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Gene Jun 2024Pancreatic adenocarcinoma (PAAD) is a life-threatening cancer. Exploring new diagnosis and treatment targets helps improve its prognosis. tRNA-derived small non-coding...
Pancreatic adenocarcinoma (PAAD) is a life-threatening cancer. Exploring new diagnosis and treatment targets helps improve its prognosis. tRNA-derived small non-coding RNAs (tsRNAs) are a novel type of gene expression regulators and their dysregulation is closely related to many human cancers. Yet the expression and functions of tsRNAs in PAAD are not well understood. Our study used RNA sequencing to identify tsRNA expression profiles in PAAD cells cultured in no or high glucose media and found tRF-18-8R6546D2 was an uncharacterized tsRNA, which has significantly high expression in PAAD cells and tissues. Clinically, tRF-18-8R6546D2 is linked to poor prognosis in PAAD patients and can be used to distinguish them from healthy populations. Functionally, in vitro and vivo, tRF-18-8R6546D2 over-expression promoted PAAD cell proliferation, migration and invasion, inhibited apoptosis, whereas tRF-18-8R6546D2 knock-down showed opposite effects. Mechanistically, tRF-18-8R6546D2 promoted PAAD malignancy partly by directly silencing ASCL2 and further regulating its downstream genes such as MYC and CASP3. These findings show that tRF-18-8R6546D2 is a novel oncogenic factor and can be a promising diagnostic or prognostic biomarker and therapeutic target for PAAD.
PubMed: 38955307
DOI: 10.1016/j.gene.2024.148739 -
Pathology, Research and Practice Jun 2024Exosomes derived from neighboring v-raf murine sarcoma viral oncogene homolog B1 inhibitor (BRAFi)-resistant melanoma cells mediate the formation of resistance in...
Exosomes derived from neighboring v-raf murine sarcoma viral oncogene homolog B1 inhibitor (BRAFi)-resistant melanoma cells mediate the formation of resistance in melanoma cells sensitive to BRAFi. The function and molecular mechanisms of exosomal miRNA in BRAFi resistance of melanoma have not been studied. We found that the expression of miR-19a in BRAFi resistant melanoma cells was significantly higher than that in sensitive cells, and miR-19a contributes to the resistance of melanoma cells to BRAFi by targeting immunoglobulin-like domains protein 1 (LRIG1). miR-19a was highly enriched in exosomes secreted from BRAFi resistant melanoma cells, and these exosomal miR-19a promote the spread of BRAFi resistant. The reactivation of Protein kinase B (AKT) and mitogen-activated protein kinase (MAPK) pathways is the main reason for the BRAFi resistant of melanoma cells. We demonstrated that exosomal miR-19a derived from melanoma cell promotes the formation and spread of BRAFi resistant in melanoma through targeting LRIG1 to reactivate AKT and MAPK pathway. Therefore, miR-19a may serve as a potential therapeutic target in melanoma patients with acquired drug resistance.
PubMed: 38955119
DOI: 10.1016/j.prp.2024.155410 -
Biomedicine & Pharmacotherapy =... Jul 2024The second most common mutation in melanoma occurs in NRAS oncogene, being a more aggressive disease that has no effective approved treatment. Besides, cellular...
The second most common mutation in melanoma occurs in NRAS oncogene, being a more aggressive disease that has no effective approved treatment. Besides, cellular plasticity limits better outcomes of the advanced and therapy-resistant patients. Peroxiredoxins (PRDXs) control cellular processes through direct hydrogen peroxide oxidation or by redox-relaying processes. Here, we demonstrated that PRDX2 could act as a modulator of multiple EMT markers in NRAS-mutated melanomas. PRDX2 knockdown lead to phenotypic changes towards invasion in human reconstructed skin and the treatment with a PRDX mimetic (gliotoxin), decreased migration in PRDX2-deficient cells. We also confirmed the favorable clinical outcome of patients expressing PRDX2 in a large primary melanoma cohort. This study contributes to our knowledge about genes involved in phenotype switching and opens a new perspective for PRDX2 as a biomarker and target in NRAS-mutated melanomas.
PubMed: 38955087
DOI: 10.1016/j.biopha.2024.116953 -
Biomedicine & Pharmacotherapy =... Jul 2024T-cell acute lymphoblastic leukemia (T-ALL) is a malignant hematological disorder characterized by an increased proliferation of immature T lymphocytes precursors. T-ALL...
