RSPO2 gene rearrangement: a powerful driver of β-catenin activation in liver tumours

Gut ◽  
2019 ◽  
Vol 68 (7) ◽  
pp. 1287-1296 ◽  
Author(s):  
Thomas Longerich ◽  
Volker Endris ◽  
Olaf Neumann ◽  
Eugen Rempel ◽  
Martina Kirchner ◽  
...  
Keyword(s):  
Malignant Transformation ◽  
Transcriptional Activation ◽  
Gene Rearrangement ◽  
Target Genes ◽  
Integration Site ◽  
Genetic Alterations ◽  
Wnt Signalling ◽  
Nuclear Accumulation ◽  
Alternative Mechanism ◽  
Mutational Status

ObjectiveWe aimed at the identification of genetic alterations that may functionally substitute for CTNNB1 mutation in ß-catenin-activated hepatocellular adenomas (HCAs) and hepatocellular carcinoma (HCC).DesignLarge cohorts of HCA (n=185) and HCC (n=468) were classified using immunohistochemistry. The mutational status of the CTNNB1 gene was determined in ß-catenin-activated HCA (b-HCA) and HCC with at least moderate nuclear CTNNB1 accumulation. Ultra-deep sequencing was used to characterise CTNNB1wild-type and ß-catenin-activated HCA and HCC. Expression profiling of HCA subtypes was performed.ResultsA roof plate-specific spondin 2 (RSPO2) gene rearrangement resulting from a 46.4 kb microdeletion on chromosome 8q23.1 was detected as a new morphomolecular driver of β-catenin-activated HCA. RSPO2 fusion positive HCA displayed upregulation of RSPO2 protein, nuclear accumulation of β-catenin and transcriptional activation of β-catenin-target genes indicating activation of Wingless-Type MMTV Integration Site Family (WNT) signalling. Architectural and cytological atypia as well as interstitial invasion indicated malignant transformation in one of the RSPO2 rearranged b-HCAs. The RSPO2 gene rearrangement was also observed in three β-catenin-activated HCCs developing in context of chronic liver disease. Mutations of the human telomerase reverse transcriptase promoter—known to drive malignant transformation of CTNNB1-mutated HCA—seem to be dispensable for RSPO2 rearranged HCA and HCC.ConclusionThe RSPO2 gene rearrangement leads to oncogenic activation of the WNT signalling pathway in HCA and HCC, represents an alternative mechanism for the development of b-HCA and may drive malignant transformation without additional TERT promoter mutation.

scholarly journals Modulating PKCα Activity to Target Wnt/β-Catenin Signaling in Colon Cancer

Cancers ◽  
2019 ◽  
Vol 11 (5) ◽  
pp. 693 ◽  
Author(s):  
Sébastien Dupasquier ◽  
Philippe Blache ◽  
Laurence Picque Lasorsa ◽  
Han Zhao ◽  
Jean-Daniel Abraham ◽  
...  
Keyword(s):  
Transcriptional Activation ◽  
Transcriptional Activity ◽  
Target Genes ◽  
Tumor Development ◽  
Orphan Receptor ◽  
Nuclear Accumulation ◽  
Kinase C ◽  
Extracellular Signal

Inactivating mutations of the tumor suppressor Adenomatosis Polyposis Coli (APC), which are found in familial adenomatosis polyposis and in 80% of sporadic colorectal cancers (CRC), result in constitutive activation of the Wnt/β-catenin pathway and tumor development in the intestine. These mutations disconnect the Wnt/β-catenin pathway from its Wnt extracellular signal by inactivating the APC/GSK3-β/axin destruction complex of β-catenin. This results in sustained nuclear accumulation of β-catenin, followed by β-catenin-dependent co-transcriptional activation of Wnt/β-catenin target genes. Thus, mechanisms acting downstream of APC, such as those controlling β-catenin stability and/or co-transcriptional activity, are attractive targets for CRC treatment. Protein Kinase C-α (PKCα) phosphorylates the orphan receptor RORα that then inhibits β-catenin co-transcriptional activity. PKCα also phosphorylates β-catenin, leading to its degradation by the proteasome. Here, using both in vitro (DLD-1 cells) and in vivo (C57BL/6J mice) PKCα knock-in models, we investigated whether enhancing PKCα function could be beneficial in CRC treatment. We found that PKCα is infrequently mutated in CRC samples, and that inducing PKCα function is not deleterious for the normal intestinal epithelium. Conversely, di-terpene ester-induced PKCα activity triggers CRC cell death. Together, these data indicate that PKCα is a relevant drug target for CRC treatment.

