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Physiological Research Oct 2023Neuroblastoma represents 8-10 % of all malignant tumors in childhood and is responsible for 15 % of cancer deaths in the pediatric population. Aggressive neuroblastomas...
Neuroblastoma represents 8-10 % of all malignant tumors in childhood and is responsible for 15 % of cancer deaths in the pediatric population. Aggressive neuroblastomas are often resistant to chemotherapy. Canonically, neuroblastomas can be classified according to the MYCN (N-myc proto-oncogene protein) gene amplification, a common marker of tumor aggressiveness and poor prognosis. It has been found that certain compounds with chelating properties may show anticancer activity, but there is little evidence for the effect of chelators on neuroblastoma. The effect of new chelators characterized by the same functional group, designated as HLZ (1-hydrazino phthalazine), on proliferation (WST-1 and methylene blue assay), cell cycle (flow cytometry), apoptosis (proliferation assay after use of specific pharmacological inhibitors and western blot analysis) and ROS production (fluorometric assay based on dichlorofluorescein diacetate metabolism) was studied in three neuroblastoma cell lines with different levels of MYCN amplification. The molecules were effective only on MYCN-non-amplified cells in which they arrested the cell cycle in the G0/G1 phase. We investigated the mechanism of action and identified the activation of cell signaling that involves protein kinase C.
Topics: Child; Humans; N-Myc Proto-Oncogene Protein; Oncogene Proteins; Nuclear Proteins; Chelating Agents; Neuroblastoma; Cell Line, Tumor; Gene Expression Regulation, Neoplastic; Apoptosis; Cell Proliferation
PubMed: 37888971
DOI: 10.33549/physiolres.935184 -
Cell Reports Aug 2023MYC proto-oncogene dysregulation alters metabolism, translation, and other functions in ways that support tumor induction and maintenance. Although Myc mice are...
MYC proto-oncogene dysregulation alters metabolism, translation, and other functions in ways that support tumor induction and maintenance. Although Myc mice are healthier and longer-lived than control mice, the long-term ramifications of more complete Myc loss remain unknown. We now describe the chronic consequences of body-wide Myc inactivation initiated postnatally. "MycKO" mice acquire numerous features of premature aging, including altered body composition and habitus, metabolic dysfunction, hepatic steatosis, and dysregulation of gene sets involved in functions that normally deteriorate with aging. Yet, MycKO mice have extended lifespans that correlate with a 3- to 4-fold lower lifetime cancer incidence. Aging tissues from normal mice and humans also downregulate Myc and gradually alter many of the same Myc target gene sets seen in MycKO mice. Normal aging and its associated cancer predisposition are thus highly linked via Myc.
Topics: Humans; Mice; Animals; Aging, Premature; Proto-Oncogene Proteins c-myc; Incidence; Neoplasms; Aging
PubMed: 37481724
DOI: 10.1016/j.celrep.2023.112830 -
JCI Insight Dec 2023Although tyrosine kinase inhibitor (TKI) therapy shows marked clinical efficacy in patients with anaplastic lymphoma kinase-positive (ALK+) and ROS proto-oncogene...
Although tyrosine kinase inhibitor (TKI) therapy shows marked clinical efficacy in patients with anaplastic lymphoma kinase-positive (ALK+) and ROS proto-oncogene 1-positive (ROS1+) non-small cell lung cancer (NSCLC), most of these patients eventually relapse with acquired resistance. Therefore, genome-wide CRISPR/Cas9 knockout screening was performed using an ALK+ NSCLC cell line established from pleural effusion without ALK-TKI treatment. After 9 days of ALK-TKI therapy, sequencing analysis was performed, which identified several tumor suppressor genes, such as NF2 or MED12, and multiple candidate genes. Among them, this study focused on ERRFI1, which is known as MIG6 and negatively regulates EGFR signaling. Interestingly, MIG6 loss induced resistance to ALK-TKIs by treatment with quite a low dose of EGF, which is equivalent to plasma concentration, through the upregulation of MAPK and PI3K/AKT/mTOR pathways. Combination therapy with ALK-TKIs and anti-EGFR antibodies could overcome the acquired resistance in both in vivo and in vitro models. In addition, this verified that MIG6 loss induces resistance to ROS1-TKIs in ROS1+ cell lines. This study found a potentially novel factor that plays a role in ALK and ROS1-TKI resistance by activating the EGFR pathway with low-dose ligands.
