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Journal of Cellular Biochemistry Nov 2018Mouse double minute 2 (Mdm2) is a multifaceted oncoprotein that is highly regulated with distinct domains capable of cellular transformation. Loss of Mdm2 is...
Mouse double minute 2 (Mdm2) is a multifaceted oncoprotein that is highly regulated with distinct domains capable of cellular transformation. Loss of Mdm2 is embryonically lethal, making it difficult to study in a mouse model without additional genetic alterations. Global overexpression through increased Mdm2 gene copy number (Mdm2 ) results in the development of hematopoietic neoplasms and sarcomas in adult animals. In these mice, we found an increase in osteoblastogenesis, differentiation, and a high bone mass phenotype. Since it was difficult to discern the cell lineage that generated this phenotype, we generated osteoblast-specific Mdm2 overexpressing (Mdm2 ) mice in 2 different strains, C57BL/6 and DBA. These mice did not develop malignancies; however, these animals and the MG63 human osteosarcoma cell line with high levels of Mdm2 showed an increase in bone mineralization. Importantly, overexpression of Mdm2 corrected age-related bone loss in mice, providing a role for the proto-oncogenic activity of Mdm2 in bone health of adult animals.
Topics: Analysis of Variance; Animals; Bone Density; Bone Remodeling; Calcification, Physiologic; Cancellous Bone; Cell Line, Tumor; Female; Humans; Male; Mice; Mice, Inbred C57BL; Mice, Inbred DBA; Osteoblasts; Osteoclasts; Osteogenesis; Osteosarcoma; Proto-Oncogene Mas; Proto-Oncogene Proteins c-mdm2; Proto-Oncogenes
PubMed: 30011084
DOI: 10.1002/jcb.27133 -
Molecules (Basel, Switzerland) Jan 2023Neuroblastoma has obvious heterogeneity. It is one of the few undifferentiated malignant tumors that can spontaneously degenerate into completely benign tumors. However,... (Review)
Review
Neuroblastoma has obvious heterogeneity. It is one of the few undifferentiated malignant tumors that can spontaneously degenerate into completely benign tumors. However, for its high-risk type, even with various intensive treatment options, the prognosis is still unsatisfactory. At the same time, a large number of research data show that the abnormal amplification and high-level expression of the gene are positively correlated with the malignant progression, poor prognosis, and mortality of neuroblastoma. In this context, this article explores the role of the N-Myc, gene expression product on its target genes related to the cell cycle and reveals its regulatory network in promoting tumor proliferation and malignant progression. We hope it can provide ideas and direction for the research and development of drugs targeting N-Myc and its downstream target genes.
Topics: Humans; Nuclear Proteins; N-Myc Proto-Oncogene Protein; Genes, myc; Cell Cycle; Neuroblastoma; Gene Expression Regulation, Neoplastic; Cell Line, Tumor
PubMed: 36770809
DOI: 10.3390/molecules28031141 -
Journal of Hematology & Oncology Mar 2021The recent approvals by the Food and Drug Administration several tumor-agnostic drugs have resulted in a paradigm shift in cancer treatment from an... (Review)
Review
The recent approvals by the Food and Drug Administration several tumor-agnostic drugs have resulted in a paradigm shift in cancer treatment from an organ/histology-specific strategy to biomarker-guided approaches. RET gene fusions are oncogenic drivers in multiple tumor types and are known to occur in 1-2% of non-squamous NSCLC patients. RET gene fusions give rise to chimeric, cytosolic proteins with constitutively active RET kinase domain. Standard therapeutic regimens provide limited benefit for NSCLC patients with RET fusion-positive tumors, and the outcomes with immunotherapy in the these patients are generally poor. Selpercatinib (LOXO-292) and pralsetinib (BLU-667) are potent and selective inhibitors that target RET alterations, including fusions and mutations, irrespective of the tissue of origin. Recently, the results from the LIBRETTO-001 and ARROW clinical trials demonstrated significant clinical benefits with selpercatinib and pralsetinib respectively, in NSCLC patients with RET gene fusions, with tolerable toxicity profiles. These studies also demonstrated that these RET-TKIs crossed the blood brain barrier with significant activity. As has been observed with other TKIs, the emergence of acquired resistance may limit long-term efficacy of these agents. Therefore, understanding the mechanisms of resistance is necessary for the development of strategies to overcome them.
