-institution, retrospective clinicopathologic study on 15 patients with molecularly confirmed DICER1-related ovarian SLCTs (January 2020 - May 2025). Clinical, surgical, pathologic, and molecular data were analyzed. The median patient age at diagnosis was 21 years (range: 3-34 years). Most patients (93.3%, 14/15) were symptomatic, with abdominal distension (53.3%) and secondary amenorrhea (33.3%) being the most common presentations. The vast majority of tumors (93.3%, 14/15) were FIGO stage I, and the median largest tumor dimension was 12.0 cm. Fertility-preserving surgery was performed in 93.3% of cases; however, intraoperative tumor rupture occurred in 46.7% (7/15). Histopathologically, all tumors demonstrated classic SLCT features and were immunopositive for inhibin and calretinin. Among the cohort with somatic DICER1 mutations, only one patient (6.7%) was found to have a concurrent germline DICER1 pathogenic variant. Notably, all tumors were moderately (60.0%, 9/15) or poorly (26.7%, 4/15) differentiated, with no well-differentiated SLCTs observed. Adjuvant platinum-based chemotherapy was administered to 53.3% (8/15) of patients, primarily those with stage IC (85.7%) or higher-stage disease. After a median follow-up of 19 months, no recurrences were observed in patients with stage I disease. This study confirms that DICER1-related SLCTs predominantly occur in young women and typically present at an early stage. Our findings suggest a favorable short-term prognosis for stage I disease. We identify a strong genotype-phenotype correlation, with DICER1 mutations being exclusively associated with non-well-differentiated histology. Meticulous surgery to prevent tumor rupture is paramount, and adjuvant chemotherapy can be effectively reserved for higher-risk patients. Longer-term follow-up is needed to fully define the prognostic implications of our observations.

To evaluate the clinical effectiveness and safety of recombinant human endostatin (rh-Endo) injection plus immune checkpoint inhibitor (ICI) treatment of non-small cell lung cancer (NSCLC) treatment. We collected the medical records and follow-up data of inoperable NSCLC patients who received the corresponding anti-tumor treatment for at least 4 cycles and were discharged from our hospital from January 2021 to January 2023 for a retrospective analysis. According to the treatment methods, they were assigned to rh-Endo+ICIs (Endostatin+ICIs) and ICIs groups. Rh-Endo injection was administered at 210 mg each time via continuous chemotherapy pump infusion for 3 days, once every 3 weeks. The use of ICIs followed the instructions. Neither rh-Endo injection nor ICIs were allowed to be administered at a reduced dose. Therapeutic efficacy was compared between groups, tumor biomarkers, health status, and life quality were observed, and the occurrence of adverse reactions was documented. Progression-free survival (PFS) and overall survival (OS) during patient follow-up (2 years) were tracked. In this study, 114 eligible cases were included, with 73 receiving ICIs+rh-Endo. The disease control rate (DCR) of the ICIs and Endostatin+ICIs groups was 46.35% and 75.34% (P=0.002), respectively. Both cohorts exhibited reduced serum cytokeratin 19 fragment (CYFRA21-1), squamous cell carcinoma antigen (SCCA), carbohydrate antigen 50 (CA50) after three cycles of treatment, especially in the Endostatin+ICIs group (P<0.05). Endostatin+ICIs also contributed to better health status and life quality in patients compared to ICIs. The Endostatin+ICIs group displayed longer mean PFS (10.6 months vs. 6.8 months) and mean OS (17.6 months vs. 8.3 months) than the ICIs group. The results indicated that rh-Endo injection plus ICIs showesno significantly difference compare to ICIs alone in the adverse reaction rate, shows superior efficacy in improving clinical efficacy, significantly prolonging PFS and OS, and boosting patients' health status and quality of life.