Carcinogenesis最新文献

Nonsmall cell lung cancer (NSCLC) harboring EGFR mutations, including the resistant T790M variant, continues to require improved therapeutic strategies despite the development of EGFR tyrosine kinase inhibitors (TKIs). This study evaluates the radiosensitizing potential of HS-10296 (almonertinib), a third-generation EGFR-TKI, in EGFR-mutant NSCLC models. In vitro studies demonstrated selective growth inhibition in mutant cells (PC-9: half-maximal inhibitory concentration (IC50) = 2.62 μM; H1975: IC50 = 5.22μM at 48 h) compared to wild-type A549 cells (IC50 = 11.42 μM). Clonogenic assays revealed significant radiosensitization in mutant cells (SER: PC-9 = 1.22; H1975 = 1.55) through multiple mechanisms including enhanced DNA damage (1.5-2.0-fold increase in comet tail moments with 4-10× persistent γH2A.X foci), marked suppression of RAD51-mediated DNA repair, and increased apoptosis (combination therapy: 19.53%-20.71% versus monotherapies: 12.08%-14.05%). Mechanistic investigation showed HS-10296 attenuated phosphorylation of EGFR and downstream effectors AKT and ERK, potentially disrupting DNA damage response pathways. In vivo validation using H1975 xenografts demonstrated superior tumor growth inhibition with the combination of HS-10296 and radiotherapy, which correlated with reduced expression of p-EGFR, p-AKT, and RAD51, along with increased γH2A.X levels. These findings establish HS-10296 as a promising radiosensitizer for EGFR-mutant NSCLC through simultaneous targeting of oncogenic signaling via PI3K/AKT and MAPK/ERK pathways and critical DNA repair mechanisms. The study provides compelling preclinical evidence supporting clinical evaluation of HS-10296 combined with radiotherapy for EGFR-driven NSCLC, including tumors with T790M-mediated resistance.

Prostate cancer (PCa) is the fourth most commonly diagnosed malignancy worldwide and remains a major clinical challenge due to its heterogeneous course and lack of reliable prognostic biomarkers. Mitochondrial ribosomal protein L23 (MRPL23) has recently emerged as a potential contributor to cancer progression, but its role in prostate cancer remains poorly understood. Formalin-fixed, paraffin-embedded (FFPE) tissue samples from 67 PCa patients who underwent radical prostatectomy were analyzed. MRPL23 expression was assessed by immunohistochemistry using a semi-quantitative immunoreactive scale (IRS). Clinicopathological data were collected for correlation analysis. Survival outcomes were evaluated using Kaplan-Meier curves and Cox proportional hazards models. MRPL23 expression differed significantly across all tissue types, with higher levels in prostate cancer tissues compared with normal epithelium, and the highest expression observed in lymph node metastases (P < .001). High MRPL23 expression was associated with shorter overall survival (P = .003) and remained an independent prognostic factor in the multivariate analysis (HR 3.99, 95% CI 1.63-9.77, P = .002). Complementary TCGA analysis confirmed elevated MRPL23 mRNA levels in prostate adenocarcinomas compared with normal tissues (P = .01) and demonstrated that high expression predicted shorter disease-free survival (10-year DFS: 75.98% versus 92.92%, log-rank P = .01). MRPL23 is a potential prognostic biomarker in prostate cancer, linked to aggressive tumor behavior and poor outcomes. Its expression in metastatic tissue suggests a role in disease progression, while TCGA data confirm its prognostic value for recurrence risk. MRPL23 may also serve as a therapeutic target in advanced PCa.

Lung cancer, particularly lung adenocarcinoma (LUAD), is the leading cause of cancer-related death globally. This study investigated the role of BRINP3 in LUAD. Immunohistochemical analysis revealed significantly upregulated BRINP3 expression in LUAD tissues compared to normal tissues, mainly located in the cytoplasm and positively correlated with tumor progression. RNA sequencing data from the TCGA-LUAD database corroborated these findings. Elevated BRINP3 expression was associated with advanced tumor stages, higher malignancy grades, and increased risk of lymphatic metastasis. Functional studies showed that BRINP3 knockdown inhibited cell proliferation, colony formation, and migration, while promoting apoptosis. Conversely, BRINP3 overexpression enhanced these malignant behaviors. Gene expression profiling identified CLOCK and CRYZL1 as potential BRINP3 targets, with BRINP3 interacting with CLOCK to regulate CRYZL1 transcription. Additionally, BRINP3 activated the AKT signaling pathway to promote LUAD progression. In vivo experiments validated the tumor-suppressing effects of BRINP3 knockdown, reducing tumor growth and metastatic potential. In conclusion, BRINP3 played a crucial role in LUAD development and progression by regulating CLOCK-mediated transcriptional regulation of CRYZL1 and activating the AKT signaling pathway. BRINP3 knockdown inhibited LUAD cell malignancy and might represent a potential therapeutic target.

