Molecular Carcinogenesis最新文献

SLC25A22 is a mitochondrial inner membrane glutamate transporter responsible for shuttling glutamate from the cytoplasm into the mitochondrial matrix. Its clinical significance in gastric cancer (GC) remains unclear. GC can be classified into four molecular subtypes: Epstein-Barr virus (EBV)-associated, microsatellite instability (MSI), genomic stability (GS), and chromosomal instability (CIN). In this study, we evaluated the distribution of GC molecular subtypes in Taiwan and examined the association between SLC25A22 expression and patient outcomes. A total of 235 patients with gastric adenocarcinoma treated at Changhua Christian Hospital were included. Tumor subtypes were determined using immunohistochemistry and Epstein-Barr encoding region (EBER) in situ hybridization according to established criteria, and SLC25A22 expression was assessed using an immunohistochemical scoring system. The prevalence of EBV-associated tumors, MMR deficiency (MSI subtype), CIN, and other subtypes was 8.1%, 6.8%, 70.2%, and 14.9%, respectively. EBV-associated tumors showed a relatively lower incidence of metastatic disease (p = 0.014). The median SLC25A22 expression scores were 85 in EBV-associated tumors, 90 in MMR-deficient tumors, 90 in CIN tumors, and 100 in other subtypes. Higher SLC25A22 expression (score > 90) was associated with poorer prognosis (p = 0.014). Our findings indicate that the MSI subtype of GC has a relatively low prevalence in Taiwan and suggest that elevated SLC25A22 expression may serve as a potential biomarker associated with unfavorable prognosis in gastric cancer. Further studies are needed to clarify the biological role of SLC25A22 in tumor progression and therapeutic resistance.

Objective: Cervical cancer (CC) ranks among the common malignant tumors. HAND2 is actively expressed in healthy endometrium, and its expression level correlates with the malignancy of uterine diseases.

Methods: The GEO dataset GSE7410 was obtained and analyzed for gene expression, and differentially expressed genes were screened using GEO2R. The expression of HAND2 in CC and normal tissues was determined using the GEPIA database. SiHa cell viability, proliferation, migratory, and invasive potential were evaluated. Glucose uptake, lactate production, and ATP levels were measured in SiHa cells. To analyze apoptosis and the cell cycle in SiHa cells, flow cytometry was performed. Western blot was performed to detect glycolysis-related genes LDHA, HK2, and PKM2, and EMT-related genes E-cadherin and N-cadherin in SiHa cells. A dual luciferase reporter assay was performed to detect the regulation of TLR4, NOX2, and DUOX2 transcription by HAND2. SiHa cells stably overexpressing HAND2 were injected into nude mice to construct CC nude mouse model and metastasis models. Tumor histopathology and metastasis were assessed.

Results: HAND2 was down-regulated in CC, and its low expression level correlated with poor prognosis in CC patients. HAND2 indirectly inhibited NOX2/DUOX2 activity through the TLR4 pathway, suppressing glycolytic metabolism, cell proliferation, and migration ability. In the tumor microenvironment, aberrant expression of NOX2 and DUOX2 led to elevated ROS levels, which in turn affected CC cell apoptosis and cell cycle.

Conclusion: The TLR4/NOX2/DUOX2 axis mediates HAND2 regulation of CC cell glycolytic metabolism, as well as cell proliferation and migration capacity.

Radiotherapy (RT) has evolved significantly since its inception from treating benign conditions to becoming a cornerstone of cancer treatment. This review examines the complex interactions between RT and the immune system, highlighting its diverse effects on various immune cell populations, and exploring emerging strategies to enhance therapeutic outcomes. We discuss lessons learned from the re-emergence of low-dose irradiation for non-malignant disorders, the use of RT in managing graft-versus-host disease, and the importance of fractionation in modulating immune responses. This review addresses abscopal effects and their clinical implications. We emphasize the critical role of tumor-draining lymph nodes in mediating systemic immune responses. Recent advancements, including FLASH radiotherapy and targeted approaches to preserving immune function, have been explored. By integrating historical insights with contemporary research, this review aims to guide future RT practices and optimize their immunomodulatory potential, while minimizing adverse effects. We conclude by emphasizing the need for personalized approaches, biomarker identification, and innovative combination therapies to maximize the efficacy of RT in oncology.