Gfi-1 Represses CDKN2B Encoding p15INK4B through Interaction with Miz-1

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3578-3578
Author(s):  
Qingquan Liu ◽  
Suchitra Basu ◽  
Yaling Qiu ◽  
Fan Dong
Keyword(s):  
Zinc Finger ◽  
Transcriptional Activation ◽  
Transcriptional Repression ◽  
Target Genes ◽  
Kinase Inhibitor ◽  
Core Promoter ◽  
Leukemic Cells ◽  
Mouse Bone Marrow ◽  
Alternative Mechanism ◽  
Human Leukemic Cells

Abstract Zinc finger (ZF) transcriptional repressor Gfi-1 plays an important role in hematopoiesis and inner ear development, and also functions as an oncoprotein that cooperates with c-Myc in lymphomagenesis. Gfi-1 represses transcription by directly binding to the consensus DNA sequence in the promoters of its target genes. We report here an alternative mechanism by which Gfi-1 represses CDKN2B encoding the cyclin-dependent kinase inhibitor p15INK4B. Gfi-1 did not directly bind to CDKN2B, but interacted with Miz-1 and, via Miz-1, was recruited to the core promoter of CDKN2B. The C-terminal zinc finger domains of Gfi-1 and Miz-1 are involved in the interaction. Miz-1 is a POZ-ZF transcription factor that has been shown to mediate transcriptional repression by c-Myc. Like c-Myc, upon recruitment to the CDKN2B promoter, Gfi-1 repressed transcriptional activation of CDKN2B by Miz-1 and in response to TGFb. Notably, Gfi-1 and c-Myc formed a ternary complex with Miz-1 and were both recruited to the CDKN2B core promoter via Miz-1, and acted in collaboration to repress CDKN2B. Consistent with its role in repressing CDKN2B transcription, knockdown of Gfi-1 in human leukemic cells resulted in augmented levels of p15INK4B, which was associated with attenuated cell proliferation. The expression of p15INK4B was also significantly higher in Gfi-1−/− mouse bone marrow (BM) cells than in Gfi-1+/+ BM cells. Our data reveal a novel mechanism of transcriptional repression by Gfi-1 and also identify CDKN2B as a new Gfi-1 target gene. The findings may have important implications for understanding the role of Gfi-1 in normal development and the cooperation between Gfi-1 and c-Myc in lymphomagenesis.

scholarly journals A new link between diabetes and cancer: enhanced WNT/β-catenin signaling by high glucose

2013 ◽  
Vol 52 (1) ◽  
pp. R51-R66 ◽  
Author(s):  
Custodia García-Jiménez ◽  
Jose Manuel García-Martínez ◽  
Ana Chocarro-Calvo ◽  
Antonio De la Vieja
Keyword(s):  
Transcriptional Activation ◽  
High Glucose ◽  
Target Genes ◽  
Epidemiological Studies ◽  
Sirtuin 1 ◽  
Nuclear Accumulation ◽  
Research Attention ◽  
Growth And Survival ◽  
Metabolic Remodeling ◽  
The Impact

Extensive epidemiological studies suggest that the diabetic population is at higher risk of site-specific cancers. The diabetes–cancer link has been hypothesized to rely on various hormonal (insulin, IGF1, adipokines), immunological (inflammation), or metabolic (hyperglycemia) characteristics of the disease and even on certain treatments. Inflammation may have an important but incompletely understood role. As a growth factor, insulin directly, or indirectly through IGF1, has been considered the major link between diabetes and cancer, while high glucose has been considered as a subordinate cause. Here we discuss the evidence that supports a role for insulin/IGF1 in general in cancer, and the mechanism by which hyperglycemia may enhance the appearance, growth and survival of diabetes-associated cancers. High glucose triggers several direct and indirect mechanisms that cooperate to promote cancer cell proliferation, migration, invasion and immunological escape. In particular, high glucose enhancement of WNT/β-catenin signaling in cancer cells promotes proliferation, survival and senescence bypass, and represents a previously unrecognized direct mechanism linking diabetes-associated hyperglycemia to cancer. Increased glucose uptake is a hallmark of tumor cells and may ensure enhanced WNT signaling for continuous proliferation. Mechanistically, high glucose unbalances acetylation through increased p300 acetyl transferase and decreased sirtuin 1 deacetylase activity, leading to β-catenin acetylation at lysine K354, a requirement for nuclear accumulation and transcriptional activation of WNT-target genes. The impact of high glucose on β-catenin illustrates the remodeling of cancer-associated signaling pathways by metabolites. Metabolic remodeling of cancer-associated signaling will receive much research attention in the coming years. Future epidemiological studies may be guided and complemented by the identification of these metabolic interplays. Together, these studies should lead to the development of new preventive strategies for diabetes-associated cancers.