Topics: Humans; Anaplastic Lymphoma Kinase; Carcinoma, Non-Small-Cell Lung; Drug Resistance, Neoplasm; Epidermal Growth Factor; ErbB Receptors; Lung Neoplasms; Neoplasm Recurrence, Local; Phosphatidylinositol 3-Kinases; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Proto-Oncogene Proteins; Receptor Protein-Tyrosine Kinases
PubMed: 37917191
DOI: 10.1172/jci.insight.173688 -
International Journal of Molecular... Sep 2023Important advances in diabetic retinopathy (DR) research and management have occurred in the last few years. Neurodegenerative changes before the onset of microvascular... (Review)
Review
Important advances in diabetic retinopathy (DR) research and management have occurred in the last few years. Neurodegenerative changes before the onset of microvascular alterations have been well established. So, new strategies are required for earlier and more effective treatment of DR, which still is the first cause of blindness in working age. We describe herein gene regulation through Lnc-RNAs as an interesting subject related to DR. Long non-coding RNAs (Lnc-RNAs) are non-protein-coding transcripts larger than 200 nucleotides. Lnc-RNAs regulate gene expression and protein formation at the epigenetic, transcriptional, and translational levels and can impact cell proliferation, apoptosis, immune response, and oxidative stress. These changes are known to take part in the mechanism of DR. Recent investigations pointed out that Lnc-RNAs might play a role in retinopathy development as Metastasis-Associated Lung Adenocarcinoma Transcript (Lnc-MALAT1), Maternally expressed gene 3 (Lnc-MEG3), myocardial-infarction-associated transcript (Lnc-MIAT), Lnc-RNA H19, Lnc-RNA HOTAIR, Lnc-RNA ANRIL B-Raf proto-oncogene (Lnc-RNA BANCR), small nucleolar RNA host gene 16 (Lnc-RNA SNHG16) and others. Several molecular pathways are impacted. Some of them play a role in DR pathophysiology, including the PI3K-Akt signaling axis, NAD-dependent deacetylase sirtuin-1 (Sirti1), p38 mitogen-activated protein kinase (P38/mapk), transforming growth factor beta signaling (TGF-β) and nuclear factor erythroid 2-related factor 2 (Nrf2). The way Lnc-RNAs affect diabetic retinopathy is a question of great relevance. Performing a more in-depth analysis seems to be crucial for researchers if they want to target Lnc-RNAs. New knowledge on gene regulation and biomarkers will enable investigators to develop more specialized therapies for diabetic retinopathy, particularly in the current growing context of precision medicine.
Topics: Humans; Diabetic Retinopathy; RNA, Long Noncoding; Phosphatidylinositol 3-Kinases; Retinal Diseases; Proto-Oncogenes; Diabetes Mellitus
PubMed: 37762249
DOI: 10.3390/ijms241813947 -
JCI Insight Nov 2023Emerging evidence shows that KRAS-mutant colorectal cancer (CRC) depends on glutamine (Gln) for survival and progression, indicating that targeting Gln metabolism may be...