Topics: Carcinoma, Non-Small-Cell Lung; Humans; Lung Neoplasms; Proto-Oncogene Proteins c-ret; Proto-Oncogenes
PubMed: 33771190
DOI: 10.1186/s13045-021-01063-9 -
General and Comparative Endocrinology Nov 2022Thyroid hormone (T3) is important for adult organ function and vertebrate development, particularly during the postembryonic period when many organs develop/mature into...
Thyroid hormone (T3) is important for adult organ function and vertebrate development, particularly during the postembryonic period when many organs develop/mature into their adult forms. Amphibian metamorphosis is totally dependent on T3 and can be easily manipulated, thus offering a unique opportunity for studying how T3 controls postembryonic development in vertebrates. Numerous early studies have demonstrated that T3 affects frog metamorphosis through T3 receptor (TR)-mediated regulation of T3 response genes, where TR forms a heterodimer with RXR (9-cis retinoic acid receptor) and binds to T3 response elements (TREs) in T3 response genes to regulate their expression. We have previously identified many candidate direct T3 response genes in Xenopus tropicalis tadpole intestine. Among them is the proto-oncogene Ski, which encodes a nuclear protein with complex function in regulating cell fate. We show here that Ski is upregulated in the intestine and tail of premetamorphic tadpoles upon T3 treatment and its expression peaks at stage 62, the climax of metamorphosis. We have further discovered a putative TRE in the first exon that can bind to TR/RXR in vitro and mediate T3 regulation of the promoter in vivo. These data demonstrate that Ski is activated by T3 through TR binding to a TRE in the first exon during Xenopus tropicalis metamorphosis, implicating a role of Ski in regulating cell fate during metamorphosis.
Topics: Animals; Gene Expression Regulation, Developmental; Intestines; Larva; Metamorphosis, Biological; Nuclear Proteins; Proto-Oncogenes; Receptors, Thyroid Hormone; Retinoid X Receptors; Thyroid Hormones; Triiodothyronine; Up-Regulation; Xenopus; Xenopus laevis
PubMed: 35944650
DOI: 10.1016/j.ygcen.2022.114102 -
BMC Cancer Mar 2022Nucleosome assembly protein 1-like 1 (NAP1L1) is highly expressed in various types of cancer and plays an important role in carcinogenesis, but its specific role in...
BACKGROUND
Nucleosome assembly protein 1-like 1 (NAP1L1) is highly expressed in various types of cancer and plays an important role in carcinogenesis, but its specific role in tumor development and progression remains largely unknown. In this study, we suggest the potential of NAP1L1 as a prognostic biomarker and therapeutic target for the treatment of ovarian cancer (OC).
METHODS
In our study, a tissue microarray (TMA) slide containing specimens from 149 patients with OC and 11 normal ovarian tissues underwent immunohistochemistry (IHC) to analyze the correlation between NAP1L1 expression and clinicopathological features. Loss-of- function experiments were performed by transfecting siRNA and following lentiviral gene transduction into SKOV3 and OVCAR3 cells. Cell proliferation and the cell cycle were assessed by the Cell Counting Kit-8, EDU assay, flow cytometry, colony formation assay, and Western blot analysis. In addition, co-immunoprecipitation (Co-IP) and immunofluorescence assays were performed to confirm the relationship between NAP1L1 and its potential targets in SKOV3/OVCAR3 cells.
