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Cancer Gene Therapy Aug 2022In spite of extensive research and advances on the molecular biology of melanoma, the process of melanocytic differentiation or its relationship with proliferation is...
In spite of extensive research and advances on the molecular biology of melanoma, the process of melanocytic differentiation or its relationship with proliferation is poorly understood. The role of proto-oncogenes in normal melanocyte biology is also intriguing. Proto-oncogene MYC is overexpressed in 40% of melanomas. It has been suggested that MYC can mediate senescence bypass in malignant melanocytes, an important event in melanoma development, likely in cooperation with other oncogenic pathways. However, despite the apparent importance of MYC in melanoma, its functions in normal melanocytes are unknown. We have overexpressed MYC in freshly isolated human primary melanocytes and studied the effects on melanocytic proliferation and differentiation. MYC promoted a transient activation of melanocytes including cell cycle entry, DNA damage and cell migration. Subsequently, MYC induced melanogenesis, increased cellular size and complexity and senescence. Interestingly, we also found strong expression of MYC in regions of human nevi displaying high pigmentation and high expression of senescence marker p16. The results altogether show that MYC drives melanocytic differentiation and suggest that senescence is associated with differentiation. We discuss the implications into the mechanisms governing melanocytic differentiation and the development of melanoma.
Topics: Cell Differentiation; Cellular Senescence; Humans; Melanocytes; Melanoma; Proto-Oncogenes; Skin Neoplasms
PubMed: 35022520
DOI: 10.1038/s41417-021-00424-3 -
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 -
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 -
Molecular Cancer Research : MCR May 2022Oncogenic activation of the RTK-RAS-RAF-MEK-ERK pathway occurs in approximately 25% of all human cancers, yet activated RAS, BRAF, or MEK expression in primary cells...
UNLABELLED
Oncogenic activation of the RTK-RAS-RAF-MEK-ERK pathway occurs in approximately 25% of all human cancers, yet activated RAS, BRAF, or MEK expression in primary cells leads to a prolonged and predominantly irreversible cell-cycle arrest termed oncogene-induced senescence (OIS). OIS acts as an intrinsic tumor suppressor mechanism, serving as a barrier to tumor progression. Screening a library of activated kinases and kinase-regulatory proteins we identified MOB3A, a Mps-one binder coactivator (MOB) protein family member, whose constitutive expression permits proliferation and suppresses senescence in response to oncogenic RAS and BRAF signals. MOB3A is one of seven human MOB genes, which are highly conserved from yeast to human and that function to activate the Hippo pathway kinases (MST/LATS) or NDR kinases through direct association. Here we show that within the MOB family of genes MOB3A and C are unique in their ability to allow primary cell proliferation in the face of sustained oncogene signaling. Unlike the canonical MOB1A/B proteins, MOB3A inhibits Hippo/MST/LATS signaling and constitutive MOB3A membrane localization phenocopies OIS bypass seen with elevated YAP expression. Moreover, inhibition of MOB3 family member expression results in decreased proliferation and tumor growth of cancer cell lines. Together these data identify MOB3A's role in bypass of oncogene induced senescence and its role as a Hippo pathway inhibitor.
IMPLICATIONS
These results suggest that MOB3 targeting to re-engage the Hippo pathway, or direct targeting of YAP/TAZ, may be viable therapeutic strategies potential for RAS-pathway driven tumours.
Topics: Humans; Cellular Senescence; Genes, ras; Hippo Signaling Pathway; Microtubule-Associated Proteins; Proto-Oncogene Proteins B-raf; Signal Transduction
PubMed: 35046109
DOI: 10.1158/1541-7786.MCR-21-0767 -
Life Sciences Mar 2024RBM10 is a well-known RNA binding protein that regulates alternative splicing in various disease states. We have shown a splicing-independent function of RBM10 that...
AIMS
RBM10 is a well-known RNA binding protein that regulates alternative splicing in various disease states. We have shown a splicing-independent function of RBM10 that regulates heart failure. This study aims to unravel a new biological function of RBM10 phosphorylation by proto-oncogene cSrc that enables anti-hypertrophy gene program and controls cardiac hypertrophy.
MATERIALS AND METHODS
We employ in vitro and in vivo approaches to characterise RBM10 phosphorylation at three-tyrosine residues (Y81, Y500, and Y971) by cSrc and target mRNA regulation. We also use isoproterenol induced rat heart and cellular hypertrophy model to determine role of cSrc-mediated RBM10 phosphorylation.
KEY FINDINGS
We show that RBM10 phosphorylation is induced in cellular and animal heart model of cardiac hypertrophy and regulates target mRNA expression and 3'-end formation. Inhibition of cSrc kinase or mutation of the three-tyrosine phosphorylation sites to phenylalanine accentuates myocyte hypertrophy, and results in advancement and an early attainment of hypertrophy in the heart. RBM10 is down regulated in the hypertrophic myocyte and that its re-expression reverses cellular and molecular changes in the myocyte. However, in the absence of phosphorylation (cSrc inhibition or phospho-deficient mutation), restoration of endogenous RBM10 level in the hypertrophic heart or ectopic re-expression in vitro failed to reverse cardiomyocyte hypertrophy. Mechanistically, loss of RBM10 phosphorylation inhibits nuclear localisation and interaction with Star-PAP compromising anti-hypertrophy gene expression.