T-cell acute lymphoblastic leukemia (T-ALL) is a malignant hematological disorder characterized by an increased proliferation of immature T lymphocytes precursors. T-ALL treatment includes chemotherapy with strong side effects, and patients that undergo relapse display poor prognosis. Although cell-intrinsic oncogenic pathways are well-studied, the tumor microenvironment, like inflammatory cellular and molecular components is less explored in T-ALL. We sought to determine the composition of the inflammatory microenvironment induced by T-ALL, and its role in T-ALL progression. We show in two mouse T-ALL cell models that T-ALLs enhance blood neutrophils and resident monocytes, accompanied with a plasmatic acute secretion of inflammatory molecules. Depleting neutrophils using anti-Ly6G treatment or resident monocytes by clodronate liposomes treatment does not modulate plasmatic inflammatory molecule secretion and mice survival. However, inhibiting the secretion of inflammatory molecules by microenvironment with NECA, an agonist of adenosine receptors, diminishes T-ALL progression enhancing mouse survival. We uncovered Hepatocyte Growth Factor (HGF), T-ALL-driven and the most decreased molecule with NECA, as a potential therapeutic target in T-ALL. Altogether, we identified a signature of inflammatory molecules that can potentially be involved in T-ALL evolution and uncovered HGF/cMET pathway as important to target for limiting T-ALL progression.
PubMed: 38955085
DOI: 10.1016/j.biopha.2024.117039 -
Bioorganic Chemistry Jun 2024The c-ros oncogene 1 (ROS1), an oncogenic driver, is known to induce non-small cell lung cancer (NSCLC) when overactivated, particularly through the formation of fusion...
The c-ros oncogene 1 (ROS1), an oncogenic driver, is known to induce non-small cell lung cancer (NSCLC) when overactivated, particularly through the formation of fusion proteins. Traditional targeted therapies focus on inhibiting ROS1 activity with ROS 1 inhibitors to manage cancer progression. However, a new strategy involving the design of protein degraders offers a more potent approach by completely degrading ROS1 fusion oncoproteins, thereby effectively blocking their kinase activity and enhancing anti-tumour potential. Utilizing PROteolysis-TArgeting Chimera (PROTAC) technology and informed by molecular docking and rational design, we report the first ROS1-specific PROTAC, SIAIS039. This degrader effectively targets multiple ROS1 fusion oncoproteins (CD74-ROS1, SDC4-ROS1 and SLC34A2-ROS1) in engineered Ba/F3 cells and HCC78 cells, demonstrating anti-tumour effects against ROS1 fusion-driven cancer cells. It suppresses cell proliferation, induces cell cycle arrest, and apoptosis, and inhibits clonogenicity. The anti-tumour efficacy of SIAIS039 surpasses two approved drugs, crizotinib and entrectinib, and matches that of the top inhibitors, including lorlatinib and taletrectinib. Mechanistic studies confirm that the degradation induced by 039 requires the participation of ROS1 ligands and E3 ubiquitin ligases, and involves the proteasome and ubiquitination. In addition, 039 exhibited excellent oral bioavailability in a mouse xenograft model, highlighting its potential for clinical application. In conclusion, our study presents a promising and novel therapeutic strategy for ROS1 fusion-positive NSCLC by targeting ROS1 fusion oncoproteins for degradation, laying the foundation for the development of further PROTAC and offering hope for patients with ROS1 fusion-positive NSCLC.
PubMed: 38955003
DOI: 10.1016/j.bioorg.2024.107590 -
EBioMedicine Jul 2024The E1A-associated protein p300 (p300) has emerged as a promising target for cancer therapy due to its crucial role in promoting oncogenic signaling pathways in various...
BACKGROUND
The E1A-associated protein p300 (p300) has emerged as a promising target for cancer therapy due to its crucial role in promoting oncogenic signaling pathways in various cancers, including prostate cancer. This need is particularly significant in prostate cancer. While androgen deprivation therapy (ADT) has demonstrated promising efficacy in prostate cancer, its long-term use can eventually lead to the development of castration-resistant prostate cancer (CRPC) and neuroendocrine prostate cancer (NEPC). Notably, p300 has been identified as an important co-activator of the androgen receptor (AR), highlighting its significance in prostate cancer progression. Moreover, recent studies have revealed the involvement of p300 in AR-independent oncogenes associated with NEPC. Therefore, the blockade of p300 may emerge as an effective therapeutic strategy to address the challenges posed by both CRPC and NEPC.