scholarly journals Caveolin 1 Reduces High Glucose-Induced Hypertrophy and Inflammatory Fibrosis of H9C2 Cardiomyocytes By Inhibiting NF-κB Signaling

2021 ◽  
Author(s):  
Wenyan Gong ◽  
Jinghua Yuan ◽  
Hui Luo ◽  
Yingying Liu ◽  
Mingwei Wang ◽  
...  
Keyword(s):  
Transcriptional Activation ◽  
High Glucose ◽  
Plasma Membranes ◽  
Target Genes ◽  
Microvascular Complications ◽  
Multiple Comparisons ◽  
Nuclear Accumulation ◽  
Dependent Manner ◽  
Caveolin 1 ◽  
H9c2 Cardiomyocytes

Abstract Background: Cardiac hypertrophy and inflammatory fibrosis are the basic pathological changes of the prevalent microvascular diabetes complication known as diabetic cardiomyopathy (DCM). Previous studies of the Caveolin 1 protein and the lipid raft structures known as caveolae—small invaginations of the plasma membranes of certain cell types (including cardiomyocytes)—have linked this protein to fat metabolism disorders, inflammation, diabetes, and cardiovascular disease. However, there are no reports linking Caveolin 1 to DCM. Here, we show that Caveolin 1 plays a vital role in the hypertrophy and inflammatory fibrosis of H9C2 cardiomyocytes induced by high glucose (HG) via inhibiting the NF-κB signaling.Methods: The H9C2 cardiomyocytes induced by HG were used as the experimental model in this study to explicit the effect of Caveolin 1 on DCM and the underlying mechanisms involved. Unpaired Student’s t test was used for comparison between two groups. For multiple comparisons, data were analyzed by one-way ANOVA with Bonferroni post hoc test multiple comparisons.Results: (1) Exposure of H9C2 cardiomyocytes to HG activated NF-κB signaling and induced the expression of downstream NF-κB target genes including both hypertrophic factors and inflammatory fibrosis factors; (2) Intriguingly, exposure of cardiomyocytes to HG led to decreased Caveolin 1 levels, and this decrease occurred in an HG-exposure-time-dependent manner; (3) Overexpression of Caveolin 1 reduces phosphorylation of p65 and blocks the nuclear accumulation of this NF-κB component in HG-exposed cardiomyocytes, and inhibits transcriptional activation of NF-κB target genes; (4) Knocking down Caveolin 1 exacerbates the HG-induced promotion of the aforementioned NF-κB hypertrophic factors and inflammatory fibrosis factors, all of which have been linked to DCM pathogenesis. Conclusions: Our study supports that Caveolin 1 can protect against hypertrophy and inflammatory fibrosis induced by HG, specifically by suppressing NF-κB signaling activity. Accordingly, some medical implications of our study include that i) Caveolin 1 may protect against the development of DCM and ii) may represent a target for developing therapeutics to protect against this highly prevalent and dangerous microvascular complications of diabetes.

scholarly journals Characterization of Differential Gene Expression in Adrenocortical Tumors Harboring β-Catenin (CTNNB1) Mutations

2011 ◽  
Vol 96 (7) ◽  
pp. E1206-E1211 ◽  
Author(s):  
Julien Durand ◽  
Antoine Lampron ◽  
Tania L. Mazzuco ◽  
Audrey Chapman ◽  
Isabelle Bourdeau
Keyword(s):  
Gene Expression ◽  
Target Genes ◽  
Adrenal Glands ◽  
Expression Profiles ◽  
Genetic Alterations ◽  
Nuclear Accumulation ◽  
Pcr Analysis ◽  
Dependent Manner ◽  
Rt Pcr ◽  
Adrenocortical Tumors

