FOXM1: A small fox that makes more tracks for cancer progression and metastasis

Seminars in Cancer Biology, Journal Year: 2023, Volume and Issue: 92, P. 1 - 15

Published: March 22, 2023

Language: Английский

---

MicroRNA-1 attenuates the growth and metastasis of small cell lung cancer through CXCR4/FOXM1/RRM2 axis

Molecular Cancer, Journal Year: 2023, Volume and Issue: 22(1)

Published: Jan. 4, 2023

Abstract Background Small cell lung cancer (SCLC) is an aggressive subtype that associated with high recurrence and poor prognosis. Due to lack of potential drug targets, SCLC patients have few therapeutic options. MicroRNAs (miRNAs) provide interesting repertoire molecules; however, the identification miRNAs regulating growth metastasis their precise regulatory mechanisms are not well understood. Methods To identify novel SCLC, we performed miRNA-sequencing from donor/patient serum samples analyzed bulk RNA-sequencing data tumors patients. Further, developed a nanotechnology-based, highly sensitive method detect microRNA-1 (miR-1, identified miRNA) in patient lines. assess miR-1, various vitro models, including miR-1 sponge (miR-1Zip) DOX-On-miR-1 (Tet-ON) inducible stable overexpression systems. Mouse models derived intracardiac injection cells (miR-1Zip DOX-On-miR-1) were established delineate role metastasis. In situ hybridization immunohistochemistry used analyze expression target proteins (mouse human tumor specimens), respectively. Dual-luciferase assay was validate chromatin immunoprecipitation investigate protein-gene interactions. Results A consistent downregulation observed tissues compared matched normal controls, these results recapitulated Gain function studies lines showed decreased oncogenic signaling, whereas loss rescued this effect. Intracardiac gain mouse decrease distant organ metastasis, potentiated Mechanistic revealed CXCR4 direct SCLC. Using unbiased transcriptomic analysis, CXCR4/FOXM1/RRM2 as unique axis regulates Our further FOXM1 directly binds RRM2 promoter its activity Conclusions findings critical regulator for decreasing It targets has development therapies. Graphical MicroRNA-1 (miR-1) important hallmark The introduction decreases Mechanistically, CXCR4, which prevents binding

Language: Английский

---

Perfluoroalkyl Substances (PFAS) Affect Inflammation in Lung Cells and Tissues

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(10), P. 8539 - 8539

Published: May 10, 2023

Adverse lung outcomes from exposure to per-and polyfluoroalkyl substances (PFAS) are known; however, the mechanism of action is poorly understood. To explore this, human bronchial epithelial cells were grown and exposed varied concentrations short-chain (perfluorobutanoic acid, perflurobutane sulfonic acid GenX) or long-chain (PFOA perfluorooctane (PFOS)) PFAS, alone in a mixture identify cytotoxic concentrations. Non-cytotoxic PFAS this experiment selected assess NLRP3 inflammasome activation priming. We found that PFOA PFOS primed activated compared with vehicle control. Atomic force microscopy showed but not significantly altered membrane properties cells. RNA sequencing was performed on lungs mice had consumed drinking water for 14 weeks. Wild type (WT), PPARα knock-out (KO) humanized (KI) PFOA. multiple inflammation- immune-related genes affected. Taken together, our study demonstrated could alter biology significant manner may contribute asthma/airway hyper-responsiveness.

Language: Английский

---

PI3K/mTOR inhibitors promote G6PD autophagic degradation and exacerbate oxidative stress damage to radiosensitize small cell lung cancer

Cell Death and Disease, Journal Year: 2023, Volume and Issue: 14(10)