Metastatic cells migrate from primary tumors and persist as dormant clusters. The mechanisms that allow these cells to escape their dormant state are an area of intense investigation. Protein phosphatase 2 (PPP2) is a tumor suppressor that dephosphorylates protein kinases involved in proliferation and metastasis. Increased PPP2 expression has been associated with progression-free survival in head and neck cancer (HNSC). A frequently altered epigenetic modifier in HNSC is the lysine demethylase KDM5A. KDM5A catalyzes demethylation of histone H3K4, resulting in chromatin compaction and repression of target genes. Despite the frequency of altered KDM5A expression in HNSC, the mechanism by which it regulates the progression of these cancers is unclear. Our present study demonstrates, using novel genetically engineered models, that PPP2 inhibition results in escape from metastatic dormancy via increased target protein phosphorylation, IL10 expression, and lymphocyte depletion. Genomic analysis demonstrated that KDM5A directly targets the PPP2 catalytic subunit. Genetic inhibition of KDM5A expression in vivo promotes HNSC metastatic dormancy via decreased IL10 expression. CRISPR-mediated ablation of KDM5A expression inhibits the proliferation of HNSC lines, and treatment with a small molecule KDM5A inhibitor results in the death of these cells. We concluded that PPP2 is required for HNSC metastatic dormancy and is regulated by KDM5A.

Oral administration of broccoli constituent sulforaphane (SFN) prevents prostate cancer development in preclinical mouse models. However, the mechanism(s) underlying prostate cancer prevention by SFN are not fully understood. In this study, we used a human relevant mouse model (Hi-Myc mice) to demonstrate restoration of immune surveillance by oral SFN administration. Treatment of Hi-Myc mice with SFN for 16 weeks resulted in about 1.33-fold increase in the number of prostate tumor-infiltrating CD8α + T cells (p = 0.02 by Student's t-test). The number of CD4+ helper T cells was not affected by SFN treatment. The number of CD11c/MHCII+ dendritic cells was increased by about 57% upon SFN administration. On the other hand, the number of NKp46+ natural killer cells was not significantly affected by SFN treatment. Oral administration of SFN resulted in about 30% decrease in the number of Gr1/CD11b+ myeloid-derived suppressor cells in the prostate tumor when compared to control mice. Plasma levels of interleukin (IL)-1α, IL-1β, IL-4, IL-5, IL-10, and C-X-C motif chemokine ligand 2 (CXCL2 or MIP-2) were statistically significantly lower in SFN-treated mice when compared to control mice. Treatment of recurrent prostate cancer patients with 200 μmol/day of SFN-rich broccoli sprout extract for 20 weeks also caused a statistically significant decrease in plasma levels of IL-1β, IL-4, and IL-13. Cell proliferation inhibition by SFN in vitro was partially but significantly attenuated by IL-4 and IL-13 supplementation in 22Rv1 cells. These results indicate restoration of immune surveillance by oral SFN treatment in Hi-Myc mouse model.

Prostate cancer (PCa) is the second most frequently diagnosed malignancy among men and the sixth leading cause of cancer-related mortality worldwide. Radical prostatectomy remains the standard treatment for localized disease; however, approximately one-third of patients develop biochemical recurrence within 10 years. Although prostate-specific antigen (PSA) is the primary biomarker used for diagnosis and monitoring, additional molecular markers such as PTEN loss and MYC amplification have been investigated to improve prognostic stratification. Liquid biopsy has emerged as a promising tool in oncology, yet the clinical significance of circulating tumor cells (CTCs) in early-stage PCa remains uncertain. This prospective, single-center study included 50 patients with localized prostate cancer from the Brazilian Amazon region who underwent radical prostatectomy in 2023. Peripheral blood samples were collected preoperatively and postoperatively for CTC enumeration and molecular characterization using Cytelligen SET-iFISH and the CellSearch system. PTEN and MYC status were evaluated to further characterize the detected CTC population. CTCs were detected in all patients prior to surgery, with a significant reduction observed after radical prostatectomy (p < 0.001); 88% of patients had no detectable CTCs postoperatively. PTEN loss was identified in 12% of patients, all of whom presented with ISUP grade ≥ 2 disease. MYC amplification was rare, observed in only one patient with Gleason score 7 and concomitant PTEN deletion. These findings suggest that perioperative CTC detection may provide clinically relevant prognostic information in localized PCa. PTEN loss appears to represent an early molecular alteration associated with adverse pathological features. Longer follow-up is needed to determine the predictive value of these biomarkers for recurrence and long-term outcomes.