RESULTS
High expression of NAP1L1 was closely related to poor clinical outcomes in OC patients. After knocking down NAP1L1 by siRNA or shRNA, both SKOV3 and OVCAR3 cells showed inhibition of cell proliferation, blocking of the G1/S phase, and increased apoptosis in vitro. Mechanism analysis indicated that NAP1L1 interacted with hepatoma-derived growth factor (HDGF) and they were co-localized in the cytoplasm. Furthermore, HDGF can interact with jun proto-oncogene (C-JUN), an oncogenic transformation factor that induces the expression of cyclin D1 (CCND1). Overexpressed HDGF in NAP1L1 knockdown OC cells not only increased the expression of C-JUN and CCND1, but it also reversed the suppressive effects of si-NAP1L1 on cell proliferation.
CONCLUSIONS
Our data demonstrated that NAP1L1 could act as a prognostic biomarker in OC and can interact with HDGF to mediate the proliferation of OC, and this process of triggered proliferation may contribute to the activation of HDGF/C-JUN signaling in OC cells.
Topics: Apoptosis; Cell Line, Tumor; Cell Proliferation; Female; Genes, jun; Humans; Intercellular Signaling Peptides and Proteins; Nucleosome Assembly Protein 1; Ovarian Neoplasms
PubMed: 35351053
DOI: 10.1186/s12885-022-09356-z -
Cold Spring Harbor Perspectives in... Oct 2014MYC is a master regulator of stem cell state, embryogenesis, tissue homeostasis, and aging. As in health, in disease MYC figures prominently. Decades of biological... (Review)
Review
MYC is a master regulator of stem cell state, embryogenesis, tissue homeostasis, and aging. As in health, in disease MYC figures prominently. Decades of biological research have identified a central role for MYC in the pathophysiology of cancer, inflammation, and heart disease. The centrality of MYC to such a vast breadth of disease biology has attracted significant attention to the historic challenge of developing inhibitors of MYC. This review will discuss therapeutic strategies toward the development of inhibitors of MYC-dependent transcriptional signaling, efforts to modulate MYC stability, and the elusive goal of developing potent, direct-acting inhibitors of MYC.
Topics: Animals; Chromosomal Instability; Drug Design; Gene Expression Regulation; Genes, myc; Humans; Neoplasms; Proto-Oncogene Proteins c-myc; Signal Transduction; Transcription, Genetic
PubMed: 25274755
DOI: 10.1101/cshperspect.a014266 -
Pharmacology & Therapeutics Feb 2016The PI3K/AKT pathway is the focus of several targeted therapeutic agents for a variety of malignancies. In ERBB2-amplified breast cancer, the hyperactivation of this... (Review)
Review
The PI3K/AKT pathway is the focus of several targeted therapeutic agents for a variety of malignancies. In ERBB2-amplified breast cancer, the hyperactivation of this signaling cascade is associated with resistance to ERBB2-targeted therapy. This can occur through gain-of-function alterations or compensatory mechanisms that enter into play upon pharmacological pressure. The strong rationale in combining anti-ERBB2 agents with PI3K/AKT inhibitors, together with the identification of genomic alterations conferring sensitivity to targeted inhibition, are guiding the design of clinical studies aimed at preventing the emergence of drug resistance and achieving more durable response. In the present review, we describe the involvement of this pathway in breast cancer pathogenesis, with an emphasis on AKT kinases, and provide insight into currently available targeted agents for the treatment of ERBB2-amplified breast cancer. Finally, we provide preliminary data on a novel AKT3 mutation detected in the context of resistance to anti-ERBB2 therapy as an example of genomics-based approaches towards uncovering novel actionable targets in this setting.
Topics: Animals; Breast Neoplasms; Drug Resistance, Neoplasm; Female; Genes, erbB-2; Humans; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Signal Transduction
PubMed: 26645663
DOI: 10.1016/j.pharmthera.2015.11.013 -
Haematologica Mar 2023
Topics: Humans; Genes, myc; Gene Rearrangement; Leukemia, B-Cell; Proto-Oncogene Proteins c-myc
PubMed: 35484663
DOI: 10.3324/haematol.2022.281112 -
Nature Cell Biology Jan 2023Oncogenic KRAS mutations occur in approximately 30% of lung adenocarcinoma. Despite several decades of effort, oncogenic KRAS-driven lung cancer remains difficult to...