Emerging evidence shows that KRAS-mutant colorectal cancer (CRC) depends on glutamine (Gln) for survival and progression, indicating that targeting Gln metabolism may be a promising therapeutic strategy for KRAS-mutant CRC. However, the precise mechanism by which Gln metabolism reprogramming promotes and coordinates KRAS-mutant CRC progression remains to be fully investigated. Here, we discovered that solute carrier 25 member 21 (SLC25A21) expression was downregulated in KRAS-mutant CRC, and that SLC25A21 downregulation was correlated with poor survival of KRAS-mutant CRC patients. SLC25A21 depletion selectively accelerated the growth, invasion, migration, and metastasis of KRAS-mutant CRC cells in vitro and in vivo, and inhibited Gln-derived α-ketoglutarate (α-KG) efflux from mitochondria, thereby potentiating Gln replenishment, accompanied by increased GTP availability for persistent KRAS activation in KRAS-mutant CRC. The restoration of SLC25A21 expression impaired the KRAS-mutation-mediated resistance to cetuximab in KRAS-mutant CRC. Moreover, the arrested α-KG efflux that occurred in response to SLC25A21 depletion inhibited the activity of α-KG-dependent DNA demethylases, resulting in a further decrease in SLC25A21 expression. Our studies demonstrate that SLC25A21 plays a significant role as a tumor suppressor in KRAS-mutant CRC by antagonizing Gln-dependent anaplerosis to limit GTP availability for KRAS activation, which suggests potential alternative therapeutic strategies for KRAS-mutant CRC.
Topics: Humans; Cell Line, Tumor; Colorectal Neoplasms; Down-Regulation; Glutamine; Guanosine Triphosphate; Proto-Oncogene Proteins p21(ras)
PubMed: 37937641
DOI: 10.1172/jci.insight.167874 -
Cell Death and Differentiation Jul 2023Oncogenic KRAS activation, inflammation and p53 mutation are key drivers of pancreatic cancer (PC) development. Here we report iASPP, an inhibitor of p53, as a...
Oncogenic KRAS activation, inflammation and p53 mutation are key drivers of pancreatic cancer (PC) development. Here we report iASPP, an inhibitor of p53, as a paradoxical suppressor of inflammation and oncogenic KRAS-driven PC tumorigenesis. iASPP suppresses PC onset driven by KRAS alone or KRAS in combination with mutant p53. iASPP deletion limits acinar-to-ductal metaplasia (ADM) in vitro but accelerates inflammation and KRAS-induced ADM, pancreatitis and PC tumorigenesis in vivo. KRAS/iASPP tumours are well-differentiated classical PCs and their derivative cell lines form subcutaneous tumours in syngeneic and nude mice. Transcriptomically, either iASPP deletion or p53 mutation in the KRAS background altered the expression of an extensively overlapping gene set, comprised primarily of NF-κB and AP1-regulated inflammatory genes. All these identify iASPP as a suppressor of inflammation and a p53-independent oncosuppressor of PC tumorigenesis.
Topics: Animals; Mice; Carcinogenesis; Carcinoma, Pancreatic Ductal; Cell Transformation, Neoplastic; Inflammation; Mice, Nude; Pancreatic Neoplasms; Proto-Oncogene Proteins p21(ras); Signal Transduction; Tumor Suppressor Protein p53
PubMed: 37270580
DOI: 10.1038/s41418-023-01168-3 -
Cancer Diagnosis & Prognosis 2023In normal epithelia, proto-oncogenes regulate critical intra- or intercellular functions, including cell growth and proliferation, apoptosis, and signaling transduction... (Review)
Review
In normal epithelia, proto-oncogenes regulate critical intra- or intercellular functions, including cell growth and proliferation, apoptosis, and signaling transduction from the cell periphery (extracellular space) to the nucleus mediated by different pathways. Oncogenes are the mutated or amplified forms of the corresponding proto-oncogenes that are crucially involved in cell neoplastic and malignant transformation during carcinogenesis. Salivary gland carcinomas (SGCs) demonstrate a variety of histogenetic types. They are characterized by a broad spectrum of chromosomal and gene alterations. In particular, amplifications in specific genes [human epidermal growth factor receptor 2 (HER2), human epidermal growth factor receptor 4 (HER4), epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), Mouse double minute 2 homolog (MDM2), androgen receptor (AR), programmed death (ligand 1 (PD-L1), neurogenic differentiation factor 2 (NEUROD2), phosphatidylinositol 3,4,5-trisphosphate-dependent RAC exchanger 1 protein (PREX1), cyclin-dependent kinase4/6 (CDK4/6), proline-rich acidic protein 1 (PRAP1), kell antigen system (KEL), glutamate receptor subunit epsilon 2 (GRIN2D), Ewing sarcoma RNA-binding protein 1 (EWSR1), MYC proto-oncogene (MYC)] combined or not with chromosomal numerical imbalances (aneuploidy/ polysomy/monosomy) form different genetic signatures affecting the response to monoclonal antibody-based, oncologicaly targeted regimens. Different SGC histotypes demonstrate specific combinations of mutated/amplified genes that modify their clinicohistological features. In the current molecular review, we present the most important amplified oncogenes and their impact on the biological behavior of SGCS.