SIGNIFICANCE
Our study establishes that cSrc-mediated RBM10 phosphorylation arbitrates anti-hypertrophy gene program. We also report a new functional regulation of RBM10 by phosphorylation that is poised to control heart failure.
Topics: Rats; Animals; Phosphorylation; Cardiomegaly; Heart Failure; Proto-Oncogenes; RNA, Messenger; Tyrosine; Myocytes, Cardiac
PubMed: 38309577
DOI: 10.1016/j.lfs.2024.122482 -
Drug Discovery Today Nov 2021Targeted-therapy failure in treating nonsmall cell lung cancer (NSCLC) frequently occurs because of the emergence of drug resistance and genetic mutations. The same... (Review)
Review
Targeted-therapy failure in treating nonsmall cell lung cancer (NSCLC) frequently occurs because of the emergence of drug resistance and genetic mutations. The same mutations also result in aerobic glycolysis, which further antagonizes outcomes by localized increases in lactate, an immune suppressor. Recent evidence indicates that enzymatic lowering of lactate can promote an oncolytic immune microenvironment within the tumour. Here, we review factors relating to lactate expression in NSCLC and the utility of lactate oxidase (LOX) for governing therapeutic delivery, its role in lactate oxidation and turnover, and relationships between lactate depletion and immune cell populations. The lactate-rich characteristic of NSCLC provides an exploitable property to potentially improve NSCLC outcomes and design new therapeutic strategies to integrate with conventional therapies.
Topics: Anaplastic Lymphoma Kinase; Animals; Carcinoma, Non-Small-Cell Lung; Citric Acid Cycle; Drug Resistance, Neoplasm; Genes, erbB-1; Glucose; Humans; Immune Checkpoint Inhibitors; L-Lactate Dehydrogenase; Lactic Acid; Lung Neoplasms; Metabolic Networks and Pathways; Mixed Function Oxygenases; Molecular Targeted Therapy; Protein Kinase Inhibitors; Proto-Oncogene Proteins p21(ras); Tumor Microenvironment
PubMed: 34325010
DOI: 10.1016/j.drudis.2021.07.014 -
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 -
Annals of Hematology Oct 2020Long non-coding RNAs (lncRNAs) have an established role in cell biology. Among their functions is the regulation of hematopoiesis. They characterize the different stages... (Review)
Review
Long non-coding RNAs (lncRNAs) have an established role in cell biology. Among their functions is the regulation of hematopoiesis. They characterize the different stages of hematopoiesis in a more lineage-restricted expression pattern than coding mRNAs. They affect hematopoietic stem cell renewal, proliferation, and differentiation of committed progenitors by interacting with master regulators transcription factors. Among these transcription factors, MYC has a prominent role. Similar to MYC's transcriptional activation/amplification of protein coding genes, MYC also regulates lncRNAs' expression profile, while it is also regulated by lncRNAs. Both myeloid and lymphoid malignancies are prone to the association of MYC with lncRNAs. Such interaction inhibits apoptosis, enhances cell proliferation, deregulates metabolism, and promotes genomic instability and resistance to treatment. In this review, we discuss the recent findings that encompass the crosstalk between lncRNAs and describe the pathways that very probably have a pathogenetic role in both acute and chronic hematologic malignancies.
Topics: Cell Self Renewal; Gene Expression Regulation, Neoplastic; Genes, myc; Hematologic Neoplasms; Hematopoiesis; Humans; Leukemia; Lymphocytes; Lymphoma; Multiple Myeloma; Myeloid Cells; Neoplasm Proteins; Proto-Oncogene Proteins c-myc; RNA, Long Noncoding; RNA, Neoplasm; Stem Cell Niche
PubMed: 32621182
DOI: 10.1007/s00277-020-04166-4 -
The Journal of Experimental Medicine Aug 2023Type I interferons are important antiviral cytokines, but prolonged interferon production is detrimental to the host. The TLR3-driven immune response is crucial for...
Type I interferons are important antiviral cytokines, but prolonged interferon production is detrimental to the host. The TLR3-driven immune response is crucial for mammalian antiviral immunity, and its intracellular localization determines induction of type I interferons; however, the mechanism terminating TLR3 signaling remains obscure. Here, we show that the E3 ubiquitin ligase ZNRF1 controls TLR3 sorting into multivesicular bodies/lysosomes to terminate signaling and type I interferon production. Mechanistically, c-Src kinase activated by TLR3 engagement phosphorylates ZNRF1 at tyrosine 103, which mediates K63-linked ubiquitination of TLR3 at lysine 813 and promotes TLR3 lysosomal trafficking and degradation. ZNRF1-deficient mice and cells are resistant to infection by encephalomyocarditis virus and SARS-CoV-2 because of enhanced type I interferon production. However, Znrf1-/- mice have exacerbated lung barrier damage triggered by antiviral immunity, leading to enhanced susceptibility to respiratory bacterial superinfections. Our study highlights the c-Src-ZNRF1 axis as a negative feedback mechanism controlling TLR3 trafficking and the termination of TLR3 signaling.
Topics: Animals; Mice; Antiviral Agents; COVID-19; Interferon Type I; SARS-CoV-2; Toll-Like Receptor 3; Genes, src
PubMed: 37158982
DOI: 10.1084/jem.20220727