Although preclinical studies consistently indicate that sulfasalazine (SAS) and disulfiram (DSF) are promising agents for the prevention and treatment of lung cancer, their clinical efficacy is limited. This discrepancy is attributed to the poor bioavailability of the drugs. Therefore, in the present study, we explored whether delivery of lower doses of SAS and DSF in nano self-emulsifying drug delivery systems (Nano-SEDDS) improves their potency and efficacy in suppressing malignant progression of lung tumors. Mice were treated with the tobacco smoke carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and once lung adenoma developed, high doses of free SAS (250 mg/kg) + DSF (100 mg/kg) or SEDDS formulations containing lower doses of SAS + DSF (40 mg/kg SAS + 8, 16 or 40 mg/kg DSF) were administered by oral gavage, every other day, for 10 weeks. Although the doses of SAS and DSF contained in SAS + DSF-SEDDS were about 6-fold and 3-15-fold lower, respectively, than the doses of the respective free drugs, SAS + DSF-SEDDS was more effective than free SAS + DSF in reducing the multiplicity of bigger lung tumors (≥1 mm). These effects were paralleled by significant reductions in the multiplicity of adenoma with progression and adenocarcinoma histopathological lesions. Also, lung tumors from mice treated with SAS + DSF-SEDDS exhibited an increase in the level of 4-hydroxynonenal (4-HNE) and malondialdehyde (MDA), lipid peroxidation products. Overall, our results show that the Nano-SEDDS formulation of SAS + DSF is a promising approach to enhance the potency and efficacy of the drugs for lung cancer chemo-interception and treatment.

World Trade Center (WTC) responders were exposed to a complex mixture of toxins and carcinogens through dust, fumes, and smoke at ground zero. Since then, studies have indicated that WTC responders have elevated cancer rates compared with the general population. While studies have detailed the overarching connection between WTC exposure and cancer, a tissue biobank is needed to enable molecular and mechanistic studies on WTC-related cancers. The cohort includes responders involved in rescue, recovery, or cleanup enrolled in the World Trade Center Health Program (WTCHP) who consented to participate in research. Responders with cancer were identified through WTCHP certification. WTCHP provided data with patients' demographic information, contact details, and cancer diagnoses. Potential participants were contacted by mail, email, or phone for consent and procedure location. If consented, samples were requested from pathology departments. A biobank of cancer tissues from WTC responders has been established with 551 distinct primary cancers from 521 patients. Of these, prostate makes up 39.0%, thyroid 9.8%, melanoma 8.9%, kidney 6.5%, bladder 6.0%, colorectal 5.8%, breast 5.6%, lung 4.7%, head and neck 4.7%, and other cancers 9%. An additional 343 patients have consented for biobank projects and their samples are being requested. To date, we have created a valuable tissue biobank available to the scientific community for high-impact oncology studies in the unique population of WTC responders. By studying links between carcinogenic exposure and cancer sites, exposure signatures, and markers of cancer aggressiveness, this biobank offers an unprecedented opportunity to advance cancer research in an exposed population.

No studies have examined the association between non-malignant hematologic diseases and the risk of various cancers. To examine the associations between non-malignant hematologic diseases and cancer risk, we performed a cohort study and Mendelian randomization analysis. The association between hematologic diseases and incident cancer risk was assessed using time-varying Cox proportional hazards regression with multivariable hazard ratios (HRs) and 95% confidence intervals (CIs). Over a total of 5 031 372 person-years of follow-up in the UK Biobank, 32 589 (6.8%) patients were diagnosed with hematologic diseases, with 2279 incident cancer cases. Multivariable time-varying Cox regression models revealed that any hematologic disease was positively associated with total cancer (HR = 1.19; 95% CI, 1.14-1.24), hematologic cancer (HR = 1.92; 95% CI, 1.69-2.17), and digestive system cancer risks (HR = 1.36; 95% CI, 1.25-1.48). Nine hematologic diseases were associated with higher hematologic cancer risk, and six of the hematologic diseases were also associated with higher risks of four types of digestive system cancer (liver, stomach, esophageal, and small intestine cancers). Mendelian randomization analysis supported the positive association of agranulocytosis with leukemia, coagulation defects and spleen diseases with lymphoma, and unspecified anemia with small intestine cancer. This study indicates that non-malignant hematologic diseases are associated with an increased risk of cancer, particularly cancers in the hematological and digestive systems.

Tyrosine kinase (TK) inhibitors improve clinical outcomes in non-small cell lung cancer (NSCLC) with targetable mutations. However, such NSCLC cases account for only about 50% in the western populations. Inhibition of the splicing factor SRSF3 has been reported to be tumor-suppressive in other cancer cell types. This study for the first time explores the tumor-suppressive activity of siRNA knockdown of SRSF3 in NSCLC cells. The cell lines used were A549 (no TK mutation; TP53 wild type), NCI-H1975 (EGFR L858R/T790M; TP53 R273H mutant), NCI-H322 (no TK mutation; TP53 R248L mutant), and NCI-H596 (no TK mutation; TP53 G245C mutant). In all these cell lines, SRSF3 knockdown increased cellular senescence, as indicated by increased senescence-associated β-galactosidase activity and reduced cell proliferation. In A549 cells, increased apoptotic cleavage of caspase-3 and poly(ADP-ribose) polymerase was also observed. A tumor-suppressive p53 isoform, p53β, was shown to be upregulated by SRSF3 knockdown. However, overexpression of p53β did not induce cellular senescence or apoptosis, suggesting that this p53 isoform is not a primary effector of SRSF3 knockdown in NSCLC cells. Gene expression analyses suggested that the SRSF3 knockdown-induced senescence in NSCLC cells may be mediated by the downregulation of TOP2A, UBE2C, or ASPM, which are known oncogenic factors associated with poor patient prognosis. We also generated SRSF3 siRNA-encapsulating lipid nanoparticles as a future therapeutic tool. This study proposes a therapeutic strategy for NSCLC that is independent of the mutation status of TP53 and TK-encoding genes.