METHODS
We employed AI-assisted design to develop a peptide-based PROTAC (proteolysis-targeting chimera) drug that targets p300, effectively degrading p300 in vitro and in vivo utilizing nano-selenium as a peptide drug delivery system.
FINDINGS
Our p300-targeting peptide PROTAC drug demonstrated effective p300 degradation and cancer cell-killing capabilities in both CRPC, AR-negative, and NEPC cells. This study demonstrated the efficacy of a p300-targeting drug in NEPC cells. In both AR-positive and AR-negative mouse models, the p300 PROTAC drug showed potent p300 degradation and tumor suppression.
INTERPRETATION
The design of peptide PROTAC drug targeting p300 is feasible and represents an efficient therapeutic strategy for CRPC, AR-negative prostate cancer, and NEPC.
FUNDING
The funding details can be found in the Acknowledgements section.
PubMed: 38954976
DOI: 10.1016/j.ebiom.2024.105212 -
Journal of Clinical Virology : the... Jun 2024Epstein-Barr virus (EBV) is a ubiquitous and oncogenic virus that is associated with various malignancies and non-malignant diseases and EBV DNA detection is widely used...
Epstein-Barr virus (EBV) is a ubiquitous and oncogenic virus that is associated with various malignancies and non-malignant diseases and EBV DNA detection is widely used for the diagnosis and prognosis prediction for these diseases. The dried blood spots (DBS) sampling method holds great potential as an alternative to venous blood samples in geographically remote areas, for individuals with disabilities, or for newborn blood collection. Therefore, the objective of this study was to assess the viability of detecting EBV DNA load from DBS. Matched whole blood and DBS samples were collected for EBV DNA extraction and quantification detection. EBV DNA detection in DBS presented a specificity of 100 %. At different EBV DNA viral load in whole blood, the sensitivity of EBV DNA detection in DBS was 38.78 % (≥1 copies/mL), 43.18 % (≥500 copies/mL), 58.63 % (≥1000 copies/mL), 71.43 % (≥2000 copies/mL), 82.35 % (≥4000 copies/mL), and 92.86 % (≥5000 copies/mL), respectively. These results indicated that the sensitivity of EBV DNA detection in DBS increased with elevating viral load. Moreover, there was good correlation between EBV DNA levels measured in whole blood and DBS, and on average, the viral load measured in whole blood was about 6-fold higher than in DBS. Our research firstly demonstrated the feasibility of using DBS for qualitative and semi-quantitative detection of EBV DNA for diagnosis and surveillance of EBV-related diseases.
PubMed: 38954911
DOI: 10.1016/j.jcv.2024.105710 -
The Oncologist Jul 2024With the widespread use of next-generation sequencing (NGS) for solid tumors, mesenchymal-to-epithelial transition factor (MET) rearrangement/fusion has been confirmed...
With the widespread use of next-generation sequencing (NGS) for solid tumors, mesenchymal-to-epithelial transition factor (MET) rearrangement/fusion has been confirmed in multiple cancer types. MET amplification and MET exon 14 skipping mutations induce protein autophosphorylation; however, the pathogenic mechanism and drug sensitivity of MET fusion remain unclear. The following report describes the clinical case of a patient diagnosed with squamous lung cancer bearing a TFG-MET gene fusion. In vitro assays demonstrated MET phosphorylation and oncogenic capacity due to the TFG-MET rearrangement, both of which were inhibited by crizotinib treatment. The patient was treated with crizotinib, which resulted in sustained partial remission for more than 17 months. Collectively, cellular analyses and our case report emphasize the potential of MET fusion as a predictive biomarker for personalized target therapy for solid tumors.
PubMed: 38954846
DOI: 10.1093/oncolo/oyae166 -
Journal of the National Cancer Institute Jul 2024Immunosuppressed individuals have elevated risk of virus-related cancers. Identifying cancers with elevated risk in people with HIV (PWH) and solid organ transplant...
BACKGROUND
Immunosuppressed individuals have elevated risk of virus-related cancers. Identifying cancers with elevated risk in people with HIV (PWH) and solid organ transplant recipients (SOTRs), two immunosuppressed populations, may help identify novel etiologic relationships with infectious agents.
METHODS
We utilized two linkages of population-based cancer registries with HIV and transplant registries in the United States. Cancer entities were systematically classified based on site and histology codes. Standardized incidence ratios (SIRs) were used to compare risk in PWH and SOTRs with the general population. For selected cancer entities, incidence rate ratios (IRRs) were calculated for indicators of immunosuppression within each population.