PubMed: 37671310
DOI: 10.21873/cdp.10250 -
Cancer Biology & Therapy Dec 2023Cancer cells show enhanced nucleotide biosynthesis, which is essential for their unlimited proliferation, but the underlying mechanisms are not entirely clear. Ubiquitin...
Cancer cells show enhanced nucleotide biosynthesis, which is essential for their unlimited proliferation, but the underlying mechanisms are not entirely clear. Ubiquitin specific peptidase 29 (USP29) was reported to sustain neuroblastoma progression by promoting glycolysis and glutamine catabolism; however, its potential role in regulating nucleotide biosynthesis in tumor cells remains unknown. In this study, we depleted endogenous USP29 in -amplified neuroblastoma SK-N-BE2 cells by sgRNAs and conducted metabolomic analysis in cells with or without USP29 depletion, we found that USP29 deficiency caused a disorder of intermediates involved in glycolysis and nucleotide biosynthesis. De novo nucleotide biosynthesis was analyzed using C glucose as a tracer under normoxia and hypoxia. The results indicated that -depleted cells showed inhibition of nucleotide anabolic intermediates derived from glucose, and this inhibition was more significant under hypoxic conditions. Analysis of RNA sequencing data in SK-N-BE2 cells demonstrated that USP29 promoted the gene expression of metabolic enzymes involved in nucleotide anabolism, probably by regulating MYC and E2F downstream pathways. These findings indicated that USP29 is a key regulator of nucleotide biosynthesis in tumor cells.
Topics: Humans; Multiomics; RNA, Guide, CRISPR-Cas Systems; Neuroblastoma; Glycolysis; Glucose; Cell Line, Tumor; N-Myc Proto-Oncogene Protein; Gene Expression Regulation, Neoplastic; Ubiquitin-Specific Proteases
PubMed: 37463886
DOI: 10.1080/15384047.2023.2237200 -
Translational Lung Cancer Research Jul 2023
PubMed: 37577325
DOI: 10.21037/tlcr-23-284 -
Nature Communications Aug 2023Chronic wounds impose a significant healthcare burden to a broad patient population. Cell-based therapies, while having shown benefits for the treatment of chronic...
Chronic wounds impose a significant healthcare burden to a broad patient population. Cell-based therapies, while having shown benefits for the treatment of chronic wounds, have not yet achieved widespread adoption into clinical practice. We developed a CRISPR/Cas9 approach to precisely edit murine dendritic cells to enhance their therapeutic potential for healing chronic wounds. Using single-cell RNA sequencing of tolerogenic dendritic cells, we identified N-myc downregulated gene 2 (Ndrg2), which marks a specific population of dendritic cell progenitors, as a promising target for CRISPR knockout. Ndrg2-knockout alters the transcriptomic profile of dendritic cells and preserves an immature cell state with a strong pro-angiogenic and regenerative capacity. We then incorporated our CRISPR-based cell engineering within a therapeutic hydrogel for in vivo cell delivery and developed an effective translational approach for dendritic cell-based immunotherapy that accelerated healing of full-thickness wounds in both non-diabetic and diabetic mouse models. These findings could open the door to future clinical trials using safe gene editing in dendritic cells for treating various types of chronic wounds.
Topics: Humans; Mice; Animals; CRISPR-Cas Systems; Wound Healing; Genes, myc; Gene Editing; Craniocerebral Trauma; Dendritic Cells
PubMed: 37550295
DOI: 10.1038/s41467-023-40519-z