Published: Oct. 6, 2023

Abstract Our previous study revealed that PI3K/AKT/mTOR signaling was associated with SCLC radioresistance. SBC2 cells were used as primary radioresistance models, while H446 continuously exposed to ionizing radiation (IR) develop acquired Cell viability and apoptosis assays investigate synergistic effects of BEZ235/GSK2126458 IR in vitro, immunoblotting, metabolite quantitative analysis bioinformatic analyses utilized explore the underlying mechanism. Both genetically engineered mouse models (GEMM) subcutaneous tumor confirm effect vivo. Key molecules upregulated after IR, which correlated radioresistance, they more expressed radioresistant cells. effectively enhanced cytotoxic IR. plus elevated γ-H2AX p-Nrf2 expression, suggesting DNA oxidative stress damage intensified. Mechanistically, significantly reduced expression G6PD protein, rate-limiting enzyme pentose phosphate pathway (PPP). In detail, PI3K/mTOR inhibitors reinforced interaction between HSPA8/HSC70, degraded by chaperone-mediated autophagy processes. Their metabolites (NADPH R-5P) decreased, ROS levels indirectly elevated, both exacerbated cell death. activator, insulin, can be attenuated N-acetylcysteine, 6-amino niacinamide. GEMM allograft transplantation further confirmed their This provided insights into connection PPP evidence mechanisms supporting possible therapeutic strategies abrogate

Language: Английский

---

Combined use of NK cells and radiotherapy in the treatment of solid tumors

Frontiers in Immunology, Journal Year: 2024, Volume and Issue: 14

Published: Jan. 9, 2024

Natural killer (NK) cells are innate lymphocytes possessing potent tumor surveillance and elimination activity. Increasing attention is being focused on the role of NK in integral antitumor strategies (especially immunotherapy). Of note, therapeutic efficacy considerable dependent two parameters: infiltration cytotoxicity microenvironment (TME), both which impaired by several obstacles (e.g., chemokines, hypoxia). Strategies to overcome such barriers needed. Radiotherapy a conventional modality employed cure solid tumors. Recent studies suggest that radiotherapy not only damages directly, but also enhances recognition immune through altering molecular expression or via

Language: Английский

---

Plasma Cell-Free Tumor Methylome as a Biomarker in Solid Tumors: Biology and Applications

Current Oncology, Journal Year: 2024, Volume and Issue: 31(1), P. 482 - 500

Published: Jan. 13, 2024

DNA methylation is a fundamental mechanism of epigenetic control in cells and its dysregulation strongly implicated cancer development. Cancers possess an extensively hypomethylated genome with focal regions hypermethylation at CPG islands. Due to the highly conserved nature cancer-specific methylation, detection cell-free plasma using liquid biopsies constitutes area interest biomarker research. The advent next-generation sequencing newer computational technologies have allowed for development diagnostic prognostic biomarkers that utilize profiling diagnose disease stratify risk. Methylome-based predictive can determine response anti-cancer therapy. An additional emerging application these minimal residual monitoring. Several key challenges need be addressed before cfDNA-based become fully integrated into practice. first relates biology stability cfDNA. second concerns clinical validity generalizability methylation-based assays, many which are type-specific. third involves their practicability, stumbling block translating from bench clinic. Future work on developing pan-cancer assays respective validities confirmed well-designed, prospective trials crucial pushing greater use tools oncology.

Language: Английский

---

Cancer-Associated Fibroblasts Promote Lymphatic Metastasis in Cholangiocarcinoma via the PDGF-BB/PDGFR-β Mediated Paracrine Signaling Network

Aging and Disease, Journal Year: 2023, Volume and Issue: 15(1), P. 369 - 369

Published: May 23, 2023

Patients with cholangiocarcinoma (CCA) lymph node metastasis (LNM) have the worst prognosis, even after complete resection; however, underlying mechanism remains unclear. Here, we established CAF-derived PDGF-BB as a regulator of LMN in CCA. Proteomics analysis revealed upregulation CAFs derived from patients CCA (LN

Language: Английский

---

Multi-dimensional characterization of immunological profiles in small cell lung cancer uncovers clinically relevant immune subtypes with distinct prognoses and therapeutic vulnerabilities

Pharmacological Research, Journal Year: 2023, Volume and Issue: 194, P. 106844 - 106844

