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Cell Death and Differentiation Feb 2024Fos-related antigen-2 (Fra-2) is the most recently discovered member of the Fos family and, by dimerizing with Jun proteins, forms the activator protein 1 (AP-1)... (Review)
Review
Fos-related antigen-2 (Fra-2) is the most recently discovered member of the Fos family and, by dimerizing with Jun proteins, forms the activator protein 1 (AP-1) transcription factor. By inducing or repressing the transcription of several target genes, Fra-2 is critically involved in the modulation of cell response to a variety of extracellular stimuli, stressors and intracellular changes. In physiological conditions, Fra-2 has been found to be ubiquitously expressed in human cells, regulating differentiation and homeostasis of bone, muscle, nervous, lymphoid and other tissues. While other AP-1 members, like Jun and Fos, are well characterized, studies of Fra-2 functions in cancer are still at an early stage. Due to the lack of a trans-activating domain, which is present in other Fos proteins, it has been suggested that Fra-2 might inhibit cell transformation, eventually exerting an anti-tumor effect. In human malignancies, however, Fra-2 activity is enhanced (or induced) by dysregulation of microRNAs, oncogenes and extracellular signaling, suggesting a multifaceted role. Therefore, Fra-2 can promote or prevent transformation, proliferation, migration, epithelial-mesenchymal transition, drug resistance and metastasis formation in a tumor- and context-dependent manner. Intriguingly, recent data reports that Fra-2 is also expressed in cancer associated cells, contributing to the intricate crosstalk between neoplastic and non-neoplastic cells, that leads to the evolution and remodeling of the tumor microenvironment. In this review we summarize three decades of research on Fra-2, focusing on its oncogenic and anti-oncogenic effects in tumor progression and dissemination.
Topics: Humans; Cell Transformation, Neoplastic; Fos-Related Antigen-2; Gene Expression Regulation; Neoplasms; Proto-Oncogene Proteins c-fos; Proto-Oncogene Proteins c-jun; Transcription Factor AP-1; Tumor Microenvironment
PubMed: 38104183
DOI: 10.1038/s41418-023-01248-4 -
Frontiers in Immunology 2023Activator protein-1 (AP-1) is a transcription factor that consists of a diverse group of members including Jun, Fos, Maf, and ATF. AP-1 involves a number of processes... (Review)
Review
Activator protein-1 (AP-1) is a transcription factor that consists of a diverse group of members including Jun, Fos, Maf, and ATF. AP-1 involves a number of processes such as proliferation, migration, and invasion in cells. Dysfunctional AP-1 activity is associated with cancer initiation, development, invasion, migration and drug resistance. Therefore, AP-1 is a potential target for cancer targeted therapy. Currently, some small molecule inhibitors targeting AP-1 have been developed and tested, showing some anticancer effects. However, AP-1 is complex and diverse in its structure and function, and different dimers may play different roles in different type of cancers. Therefore, more research is needed to reveal the specific mechanisms of AP-1 in cancer, and how to select appropriate inhibitors and treatment strategies. Ultimately, this review summarizes the potential of combination therapy for cancer.
Topics: Humans; Transcription Factor AP-1; Proto-Oncogene Proteins c-fos; Proto-Oncogene Proteins c-jun; Gene Expression Regulation; Neoplasms
PubMed: 37483616
DOI: 10.3389/fimmu.2023.1224892 -
Frontiers in Immunology 2023Langerhans cell histiocytosis (LCH) is a rare and clinically heterogeneous hematological disease characterized by the accumulation of mononuclear phagocytes in various... (Review)
Review
Langerhans cell histiocytosis (LCH) is a rare and clinically heterogeneous hematological disease characterized by the accumulation of mononuclear phagocytes in various tissues and organs. LCH is often characterized by activating mutations of the mitogen-activated protein kinase (MAPK) pathway with being the most recurrent mutation. Although this discovery has greatly helped in understanding the disease and in developing better investigational tools, the process of malignant transformation and the cell of origin are still not fully understood. In this review, we focus on the newest updates regarding the molecular pathogenesis of LCH and novel suggested pathways with treatment potential.