Cancer stem cells (CSCs) are characterized by various properties such as hyperactive Wnt pathway, increased chemoresistance, angiogenesis, autophagy, EMT and decreased apoptotic activity. SFRP4 micropeptides, SC-301 and SC-401 derived from cysteine rich domain (CRD) and netrin like domain (NLD) domains respectively have shown to exhibit significant anti-CSC properties. In this study, based on our preliminary investigation, which showed that miR-203a was downregulated in ovarian CSCs and was subsequently activated by treatment with SFRP4 micropeptides, we investigated whether miR-203a plays any part in SFRP4 micropeptide-mediated ovarian CSC inhibition in PA-1 and SKOV-3 cell lines. SFRP4 micropeptide-treated and miR-203a mimic-overexpressing ovarian CSCs were subjected to various assays, and the results showed that miR-203a overexpression by the SFRP4 micropeptide treatment resulted in disruption of sphere-forming capacity and induction of caspase activity in ovarian CSCs. Furthermore, miR-203a expression upon micropeptide treatment resulted in the increased levels of E-cad and decreased levels of N-cad, Snail and Twist, indicating reversal of EMT along with the significant reduction in migratory potential of ovarian CSCs. Our findings for the first time indicated the possible role of miR-203a in regulating autophagy in ovarian CSCs, and reactivation of miR-203a by SFRP4 micropeptides was sufficient to halt the autophagic machinery in ovarian CSCs.

Pancreatic cancer (PC) endangers patients' lives and health, and the current diagnosis and treatment situation is not optimistic. Bile acids level was reported to be involved in PC progression, but how they regulate PC progression at the molecular level remains unclear. There is an urgent need to conduct in-depth research. Clinical samples from 58 PC patients and PC cells, including PANC-1 cells and CFAC-1 cells, served as the main research objects. RT-qPCR, IHC, and western blot were used to detect the levels of related molecules. Bile acids, lactate, triglycerides, and cholesterol levels were measured by commercial kits and the lipid levels were evaluated by Oil Red O assay. CCK-8, EdU, and Transwell assays were employed to detect malignant features of PC cells. In PC clinical samples, fatty acid-binding protein 6 (FABP6) expression and endogenous bile acid levels were abnormally elevated. Besides, FABP6 overexpression could accelerate tumor growth and metastasis and facilitated lipid metabolism reprogramming in PC mice. In addition, in PC cells, FABP6 overexpression promoted cellular lipid metabolism by enhancing intracellular bile acid transport, which promoted the malignant characteristics of PC cells. As expected, FABP6 silencing achieved opposite results. Moreover, FABP6 overexpression affected lipid metabolism reprogramming and promoted PC cell malignant features by strengthening intracellular bile acid transport to activate NR1H2/3. FABP6 overexpression promoted lipid metabolism reprogramming by enhancing intracellular bile acid transport to activate NR1H2/3, thereby accelerating PC progression. These findings offered new insights into PC molecular mechanisms and potential therapeutic targets.

Hypoxic and nutrient-deprived conditions are characteristics of the solid tumors' microenvironment (TME), where hypoxia-inducible factor (HIF) and autophagy serve as the central modulators in cancer cells. Herein, we synthesize decades of research regarding HIF and autophagy in cancer, highlighting their regulatory roles in modulating progression, such as HIF-1α-BNIP3/BNIP3L-Beclin-1 complex signaling and HIF-mTOR-ULK1 axis. Given the paucity of comprehensive syntheses regarding this intricate interplay, we systematically deconstruct recent findings to map the molecular landscape connecting HIF-1 to autophagic flux and cell death. Specifically, we explore the metabolic bridges linking HIF and autophagy, including glycolysis and reactive oxygen species (ROS). Furthermore, by refining the content of dual-target molecules, we propose strategies for co-targeting HIF and autophagy, aiming to catalyze the development of novel therapeutic interventions.