Abstract Background: Mutations of β-catenin gene (CTNNB1) are frequent in adrenocortical adenomas (AA) and adrenocortical carcinomas (ACC). However, the target genes of β-catenin have not yet been identified in adrenocortical tumors. Objective: Our objective was to identify genes deregulated in adrenocortical tumors harboring CTNNB1 genetic alterations and nuclear accumulation of β-catenin. Methods: Microarray analysis identified a dataset of genes that were differently expressed between AA with CTNNB1 mutations and wild-type (WT) tumors. Within this dataset, the expression profiles of five genes were validated by real time-PCR (RT-PCR) in a cohort of 34 adrenocortical tissues (six AA and one ACC with CTNNB1 mutations, 13 AA and four ACC with WT CTNNB1, and 10 normal adrenal glands) and two human ACC cell lines. We then studied the effects of suppressing β-catenin transcriptional activity with the T-cell factor/β-catenin inhibitors PKF115-584 and PNU74654 on gene expression in H295R and SW13 cells. Results: RT-PCR analysis confirmed the overexpression of ISM1, RALBP1, and PDE2A and the down-regulation of PHYHIP in five of six AA harboring CTNNB1 mutations compared with WT AA (n = 13) and normal adrenal glands (n = 10). RALBP1 and PDE2A overexpression was also confirmed at the protein level by Western blotting analysis in mutated tumors. ENC1 was specifically overexpressed in three of three AA harboring CTNNB1 point mutations. mRNA expression and protein levels of RALBP1, PDE2A, and ENC1 were decreased in a dose-dependent manner in H295R cells after treatment with PKF115-584 or PNU74654. Conclusion: This study identified candidate genes deregulated in CTNNB1-mutated adrenocortical tumors that may lead to a better understanding of the role of the Wnt-β-catenin pathway in adrenocortical tumorigenesis.

Proto-Oncogenes β- and γ-Catenin in Leukemogenesis in Severe Congenital Neutropenia (CN).

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 94-94
Author(s):  
Julia Skokowa ◽  
Gunnar Cario ◽  
Lan Dan ◽  
Cornelia Zeidler ◽  
Vesna Bucan ◽  
...  
Keyword(s):  
Malignant Transformation ◽  
Target Genes ◽  
Nuclear Translocation ◽  
Nuclear Accumulation ◽  
Healthy Controls ◽  
Severe Congenital Neutropenia ◽  
Congenital Neutropenia ◽  
Altered Expression ◽  
E Cadherin ◽  
Myeloid Progenitors

Abstract Severe congenital neutropenia (CN) is characterized by a “maturation arrest” of myeloid progenitors at the promyelocytic stage with few or no mature neutrophils in the bone marrow and blood. Administration of granulocyte colony-stimulating factor (G-CSF) increases neutrophil numbers in most CN patients. Approximately 10–15 % of CN patients develop AML or MDS by mechanisms that are as yet unknown. Since AML/MDS are not observed in cyclic (CyN) or idiopathic neutropenia patients treated with G-CSF, an underlying defect of hematopoiesis rather than G-CSF therapy per se predisposes to malignant transformation in CN patients. Recently, activation of Wnt/β-catenin-/γ-catenin-signaling cascade has been considered as important mechanism in the pathogenesis of AML and CML by enhancement of self-renewal activity and by increase of leukemic potential of myeloid progenitors. Moreover, stabilization of β-catenin led to an increased formation of nuclear β-catenin-T-cell factor complexes and altered expression of Wnt-inducible target genes in a variety of human malignancies. In the present study we investigated the role of β-catenin/γ-catenin in leukemogenesis in CN patients. CD33+ progenitors from CN patients expressed 2.5 times higher levels of b-catenin and 4 times higher levels of γ-catenin mRNA and protein, as assessed by quantitative real-time PCR and Western Blot analysis. Most important, in CN patients this increase was paralleled by dramatically elevated levels of activated nuclear β-catenin and intracellular γ-catenin proteins in CD33+ cells, as compared to G-CSF-treated healthy controls and CyN patients. Moreover, mRNA and protein levels of β- and γ-catenins were further increased in CD33+ cells and leukemic blasts from 4 CN patients, who developed AML. In line with high β-/γ-catenins levels, expression of target genes c-jun, fra-1 and PPARD was also up-regulated. There was no correlation between activated Wnt/β-/γ-catenin signaling system and mutations in G-CSF receptor, or ELA2 gene. To investigate the mechanisms of stabilization and increased nuclear translocation of b-catenin, we analyzed the components of b-catenin-degradation multiprotein complex, which contains of Axin, GSK3β, and APC. No differences in expression of Axin, GSK3β and APC as well as in phosphorylation status of GSK3β in CD33+ cells from CN patients and controls were observed. Sequence analysis revealed no mutations in β-catenin gene. Furthermore we analysed the expression of E-cadherin, which forms the transmembrane core of adherent junctions by bridging to β-catenin and therefore modulates its subcellular localization and nuclear translocation. E-cadherin mRNA and protein expression was dramatically downregulated in CD33+ myeloid progenitors from CN patients, in comparison to G-CSF treated healthy controls. Moreover, confocal microscopy revealed very low levels of co-localized E-cadherin and β-catenin in CD33+ cells from CN patients. Therefore, we hypothesize that loss of E-cadherin expression results in nuclear accumulation of β-catenin and activation of its downstream signaling in CN. Taken together, high expression of the proto-oncogenes β- and γ-catenins and nuclear accumulation of β-catenin could contribute to the malignant transformation of myelopoiesis in CN.