Topics: Humans; Proto-Oncogene Proteins B-raf; Histiocytosis, Langerhans-Cell; Mutation; Mitogen-Activated Protein Kinases; Gain of Function Mutation
PubMed: 37965340
DOI: 10.3389/fimmu.2023.1275085 -
International Journal of Molecular... Jun 2024The MET receptor is one of the main drivers of 'invasive growth', a multifaceted biological response essential during embryonic development and tissue repair that is... (Review)
Review
The MET receptor is one of the main drivers of 'invasive growth', a multifaceted biological response essential during embryonic development and tissue repair that is usurped by cancer cells to induce and sustain the malignant phenotype. MET stands out as one of the most important oncogenes activated in cancer and its inhibition has been explored since the initial era of cancer-targeted therapy. Different approaches have been developed to hamper MET signaling and/or reduce MET (over)expression as a hallmark of transformation. Considering the great interest gained by cancer immunotherapy, this review evaluates the opportunity of targeting MET within therapeutic approaches based on the exploitation of immune functions, either in those cases where MET impairment is crucial to induce an effective response (i.e., when MET is the driver of the malignancy), or when blocking MET represents a way for potentiating the treatment (i.e., when MET is an adjuvant of tumor fitness).
Topics: Humans; Proto-Oncogene Proteins c-met; Neoplasms; Immunotherapy; Animals; Oncogenes; Molecular Targeted Therapy; Signal Transduction
PubMed: 38892318
DOI: 10.3390/ijms25116109 -
Oncotarget Jul 2023Ras proteins are small GTPases that regulate cell growth and division. Mutations in Ras genes are associated with many types of cancer, making them attractive targets... (Review)
Review
Ras proteins are small GTPases that regulate cell growth and division. Mutations in Ras genes are associated with many types of cancer, making them attractive targets for cancer therapy. Despite extensive efforts, targeting Ras proteins with small molecules has been extremely challenging due to Ras's mostly flat surface and lack of small molecule-binding cavities. These challenges were recently overcome by the development of the first covalent small-molecule anti-Ras drug, sotorasib, highlighting the efficacy of Ras inhibition as a therapeutic strategy. However, this drug exclusively inhibits the Ras G12C mutant, which is not a prevalent mutation in most cancer types. Unlike the G12C variant, other Ras oncogenic mutants lack reactive cysteines, rendering them unsuitable for targeting via the same strategy. Protein engineering has emerged as a promising method to target Ras, as engineered proteins have the ability to recognize various surfaces with high affinity and specificity. Over the past few years, scientists have engineered antibodies, natural Ras effectors, and novel binding domains to bind to Ras and counteract its carcinogenic activities via a variety of strategies. These include inhibiting Ras-effector interactions, disrupting Ras dimerization, interrupting Ras nucleotide exchange, stimulating Ras interaction with tumor suppressor genes, and promoting Ras degradation. In parallel, significant advancements have been made in intracellular protein delivery, enabling the delivery of the engineered anti-Ras agents into the cellular cytoplasm. These advances offer a promising path for targeting Ras proteins and other challenging drug targets, opening up new opportunities for drug discovery and development.
Topics: Humans; Genes, ras; ras Proteins; Neoplasms; Mutation; Protein Engineering; Proto-Oncogene Proteins p21(ras)
PubMed: 37395750
DOI: 10.18632/oncotarget.28469 -
Nature Communications Aug 2023Whether TMPRSS2-ERG fusion and TP53 gene alteration coordinately promote prostate cancer (PCa) remains unclear. Here we demonstrate that TMPRSS2-ERG fusion and TP53...