Oncogenic KRAS mutations occur in approximately 30% of lung adenocarcinoma. Despite several decades of effort, oncogenic KRAS-driven lung cancer remains difficult to treat, and our understanding of the regulators of RAS signalling is incomplete. Here to uncover the impact of diverse KRAS-interacting proteins on lung cancer growth, we combined multiplexed somatic CRISPR/Cas9-based genome editing in genetically engineered mouse models with tumour barcoding and high-throughput barcode sequencing. Through a series of CRISPR/Cas9 screens in autochthonous lung cancer models, we show that HRAS and NRAS are suppressors of KRAS-driven tumour growth in vivo and confirm these effects in oncogenic KRAS-driven human lung cancer cell lines. Mechanistically, RAS paralogues interact with oncogenic KRAS, suppress KRAS-KRAS interactions, and reduce downstream ERK signalling. Furthermore, HRAS and NRAS mutations identified in oncogenic KRAS-driven human tumours partially abolished this effect. By comparing the tumour-suppressive effects of HRAS and NRAS in oncogenic KRAS- and oncogenic BRAF-driven lung cancer models, we confirm that RAS paralogues are specific suppressors of KRAS-driven lung cancer in vivo. Our study outlines a technological avenue to uncover positive and negative regulators of oncogenic KRAS-driven cancer in a multiplexed manner in vivo and highlights the role RAS paralogue imbalance in oncogenic KRAS-driven lung cancer.
Topics: Mice; Animals; Humans; Proto-Oncogene Proteins p21(ras); Cell Transformation, Neoplastic; Signal Transduction; Lung Neoplasms; Genes, ras; Mutation; Membrane Proteins; GTP Phosphohydrolases
PubMed: 36635501
DOI: 10.1038/s41556-022-01049-w -
Molecular Oncology Mar 2023Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) has a high prevalence of up to 15% and accounts for 90-95% of prostatitis diagnoses, and yet its...
Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) has a high prevalence of up to 15% and accounts for 90-95% of prostatitis diagnoses, and yet its etiopathogenesis and link to prostate cancer (PCa) are still unclear. Here, we investigated microRNAs in exosomes isolated from blood and post-prostatic-massage urine of CP/CPPS type IIIb patients and healthy men. THP-1 monocytes (human leukemia monocytic cell line) were treated with exosomes and subjected to mRNA arrays "Cancer Inflammation and Immunity Crosstalk" and "Transcription Factors." Using The Cancer Genome Atlas, the expression of CP/CPPS-associated microRNAs was analyzed in PCa and normal prostate tissue. In silico functional studies were carried out to explore the disease ontology of CP/CPPS. In CP/CPPS, urine exosomes exhibited significant upregulation of eight PCa-specific microRNAs (e.g., hsa-miR-501, hsa-miR-20a, and hsa-miR-106), whose target genes were significantly enriched for GO terms, hallmark gene sets, and pathways specific for carcinogenesis. In THP-1 monocytes, CP/CPPS-derived urine exosomes induced upregulation of PCa-associated proinflammatory genes (e.g., CCR2 and TLR2) and proto-oncogene transcription factors (e.g., MYB and JUNB). In contrast, CP/CPPS-derived blood exosomes exhibited molecular properties similar to those of healthy men. Thus, CP/CPPS exhibits molecular changes that constitute a risk for PCa and should be considered in the development of PCa biomarkers and cancer screening programs.
Topics: Male; Humans; Prostatitis; Chronic Disease; Prostate; Exosomes; Pelvic Pain; Prostatic Neoplasms; MicroRNAs; Proto-Oncogenes; Massage
PubMed: 36321189
DOI: 10.1002/1878-0261.13329