AML1-ETO Inhibits DNA Repair Pathways and Promotes the Accumulation of DNA Damage and the Activation of p53.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1412-1412
Author(s):  
Ondrej Krejci ◽  
Mark Wunderlich ◽  
Junping Wei ◽  
Paul R. Andreassen ◽  
Thomas X. Lu ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Gamma Irradiation ◽  
Malignant Transformation ◽  
Target Genes ◽  
Excision Repair ◽  
Genetic Alterations ◽  
P53 Pathway ◽  
Genetic Changes ◽  
Repair Pathways

Abstract Malignant transformation is a multistep process that is promoted by the accumulation of genetic changes over time. The contribution of individual genetic changes to the development of leukemia and the processes that induce these changes are not yet fully understood. The generation of the fusion gene AML1-ETO is thought to be an early event in the development of AML with t(8;21). Cells expressing AML1-ETO have been detected in samples from healthy newborns, as well as in patient samples analyzed long before the manifestation of AML. For these reasons it is assumed that a pre-leukemic clone expressing AML1-ETO requires additional genetic changes to complete the malignant transformation. However, the mechanism whereby these changes are acquired and the role that AML1-ETO plays in this process remain unclear. We used a model of human CD34+ cells expressing the AML1-ETO fusion protein to elucidate the role of AML1-ETO in leukemogenesis. AML1-ETO expressing (AE) cells displayed characteristics of a pre-leukemia, with enhanced self-renewal and NOD/SCID engraftment but no ability to induce malignancy in vivo. Analysis of gene expression using Affymetrix HG U133 Plus2.0 gene chips revealed that multiple genes important in various DNA repair pathways were suppressed in AE cells: OGG1, UNG, TDG, MBD4, POLB, POLE and FEN1 (Base Excision Repair), MRE11, RAD50, ATM, CHEK1 and CDC25A (ATM pathway), and FANCA, FANCL and BRCA2 (Fanconi anemia proteins). Treatment with DNA interstrand crosslinking agents mitomycin C or melphalan revealed a block in the S-phase of the cell cycle in AE cells at doses not affecting control cells. AE cells were also more sensitive to gamma irradiation compared to vector-transduced cells. In AE cultures, a gradual accumulation of cells with DNA damage was detected by immunofluorescence microscopy, using phosphorylated histone H2A.X as a marker. AE cells had a hyperactive p53 pathway with increased p53 protein levels, upregulation of its target genes (p21, TP53I3 and DAPK1), and increased apoptosis compared to control cultures, as might be expected in cells with chronic DNA damage. Incubation under low oxygen conditions prevented the accumulation of DNA damage and resulted in decreased expression of p53 target genes (TP53I3 and DAPK1), indicating that a sub-optimal response to the high oxygen stress of culture could be responsible for the accumulation of DNA damage foci and activation of the p53 pathway in AE cultures. Inhibition of p53 by shRNA led to increased resistance of AE cells to gamma irradiation but with continued high levels of DNA damage as shown by phosphorylated H2A.X. Interestingly, the POU4f1 transcription factor, a modifier of the p53 response pathway, has been found to be overexpressed in t(8;21) patient samples. In our system, AE cells that ectopically overexpressed POU4f1 following retroviral transduction showed decreased levels of p53 compared to vector-transduced AE cells. Inhibition of the p53 pathway in pre-leukemic clones expressing AML1-ETO could lead to a proliferative or survival advantage during periods of genotoxic stress. The impairment of DNA repair pathways and the accumulation of DNA damage in AML1-ETO-expressing cells may promote an elevated mutation rate and increase the chances of acquiring subsequent genetic alterations.