Whether TMPRSS2-ERG fusion and TP53 gene alteration coordinately promote prostate cancer (PCa) remains unclear. Here we demonstrate that TMPRSS2-ERG fusion and TP53 mutation / deletion co-occur in PCa patient specimens and this co-occurrence accelerates prostatic oncogenesis. p53 gain-of-function (GOF) mutants are now shown to bind to a unique DNA sequence in the CTNNB1 gene promoter and transactivate its expression. ERG and β-Catenin co-occupy sites at pyrimidine synthesis gene (PSG) loci and promote PSG expression, pyrimidine synthesis and PCa growth. β-Catenin inhibition by small molecule inhibitors or oligonucleotide-based PROTAC suppresses TMPRSS2-ERG- and p53 mutant-positive PCa cell growth in vitro and in mice. Our study identifies a gene transactivation function of GOF mutant p53 and reveals β-Catenin as a transcriptional target gene of p53 GOF mutants and a driver and therapeutic target of TMPRSS2-ERG- and p53 GOF mutant-positive PCa.
Topics: Animals; Humans; Male; Mice; beta Catenin; Gain of Function Mutation; Oncogene Proteins, Fusion; Prostatic Neoplasms; Proto-Oncogenes; Pyrimidines; Transcriptional Regulator ERG; Tumor Suppressor Protein p53
PubMed: 37537199
DOI: 10.1038/s41467-023-40352-4 -
Cell Death & Disease Oct 2023Hypoxia is an essential hallmark of solid tumors and HIF1α is a central regulator of tumor cell adaptation and survival in the hypoxic environment. In this study, we...
Hypoxia is an essential hallmark of solid tumors and HIF1α is a central regulator of tumor cell adaptation and survival in the hypoxic environment. In this study, we explored the biological functions of cell cycle division-related gene 8 (CDCA8) in bladder cancer (BCa) cells in the hypoxic settings. Specifically, we found that CDCA8 was significantly upregulated in BCa cell lines and clinical samples and its expression was positively correlated with advanced BCa stage, grade, and poor overall survival (OS). The expression of CDCA8 proteins was required for BCa cells to survive in the hypoxic condition. Mechanistically, CDCA8 stabilizes HIF1α by competing with PTEN for AKT binding, consequently leading to PTEN displacement and activation of the AKT/GSK3β signaling cascade that stimulates HIF1α protein stability. Significantly, HIF1α proteins bind to CDCA8 promoter for transcriptional activation, forming a positive-feedback loop to sustain BCa tumor cells under oxygen-deficient environment. Together, we defined CDCA8 as a key regulator for BCa cells to sense and prevail oxygen deprivation and as a novel BCa therapeutic target.
Topics: Humans; Cell Cycle Proteins; Cell Hypoxia; Cell Line; Cell Line, Tumor; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit; Oxygen; Proto-Oncogene Proteins c-akt; Urinary Bladder Neoplasms
PubMed: 37813876
DOI: 10.1038/s41419-023-06189-x -
International Journal of Molecular... Jul 2023Colorectal cancer (CRC) is a heterogeneous disease with a myriad of alterations at the cellular and molecular levels. Kristen rat sarcoma (KRAS) mutations occur in up to... (Review)
Review
Colorectal cancer (CRC) is a heterogeneous disease with a myriad of alterations at the cellular and molecular levels. Kristen rat sarcoma (KRAS) mutations occur in up to 40% of CRCs and serve as both a prognostic and predictive biomarker. Oncogenic mutations in the KRAS protein affect cellular proliferation and survival, leading to tumorigenesis through RAS/MAPK pathways. Until recently, only indirect targeting of the pathway had been investigated. There are now several KRAS allele-specific inhibitors in late-phase clinical trials, and many newer agents and targeting strategies undergoing preclinical and early-phase clinical testing. The adequate treatment of KRAS-mutated CRC will inevitably involve combination therapies due to the existence of robust adaptive resistance mechanisms in these tumors. In this article, we review the most recent understanding and findings related to targeting KRAS mutations in CRC, mechanisms of resistance to KRAS inhibitors, as well as evolving treatment strategies for KRAS-mutated CRC patients.