Published: June 29, 2023

Small-cell lung cancer (SCLC) is generally considered a 'homogenous' disease, with little documented inter-tumor heterogeneity in treatment guidance or prognosis evaluation. The precise identification of clinically relevant molecular subtypes remains incomplete and their translation into clinical practice limited. In this retrospective cohort study, we comprehensively characterized the immune microenvironment SCLC by integrating transcriptional protein profiling formalin-fixation-and-paraffin-embedded (FFPE) samples from 29 patients. We identified two distinct disease subtypes: immune-enriched (IE-subtype) immune-deprived (ID-subtype), displaying immunological, biological, features. IE-subtype was abundant infiltrate elevated levels interferon-alpha/gamma (IFNα/IFNγ) inflammatory response, while ID-subtype featured complete lack infiltration more proliferative phenotype. These are associated benefits patients treated adjuvant therapy, exhibiting favorable response leading to improved survival reduced recurrence risk. Additionally, validated personalized prognosticator immunophenotyping, CCL5/CXCL9 chemokine index (CCI), using machine learning. CCI demonstrated superior predictive abilities for patients, our institute immunohistochemistry multicenter bulk transcriptomic data cohorts. conclusion, study provides comprehensive multi-dimensional characterization architecture FFPE proposes new subtyping conceptual framework enabling risk stratification appropriate selection individualized therapy.

Language: Английский

---

Development of a small cell lung cancer organoid model to study cellular interactions and survival after chemotherapy

Frontiers in Pharmacology, Journal Year: 2023, Volume and Issue: 14

Published: Aug. 7, 2023

Introduction: Small-cell-lung-cancer (SCLC) has the worst prognosis of all lung cancers because a high incidence relapse after therapy. While cancer is second most common malignancy in US, only about 10% cases are SCLC, therefore, it categorized as rare and recalcitrant disease. Therapeutic discovery for SCLC been challenging existing pre-clinical models often fail to recapitulate actual tumor pathophysiology. To address this, we developed bioengineered 3-dimensional (3D) co-culture organoid model phenotypic tool study kinetics SCLC-fibroblast interactions chemotherapy. Method: We used functionalized alginate microbeads scaffold mimic alveolar architecture co-cultured cell lines with primary adult fibroblasts (ALF). found that SCLCs proliferated extensively, invaded microbead formed tumors within just 7 days. compared patient them pathology immunophenotyping tumors. When treated standard chemotherapy drugs, etoposide cisplatin, observed some cells survived reformed model. Result Discussion: Co-culture ALFs revealed play key role inducing faster more robust regrowth This likely due paracrine effect, conditioned media from same could also support this accelerated regrowth. can be cell-cell response scalable amenable throughput or targeted drug screening find new therapeutics SCLC.

Language: Английский

---

Exploring resistance to initial chemotherapy in small cell lung cancer: The role of bone metastasis and other clinicopathologic characteristics

Medicine, Journal Year: 2025, Volume and Issue: 104(12), P. e41953 - e41953

Published: March 21, 2025

Clinically, approximately 10% to 20% of small cell lung cancer (SCLC) patients do not respond well initial platinum-based first-line chemotherapy. Knowledge about the clinicopathologic characteristics these primary drug-resistant populations is limited. This study aimed explore in SCLC insensitive enrolled with insensitivity chemotherapy and analyzed their clinicopathological characteristics. Binary logistic regression analysis was used determine independent factors that influence chemosensitivity. The evaluated 142 cases Between chemotherapy-insensitive group (n = 32) chemotherapy-sensitive 110), no significant differences were observed sex, age, smoking status, tumor size, lymph-node metastasis, vascular invasion, carcinomatous lymphangitis, mediastinal superior vena cava syndrome, stage, brain metastases, pleural adrenal or immunohistochemical markers cytokeratin, synaptophysin, chromogranin A, thyroid transcription factor-1, Ki-67 (all P > .05). However, liver metastasis (P .005), bone < .001), neural adhesion molecule expression .027) identified. revealed .008) an high-risk factor for Bone SCLC. Enhancing our understanding biology osteoimmuno-oncology could identify new vulnerabilities better define patient may benefit from tailored clinical treatments overcome drug resistance.

Language: Английский

---