Landmark Studies of Targeted Therapies for Advanced Non-Small Cell Lung Cancer: A Guide for Pulmonologists

2020 ◽  
Vol 16 (1) ◽  
pp. 5-10
Author(s):  
Adrien Costantini ◽  
Theodoros Katsikas ◽  
Clementine Bostantzoglou
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Standard Of Care ◽  
Genetic Alterations ◽  
Small Cell ◽  
Extensive Literature ◽  
Small Cell Lung ◽  
Anaplastic Lymphoma ◽  
Mutational Status

Over the past decade, major breakthroughs in the understanding of lung cancer histology and mutational pathways have radically changed diagnosis and management. More specifically, in non-small cell lung cancer (NSCLC), tumour characterisation has shifted from differentiating based solely on histology to characterisation that includes genetic profiling and mutational status of Epidermal Growth Factor (EGFR), Anaplastic Lymphoma Kinase (ALK), c-ros oncogene 1 (ROS1) and BRAF. These genetic alterations can be targeted by specific drugs that result in improved progression-free survival, as well as higher response rates and are currently standard of care for NSCLC patients harbouring these mutations. In this a narrative, non-systematic review we aim to handpick through the extensive literature and critically present the ground-breaking studies that lead to the institution of tailored treatment options as the standard of care for the main targetable genetic alterations.

scholarly journals The Non-Canonical Aspects of MicroRNAs: Many Roads to Gene Regulation

Cells ◽  
2019 ◽  
Vol 8 (11) ◽  
pp. 1465 ◽  
Author(s):  
Christiaan J. Stavast ◽  
Stefan J. Erkeland
Keyword(s):  
Rna Polymerase Ii ◽  
Transcriptional Activation ◽  
Small Rnas ◽  
Target Genes ◽  
Biological Functions ◽  
Rnase Iii ◽  
Mrna Targets ◽  
Argonaute Proteins ◽  
Epigenetic Modifiers ◽  
Encoding Genes

MicroRNAs (miRNAs) are critical regulators of gene expression. As miRNAs are frequently deregulated in many human diseases, including cancer and immunological disorders, it is important to understand their biological functions. Typically, miRNA-encoding genes are transcribed by RNA Polymerase II and generate primary transcripts that are processed by RNase III-endonucleases DROSHA and DICER into small RNAs of approximately 21 nucleotides. All miRNAs are loaded into Argonaute proteins in the RNA-induced silencing complex (RISC) and act as post-transcriptional regulators by binding to the 3′- untranslated region (UTR) of mRNAs. This seed-dependent miRNA binding inhibits the translation and/or promotes the degradation of mRNA targets. Surprisingly, recent data presents evidence for a target-mediated decay mechanism that controls the level of specific miRNAs. In addition, several non-canonical miRNA-containing genes have been recently described and unexpected functions of miRNAs have been identified. For instance, several miRNAs are located in the nucleus, where they are involved in the transcriptional activation or silencing of target genes. These epigenetic modifiers are recruited by RISC and guided by miRNAs to specific loci in the genome. Here, we will review non-canonical aspects of miRNA biology, including novel regulators of miRNA expression and functions of miRNAs in the nucleus.

scholarly journals Mutated p53 in HGSC—From a Common Mutation to a Target for Therapy

Cancers ◽  
2021 ◽  
Vol 13 (14) ◽  
pp. 3465
Author(s):  
Aya Saleh ◽  
Ruth Perets
Keyword(s):  
Cancer Progression ◽  
Target Genes ◽  
P53 Protein ◽  
Genetic Alterations ◽  
Common Mutation ◽  
Missense Mutations ◽  
P53 Expression ◽  
Histologic Subtype ◽  
Tp53 Mutations

Mutations in tumor suppressor gene TP53, encoding for the p53 protein, are the most ubiquitous genetic variation in human ovarian HGSC, the most prevalent and lethal histologic subtype of epithelial ovarian cancer (EOC). The majority of TP53 mutations are missense mutations, leading to loss of tumor suppressive function of p53 and gain of new oncogenic functions. This review presents the clinical relevance of TP53 mutations in HGSC, elaborating on several recently identified upstream regulators of mutant p53 that control its expression and downstream target genes that mediate its roles in the disease. TP53 mutations are the earliest genetic alterations during HGSC pathogenesis, and we summarize current information related to p53 function in the pathogenesis of HGSC. The role of p53 is cell autonomous, and in the interaction between cancer cells and its microenvironment. We discuss the reduction in p53 expression levels in tumor associated fibroblasts that promotes cancer progression, and the role of mutated p53 in the interaction between the tumor and its microenvironment. Lastly, we discuss the potential of TP53 mutations to serve as diagnostic biomarkers and detail some more advanced efforts to use mutated p53 as a therapeutic target in HGSC.

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