FINDINGS
We identified 38,047 cancer cases in SOTRs and 53,592 in PWH, yielding overall SIRs of 1.66 (95%CI = 1.65-1.68) and 1.49 (95%CI = 1.47-1.50), respectively. Forty-three cancer entities met selection criteria, including conjunctival squamous cell carcinoma (SCC) (PWH SIR = 7.1, 95%CI = 5.5-9.2; SOTRs SIR = 9.4; 95%CI = 6.8-12.6). Sebaceous adenocarcinoma was elevated in SOTRs (SIR = 16.2; 95%CI = 14.0-18.6) and, among SOTRs, associated with greater risk in lung/heart transplant recipients compared to recipients of other organs (IRR = 2.3; 95%CI = 1.7-3.2). Salivary gland tumors, malignant fibrous histiocytoma (MFH), and intrahepatic cholangiocarcinoma showed elevated risk in SOTRs (SIR = 3.9; SIR = 4.7; and SIR = 3.2, respectively) but not in PWH. However, risks for these cancers were elevated following an AIDS diagnosis among PWH (IRR = 2.4; IRR = 4.3; and IRR = 2.0, respectively).
INTERPRETATION
Elevated SIRs among SOTRs and PWH, and associations with immunosuppression within these populations, suggest novel infectious causes for several cancers including conjunctival SCC, sebaceous adenocarcinoma, salivary gland tumors, MFH, and intrahepatic cholangiocarcinoma.
PubMed: 38954841
DOI: 10.1093/jnci/djae159 -
Growth Factors (Chur, Switzerland) May 2024Dysregulated expression of Forkhead Box N2 (FOXN2) has been detected in various cancer types. However, the underlying mechanisms by which FOXN2 contributes to the onset...
FOXN2, identified as a novel biomarker in serum, modulates the transforming growth factor-beta signaling pathway through its interaction with partitioning defective 6 homolog alpha, contributing to the pathogenesis of gastric cancer.
BACKGROUND AND OBJECTIVE
Dysregulated expression of Forkhead Box N2 (FOXN2) has been detected in various cancer types. However, the underlying mechanisms by which FOXN2 contributes to the onset and progression of gastric cancer (GC) remain largely unexplored. This study aimed to elucidate the potential role of FOXN2 within GC, its downstream molecular mechanisms, and its feasibility as a novel serum biomarker for GC.
METHODS
Tissue samples from GC patients and corresponding non-cancerous tissues were collected. Peripheral blood samples were obtained from GC patients and healthy controls. The expression of FOXN2 was determined using quantitative real-time PCR, western blotting, and immunohistochemistry. The expression of FOXN2 in GC cells was modulated by transfection with small interfering RNA (siRNA) or the pcDNA 3.1 expression vector. Cell proliferation was assessed using the Cell Counting Kit-8 and 5-ethynyl-2'-deoxyuridine incorporation assays. The migratory and invasive capacities of cells were evaluated by Transwell assays, apoptosis rates were measured by flow cytometry, and the expression of proliferative, apoptotic, and epithelial-mesenchymal transition (EMT) markers were assessed by western blot analysis.
RESULTS
FOXN2 was found to be overexpressed in the serum, tissues, and cells of GC, correlating with distant metastasis and TNM staging. FOXN2 demonstrated diagnostic value in differentiating GC patients from healthy individuals, with higher levels of FOXN2 being indicative of poorer survival rates. Silencing FOXN2 in vitro inhibited the proliferation, invasion, migration, and EMT of GC cells, while promoting apoptosis. FOXN2 was shown to regulate the transforming growth factor-beta (TGFβ) receptor signaling pathway in GC cells via its interaction with Partitioning Defective 6 Homolog Alpha (PARD6A).
CONCLUSION
In summary, our data suggest that FOXN2 acts as an oncogenic factor in GC, modulating the TGFβ pathway by binding to PARD6A, thereby influencing gastric carcinogenesis. This study underscores the functional significance of FOXN2 as a potential serum biomarker and therapeutic target in GC.
Topics: Humans; Stomach Neoplasms; Forkhead Transcription Factors; Signal Transduction; Biomarkers, Tumor; Male; Female; Middle Aged; Transforming Growth Factor beta; Epithelial-Mesenchymal Transition; Cell Proliferation; Cell Line, Tumor; Apoptosis; Cell Movement; Aged; Gene Expression Regulation, Neoplastic
PubMed: 38954805
DOI: 10.1080/08977194.2023.2297700