Topics: Humans; Colorectal Neoplasms; Proto-Oncogene Proteins p21(ras); Carcinogenesis; Cell Transformation, Neoplastic; Cell Proliferation; Mutation
PubMed: 37569406
DOI: 10.3390/ijms241512030 -
Cell Death & Disease Aug 2023Hyperthermic intraperitoneal administration of chemotherapy (HIPEC) increases local drug concentrations and reduces systemic side effects associated with prolonged...
Hyperthermic intraperitoneal administration of chemotherapy (HIPEC) increases local drug concentrations and reduces systemic side effects associated with prolonged adjuvant intraperitoneal exposure in patients affected by either peritoneal malignancies or metastatic diseases originating from gastric, colon, kidney, and ovarian primary tumors. Mechanistically, the anticancer effects of HIPEC have been poorly explored. Herein we documented that HIPEC treatment promoted miR-145-5p expression paired with a significant downregulation of its oncogenic target genes c-MYC, EGFR, OCT4, and MUC1 in a pilot cohort of patients with ovarian peritoneal metastatic lesions. RNA sequencing analyses of ovarian peritoneal metastatic nodules from HIPEC treated patients unveils HSF-1 as a transcriptional regulator factor of miR-145-5p expression. Notably, either depletion of HSF-1 expression or chemical inhibition of its transcriptional activity impaired miR-145-5p tumor suppressor activity and the response to cisplatin in ovarian cancer cell lines incubated at 42 °C. In aggregate, our findings highlight a novel transcriptional network involving HSF-1, miR145-5p, MYC, EGFR, MUC1, and OCT4 whose proper activity contributes to HIPEC anticancer efficacy in the treatment of ovarian metastatic peritoneal lesions.
Topics: Humans; Female; Hyperthermic Intraperitoneal Chemotherapy; Genes, myc; Heat Shock Transcription Factors; Ovarian Neoplasms; Transcription Factors; Cell Line; ErbB Receptors; MicroRNAs
PubMed: 37598177
DOI: 10.1038/s41419-023-06064-9 -
Seminars in Neurology Dec 2023Brain metastases (BMs) represent the most common intracranial tumors in adults, and most commonly originate from lung, followed by breast, melanoma, kidney, and... (Review)
Review
Brain metastases (BMs) represent the most common intracranial tumors in adults, and most commonly originate from lung, followed by breast, melanoma, kidney, and colorectal cancer. Management of BM is individualized based on the size and number of brain metastases, the extent of extracranial disease, the primary tumor subtype, neurological symptoms, and prior lines of therapy. Until recently, treatment strategies were limited to local therapies, like surgical resection and radiotherapy, the latter in the form of whole-brain radiotherapy or stereotactic radiosurgery. The next generation of local strategies includes laser interstitial thermal therapy, magnetic hyperthermic therapy, post-resection brachytherapy, and focused ultrasound. New targeted therapies and immunotherapies with documented intracranial activity have transformed clinical outcomes. Novel systemic therapies with intracranial utility include new anaplastic lymphoma kinase inhibitors like brigatinib and ensartinib; selective "rearranged during transfection" inhibitors like selpercatinib and pralsetinib; B-raf proto-oncogene inhibitors like encorafenib and vemurafenib; Kirsten rat sarcoma viral oncogene inhibitors like sotorasib and adagrasib; ROS1 gene rearrangement (ROS1) inhibitors, anti-neurotrophic tyrosine receptor kinase agents like larotrectinib and entrectinib; anti-human epidermal growth factor receptor 2/epidermal growth factor receptor exon 20 agent like poziotinib; and antibody-drug conjugates like trastuzumab-emtansine and trastuzumab-deruxtecan. This review highlights the modern multidisciplinary management of BM, emphasizing the integration of systemic and local therapies.
Topics: Adult; Humans; Proto-Oncogene Proteins; Trastuzumab; Vemurafenib; Protein Kinase Inhibitors; Brain Neoplasms
PubMed: 38011864
DOI: 10.1055/s-0043-1776782